WO2023198757A1

WO2023198757A1 - Alpha-1-antitrypsin for treating paramyxoviridae or orthomyxoviridae infections

Info

Publication number: WO2023198757A1
Application number: PCT/EP2023/059526
Authority: WO
Inventors: Thomas Grunwald; Leila ISSMAIL; Jan MÜNCH; Lukas WETTSTEIN
Original assignee: Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
Priority date: 2022-04-14
Filing date: 2023-04-12
Publication date: 2023-10-19

Abstract

The present invention relates to human alpha-1-antitrypsin or a derivative thereof for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family.

Description

Alpha-1 -antitrypsin for treating Paramyxoviridae or Orthomyxoviridae infections

The present invention relates to human alpha-1 -antitrypsin or a derivative thereof for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family. The present invention further relates to human alpha-1 -antitrypsin or a derivative thereof for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family or a virus from the Orthomyxoviridae family.

Background

Viral infections are one of the major causes of morbidity and mortality worldwide and continue to threaten global public health causing a significant impact on society and economy. Within the Paramyxoviridae and Orthomyxoviridae families of viruses, numerous pathogenic viruses exist which infect humans. There is still a large group of infectious viruses for which no efficient vaccine or therapy is available. For example, the Respiratory Syncytial Virus (RSV) that can lead to serious respiratory complications in premature infants, immunocompromised patients and elderly. Despite research efforts, there is neither a preventive vaccine nor an efficient treatment against RSV infection. Besides the known viral strains with no available antiviral therapy, new strains emerge that might have epidemic potential and can rapidly spread worldwide leading to global pandemics. This applies for e.g. for Influenza viruses. An attractive and rapid approach to develop antiviral drugs, is the repositioning of approved compounds for the usage as antiviral therapies. For the Measles virus, and efficient vaccine is available. However, in case of a Measles virus infection, no therapy is available.

Until now, no effective prophylactic and/or therapeutic approach has been developed for infections with Paramyxoviridae and Orthomyxoviridae families of viruses. Further, neither an effective prophylactic nor effective therapeutic approach has been developed for infections with RSV. Many attempts for the development of effective vaccines or antibodies against RSV failed to confer protection either at preclinical or clinical stages. The only commercially available product is the monoclonal antibody Palivizumab (Synagis®, licensed in 1998). Palivizumab is used exclusively for seasonal immunoprophylaxis of RSV infection in populations with high risk for severe illness including premature infants and those suffering from chronic pulmonary disease. Palivizumab has limitations in clinical applications due to its high costs (Five doses of Palivizumab for a 5 kg infant cost approximately $5600) and requirement of repetitive administrations (Homaira, Nusrat; Rawlinson, William; Snelling, Thomas L.; Jaffe, Adam (2014): Effectiveness of Palivizumab in Preventing RSV Hospitalization in High Risk Children: A Real-World Perspective. In International journal of pediatrics 2014, p. 571609. DOI: 10.1155/2014/571609.; IAN (1998): Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. In PEDIATRICS 102 (3), pp. 531-537. DOI:

10.1542/peds.102.3.531 ). The treatment of RSV involves mainly symptom management and supportive care. Inhaled corticosteroids might be helpful in reducing RSV associated bronchiolitis symptoms. Ribavirin, a nucleoside analogue that blocks viral replication, is prescribed as a treatment in severe cases of RSV infection, but has little or no significant effect on reduction of RSV load. Besides, ribavirin is expensive, has teratogenic effects in animals and cannot be taken in pregnancy (Ganz, David (2009): Review article. When is a library not a library? In Early Medieval Europe 17 (4), pp. 444-453. DOI: 10.1111/j.1468- 0254.2009.00285.x.).

Thus, an unmet medical need for novel clinical and cost-effective antiviral agents against viruses of the Paramyxoviridae and Orthomyxoviridae families, such as RSV, Influenza and Measles remains a significant problem.

The present invention relates to a new medical use of human alpha-1 -antitrypsin (also often termed “a1AT” or “A1AT”). Five human alpha-1 -antitrypsin products are currently approved for the treatment of patients with a1AT deficiency and include Aralast NP^TM, Zemaira®, Glassia® and Prolastin-C®, which has been marketed since 1988 and has a good safety record. Human alpha-1 -antitrypsin is a protease inhibitor belonging to the serpin superfamily. It is also been referred to as serum trypsin inhibitor and alpha-1 proteinase inhibitor (A1 P1 ), because it inhibits a wide variety of proteases. Alpha-1 antitrypsin deficiency (a1 -antitrypsin deficiency, A1 AD) is a genetic disorder that causes defective production of alpha-1 antitrypsin (A1 AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1 AT protein in liver cells resulting in respiratory complications such as emphysema, or COPD (chronic obstructive pulmonary disease) in adults and cirrhosis in adults or children. Current therapy for alpha-1 -antitrypsin deficiency associated lung disease is augmentation or replacement therapy with alpha-1 antitrypsin protein (A1AT) from the blood plasma of healthy human donors to increase levels of the protein circulating in the blood and lungs. Lung-affected A1AT patients can receive intravenous infusions of therapeutic concentrations of products derived from human plasma of blood donors.

Summary of the present Invention

In the present invention, human alpha-1 antitrypsin protein (A1AT) is identified as a potent inhibitor of Paramyxoviridae and Orthomyxoviridae viruses, as experimentally demonstrated for RSV, Influenza virus and Measles virus strains.

In one aspect, the present invention relates to human alpha-1 -antitrypsin or a derivative thereof for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family.

In a preferred embodiment of any of the uses herein, the virus of the Paramyxoviridae family is selected from a Pneumovirus, a Paramyxovirus or a Morbillivirus.

In another preferred embodiment of any of the uses herein

(i) the Pneumovirus is selected from Respiratory Syncytial Virus (RSV) and Metapneumovirus; or

(ii) the Paramyxovirus is selected from a Parainfluenza virus and mumps virus; or

(iii) the Morbillivirus is the measles virus.

In another preferred embodiment of any of the uses herein, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) or Metapneumovirus.

In another preferred embodiment of any of the uses herein, at least one symptom of the disease or disorder is/are treated, ameliorated or prevented. In another preferred embodiment of any of the uses herein, the human alpha-1 - antitrypsin or derivative thereof is administered intranasally and/or via inhalation and/or transmucosally or systemically.

In another preferred embodiment of any of the uses herein, human alpha-1 - antitrypsin or derivative is selected from human plasma-derived human alpha-1 - antitrypsin, recombinant human alpha-1 -antitrypsin, and derivatives thereof with engineered glycan content, and/or an N- and/or C-terminally modified human alpha- 1 -antitrypsin.

In another preferred embodiment of any of the uses herein, the human patient is selected from an immunosuppressed patient, an immunocompromised patient, an elderly patient, a cancer patient, a premature infant, a patient which does not respond to vaccines, a patient suffering from an autoimmune disease, a patient suffering from a chronic pulmonary disease, a patient suffering from a cardiac disease, an asthma patient, and/or a patient suffering from a neurological disease.

In another preferred embodiment of any of the uses herein, the human alpha-1 - antitrypsin or derivative thereof is administered between day 0 and day 7 of initial viremia with the pathogenic virus and/or between day 0 and day 7 of initial occurrence of symptom(s) of the disease or disorder.

In another preferred embodiment of any of the uses herein, the human alpha-1 - antitrypsin or derivative thereof is administered to a human patient infected with the pathogenic virus, and wherein the human alpha-1 -antitrypsin or derivative thereof is for treatment, and/or amelioration of the disease or disorder.

In another preferred embodiment of any of the uses herein, the administration of human alpha-1 -antitrypsin or the derivative thereof:

(i) blocks or reduces entry of the pathogenic virus into epithelial cells,

(ii) blocks or reduces entry of the pathogenic virus into cells of the respiratory tract of the patient, and/or

(iii) reduces the severity of co-infections with one or more further pathogens, optionally wherein the one or more further pathogens are virus(es) of the Paramyxoviridae or Orthomyxoviridae family.

In another preferred embodiment of any of the uses herein, the administration of human alpha-1 -antitrypsin or the derivative thereof (i) reduces the severity of a co-infection with one or more further virus(es) selected from viruses of the Paramyxoviridae and Orthomyxoviridae family; and/or

(ii) treats, ameliorates and/or prevents the co-infection with one or more further virus(es) selected from viruses of the Paramyxoviridae and Orthomyxoviridae family.

In another preferred embodiment of any of the uses herein, the virus of the Orthomyxoviridae family is an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus.

In another preferred embodiment of any of the uses herein, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and wherein the one or more further virus(es) or pathogen(s) are selected from a Metapneumovirus, a Paramyxovirus selected from a Parainfluenza virus and mumps virus; the measles virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus.

In another preferred embodiment of any of the uses herein, the patient is not infected with the virus, and wherein the human alpha-1 -antitrypsin or derivative thereof is for prophylaxis of the disease or disorder caused by the infection with the pathogenic virus.

In another preferred embodiment of any of the uses herein, wherein the administration of human alpha-1 -antitrypsin or the derivative thereof:

(i) blocks or reduces entry of the pathogenic virus into epithelial cells, and/or.

(ii) blocks or reduces entry of the pathogenic virus into cells of the respiratory tract of the patient.

In another preferred embodiment of any of the uses herein, the human alpha-1 - antitrypsin or derivative thereof is in a pharmaceutical composition comprising human alpha-1 -antitrypsin or derivative thereof and at least one pharmaceutically acceptable excipient, carrier or diluent.

In another preferred embodiment of any of the uses herein: the human alpha-1 -antitrypsin or derivative thereof is formulated for administration as an aerosol or for intravenous administration, and/or the pharmaceutical composition comprises or consists of lyophilized human alpha- 1 -antitrypsin or a derivative thereof, or human alpha-1 -antitrypsin or a derivative thereof in water or aqueous solution, and/or the pharmaceutical composition is for administration of human alpha-1 -antitrypsin or a derivative thereof in a dosage of between about 20 and 500 mg/kg/day of body weight, and/or the single unit dose comprises between about 20 mg and 20 g of human alpha-1 - antitrypsin or a derivative thereof.

In another preferred embodiment of any of the uses herein, the pharmaceutical composition is comprised:

(i) in a pulmonary drug delivery kit comprising: a) an inhaler; and b) the pharmaceutical composition; or

(ii) in a pharmaceutical package comprising: a) the pharmaceutical composition; and b) a nebulizer.

In another aspect, the present invention relates to human alpha-1 -antitrypsin or a derivative thereof for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family or a virus from the Orthomyxoviridae family.

In a preferred embodiment of the use herein, (i) the virus of the Paramyxoviridae family is selected from a Pneumovirus, a Paramyxovirus ora Morbillivirus, or (ii) the virus of the Orthomyxoviridae family is selected from an Influenza virus.

In another preferred embodiment of the use herein

(iii) the Morbillivirus is the Measles virus; or

(iv) the Influenza virus is a Type A or Type B Influenza virus.

In another preferred embodiment of the use herein, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) or Metapneumovirus.

In another preferred embodiment of the use herein, at least one symptom of the disease or disorder is/are treated, ameliorated or prevented. In another preferred embodiment of the use herein, the human alpha-1 -antitrypsin or derivative thereof is administered intranasally and/or via inhalation and/or transmucosally or systemically.

In another preferred embodiment of the use herein, human alpha-1 -antitrypsin or derivative is selected from human plasma-derived human alpha-1 -antitrypsin, recombinant human alpha-1 -antitrypsin, and derivatives thereof with engineered glycan content, and/or an N- and/or C-terminally modified human alpha-1 - antitrypsin.

In another preferred embodiment of the use herein, the human patient is selected from an immunosuppressed patient, an immunocompromised patient, an elderly patient, a cancer patient, a premature infant, a patient which does not respond to vaccines, and/or a patient suffering from an autoimmune disease.

In another preferred embodiment of the use herein, the human alpha-1 -antitrypsin or derivative thereof is administered between day 0 and day 7 of initial viremia with the pathogenic virus and/or between day 0 and day 7 of initial occurrence of symptom(s) of the disease or disorder.

In another preferred embodiment of the use herein, the human alpha-1 -antitrypsin or derivative thereof is administered to a human patient infected with the pathogenic virus, and the human alpha-1 -antitrypsin or derivative thereof is for treatment, and/or amelioration of the disease or disorder.

In another preferred embodiment of the use herein, the administration of human alpha-1 -antitrypsin or the derivative thereof:

(i) blocks or reduces entry of the pathogenic virus into epithelial cells,

(iii) reduces the severity of co-infections with one or more further pathogens.

In another preferred embodiment of the use herein, the patient is not infected with the virus, and the human alpha-1 -antitrypsin or derivative thereof is for prophylaxis of the disease or disorder caused by the infection with the pathogenic virus. In another preferred embodiment of the use herein, the human alpha-1 -antitrypsin or derivative thereof is in a pharmaceutical composition comprising human alpha-1 - antitrypsin or derivative thereof and at least one pharmaceutically acceptable excipient, carrier or diluent.

In another preferred embodiment of the use herein, the human alpha-1 -antitrypsin or derivative thereof is formulated for administration as an aerosol or for intravenous administration, and/or the pharmaceutical composition comprises or consists of lyophilized human alpha- 1 -antitrypsin or a derivative thereof, or human alpha-1 -antitrypsin or a derivative thereof in water or aqueous solution, and/or the pharmaceutical composition is for administration of human alpha-1 -antitrypsin or a derivative thereof in a dosage of between about 20 and 500 mg/kg/day of body weight, and/or the single unit dose comprises between about 20 mg and 20 g of human alpha-1 - antitrypsin or a derivative thereof.

In another preferred embodiment of the use herein, the pharmaceutical composition is comprised (i) in a pulmonary drug delivery kit comprising: a) an inhaler; and b) the pharmaceutical composition; or (ii) in a pharmaceutical package comprising: a) the pharmaceutical composition; and b) a nebulizer.

Figures Legend

Figure 1 : Antiviral activity of human alpha-1 -Antitrypsin (A1 AT ; Prolastin®) against RSV in vitro. (A) and (C): RSV-Long strain; (B): RSV-A2 strain. 15000 human epithelial (HEp-2) cells per well were seeded in 96-well plate 24 h prior to infection. The next day, cells were treated with either PBS or A1 AT, at indicated concentrations for 1 hour and then infected either with RSV-Long strain (A) and (C) or RSV-A2 strain (B) at MOI of 0.01. Infection rates were analyzed at 2 dpi using ICC-staining with RSV- specific monoclonal antibody. Shown are mean values of triplicates normalized to mock-treated controls ± SD. IC50 values were calculated using nonlinear regression in GraphPad Prism.

Figure 2: Antiviral activity of human alpha-1 -antitrypsin (Prolastin®) against Influenza virus in vitro. Three independent experiments were performed, each in triplicates. The graph shows %-lnfection of Caco-2 cells by Influenza virus strain A/PR/8/34 (H1 N1 ).

Figure 3: Antiviral activity of human alpha-1 -antitrypsin (Prolastin®) against the Measles virus in vitro. Three independent experiments were performed, each in triplicates. The graph shows %-lnfection of A549 cells by Measles virus Schwarz-ATU eGFP.

Detailed Description of the Invention

In the present invention, human alpha-1 antitrypsin protein (A1AT) is identified as a potent inhibitor of Paramyxoviridae and Orthomyxoviridae viruses, as experimentally demonstrated for RSV, Influenza virus and Measles virus strains. The compound human alpha-1 antitrypsin was surprisingly found to prevent viral entry of these viruses into human cells, in particular human epithelial cells. As shown in the Examples, human alpha-1 antitrypsin protein was found to reduce the % infection of human epithelial cells by these pathogenic viruses in a dose-dependent manner.

Accordingly, it is demonstrated herein that human alpha-1 -antitrypsin exhibits antiviral activity against RSV, Influenza virus and Measles virus in vitro as exemplary Paramyxoviridae and Orthomyxoviridae viruses. It was found that human alpha-1 - antitrypsin blocks or reduces entry of these pathogenic viruses into epithelial cells, and can thereby block or reduce entry of the pathogenic virus into cells of the respiratory system tract of a patient. It is expected that human alpha-1 -antitrypsin further reduces the severity of co-infections with one or more further pathogens in addition to an infection with a Paramyxoviridae and Orthomyxoviridae virus. For example, the one or more further pathogens may be virus(es) of the Paramyxoviridae or Orthomyxoviridae family. Also, it is expected that human alpha- 1 -antitrypsin further reduces the severity of co-infections with infection with one or more further virus(es) selected from viruses of the Paramyxoviridae and Orthomyxoviridae family in addition to an infection with a Paramyxoviridae virus.

Several products containing human alpha-1 antitrypsin protein as active agent are approved for use in the human. Also, human alpha-1 antitrypsin protein is known to have an advantageous side effect profile and is in general considered as safe and exhibit good tolerability. Human alpha-1 antitrypsin protein can therefore serve as an effective and cost- effective prophylactic and/or therapeutic antiviral agent. Human alpha-1 antitrypsin protein may be used either alone or in combinations with other viral inhibitors to treat, ameliorate and/or prevent an infection with a pathogenic of the Paramyxoviridae family or the Orthomyxoviridae family. Such infection may be a single infection with one virus of the Paramyxoviridae family or a virus from the Orthomyxoviridae family, or may be co-infections with one or more further pathogens, such as a further pathogenic virus. Further, may be used either alone or in combinations with other viral inhibitors to treat, ameliorate and/or prevent an infection with a pathogenic of the Paramyxoviridae family. Such infection may be a single infection with one virus of the Paramyxoviridae family, or may be co-infections with one or more further pathogens, such as a further pathogenic virus.

It was surprisingly found in the examples that human alpha-1 antitrypsin protein from commercially available Prolastin® effectively prevented various RSV, Influenza and Measles strains from entering human epithelial cells in vitro.

The cells used in the Examples are human epithelial cells. The HEp-2 cell line used in the Examples for RSV is a cell line from epidermoid carcinoma tissue from the larynx of a human. The Caco-2 cells used in the Examples for Influenza are epithelial cells isolated from colon tissue derived from a colorectal adenocarcinoma. The A549 cells used in the Examples for the Measles virus are adenocarcinomic human alveolar basal epithelial cells. The cells are therefore a model for epithelial cells of the respiratory tract, in particular of the upper respiratory tract, such as the nose, mouth or larynx, or of the lower respiratory tract such the lungs or bronchi.

Pathogenic Paramyxoviridae viruses and Orthomyxoviridae typically initially infect patients by entering human cells of the respiratory tract, in particular cells of the upper respiratory tract and/or lower respiratory tract. This also applies for those viruses which do not necessarily or predominantly show respiratory symptoms in later phases or viremia, such as the Measles virus. Without being bound to the theory, it is believed that, by preventing pathogenic Paramyxoviridae viruses or Orthomyxoviridae from entering human epithelial cells, human alpha-1 antitrypsin (A1AT) and derivatives thereof can effectively prevent, ameliorate and treat infections with these viruses. This is expected to apply in particular for the phase of initial viremia.

As human alpha-1 antitrypsin products are approved since decades, the use of human alpha-1 antitrypsin as antiviral agent herein provides a both cost-effective and safe treatment and prophylactic regimen. Moreover, the administration of human alpha-1 antitrypsin as antiviral agent provides an alternative prophylactic approach for pathogenic viruses for which no vaccine is available or for population groups for which the benefits of vaccination are limited such as immunocompromised patients, immunosuppressed patients, premature infants and elderly patients. In addition, it is expected that the risk of developing viral resistance is considered to be comparably low for human alpha-1 antitrypsin when used for treatment, amelioration or prophylaxis.

In the present invention, human alpha-1 -antitrypsin or a derivative thereof is used for medical use.

The terms “human alpha-1 -Antitrypsin”, “A1AT”, “AAT” “a1AT”, “alpha-1 antitrypsin”, “alphal -proteinase inhibitor (human)”, “human alphal -proteinase inhibitor”, “a1- antitrypsin”, “A1AT”, “a1AT, “A1A”, or “AAT” are used as synonyms herein. The International Non-Proprietary (INN) name of human alpha-1 -antitrypsin for medical applications is “alphal -proteinase inhibitor (human)” or “human alphal -proteinase inhibitor”. Human alpha-1 -antitrypsin is a about 52 kDa glycoprotein belonging to the serine protease inhibitor (serpin) superfamily. Examples of proteases inhibited by human alpha-1 -antitrypsin include neutrophil elastase (NE). The sequence of human alpha-1 -antitrypsin is well-known in the art. Approved medical products containing human alpha-1 -antitrypsin as active agent contain human alpha-1 - antitrypsin isolated and prepared from human plasma. Such human alpha-1 - antitrypsin is referred to as “human plasma-derived human alpha-1 -antitrypsin”. Alpha-1 proteinase inhibitor (human) or human alpha-1 -antitrypsin, as approved for administration to humans, is prepared from human plasma via Cohn alcohol fractionation followed by PEG and zinc chloride fractionation. For example, Prolastin® as approved medical product is prepared from pooled human plasma of normal donors by modification and refinements of the cold ethanol method of Coan et al. (Coan MH, Brockway WJ, Eguizabal H, et al: Preparation and properties of alphal -proteinase inhibitor concentrate from human plasma. Vox Sang 48(6):333- 42, 1985). Moreover, recombinantly produced human alpha-1 -Antitrypsin (rA1AT) is encompassed by the term “human alpha-1 -Antitrypsin”. For example, an rA1AT with modified glycoprotein is disclosed in WO2019/177982. A recombinantly produced human alpha-1 -Antitrypsin encompasses a human alpha-1 -Antitrypsin which differs human alpha-1 -antitrypsin isolated and prepared from human plasma in amount and/or composition and/or heterogeneity of glycosylation. A derivative of human alpha-1 -Antitrypsin encompasses human alpha-1 -Antitrypsin with engineered glycan content, and/or an N- and/or C-terminally modified human alpha-1 - antitrypsin. For example, a derivative of human alpha-1 -Antitrypsin encompasses a human alpha-1 -Antitrypsin further comprising one or more moieties linked to the N- terminus, C-terminus or an internal amino acid side chain. For example, an N- terminal peptide tag and/or a C-terminal peptide tag may be linked to the human alpha-1 -Antitrypsin protein. For example, such tag may have a length of 1 to 5, 1 to 10 or 1 to 100 amino acids. Alternatively, the N-terminal and/or C-terminal 1 to 5, such as 1 to 4, 1 to 3, 1 to 2 amino acids may be deleted from human alpha-1 - antitrypsin. The sequence of human alpha-1 -Antitrypsin in approved medical products is described e.g. in DrugBank Accession No: DB00058. The sequence is as follows:

EDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEFAFSLYRQLAHQSNSTNIFFSPVSIATA FAMLSLGTKADTHDEILEGLNFNLTEIPEAQIHEGFQELLRTLNQPDSQLQLTTGNGLFL SEGLKLVDKFLEDVKKLYHSEAFTVNFGDTEEAKKQINDYVEKGTQGKIVDLVKELDRDT VFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVL LMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLK SVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEAIPMSI PPEVKFNKPFVFLMIEQNTKSPLFMGKWNPTQK (SEQ ID NO: 1) Boerema D. J. et al. (Biologicals, 2017, 50: 63-72) compared the four plasma-derived human alpha-1 -Antitrypsin products commercially available in Europe respect to function, purity, structure, and chemical modifications and found that the human alpha-1 -Antitrypsin products differed in cysteine oxidation state and C-terminal lysine status as well as in purity and concentration. Any of the approved A1AT may be used according to the invention. The term “human alpha-1 -antitrypsin” therefore encompasses human alpha-1 -antitrypsin protein in which the C-terminal Lysine (Lys394) is deleted, or is present, or is deleted in part of a human alpha-1 -antitrypsin protein population comprising 2 or more human alpha-1 -antitrypsin proteins.

Human alpha-1 -antitrypsin derived from human plasma or human plasma-derived alpha-1 -antitrypsin is a preferred human alpha-1 -antitrypsin or derivative thereof for use of the invention.

In a preferred human alpha-1 -antitrypsin for use in the invention, the C-terminal Lysine (Lys394) is deleted, or is present, or is deleted in part of a human alpha-1 - antitrypsin protein population comprising 2 or more human alpha-1 -antitrypsin proteins.

The present invention is directed to the human alpha-1 -antitrypsin or a derivative thereof for administration to a human patient.

It is possible to administer human alpha-1 -antitrypsin or a derivative thereof to any mammal, including humans, monkeys, horses, cows, sheep, dogs, cats, cattle, rats and mice. As human alpha-1 -antitrypsin is derived from human, it is, however, preferred that the human alpha-1 -antitrypsin or a derivative thereof is administered to a human.

According to the invention, the human alpha-1 -antitrypsin or a derivative thereof is administered to a human patient. A human patient is understood as human in need of thereof. Such human in need of thereof may be a patient infected with a pathogenic virus of the Paramyxoviridae family or a virus from the Orthomyxoviridae family. In such case, the human alpha-1 -antitrypsin or derivative thereof can be used for treating and/or ameliorating an infection with the virus. Alternatively, the human in need of thereof may be a human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family. In such case, the human alpha-1 -antitrypsin or derivative thereof can be used for preventing an infection with the virus and/or for corresponding prophylaxis. A human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a human alpha-1 -antitrypsin virus from the Orthomyxoviridae family may be a healthy person or a person suffering from further diseases or disorders. For example, a human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family may be a person that was, is or will be in contact with a another human infected or suspected to be infected with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family or a sample containing or suspected to contain a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family. Further, a human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family may be a hospitalized human, and/or a human selected from an immunosuppressed patient, an immunocompromised patient, an elderly patient, a cancer patient, a premature infant, a patient which does not respond to vaccines, a patient suffering from an autoimmune disease, a patient suffering from a chronic pulmonary disease, a patient suffering from a cardiac disease, an asthma patient, and/or a patient suffering from a neurological disease.

The term “immunocompromised” refers to a subject having a weakened or impaired immune system and/or associated immune response to a pathogen, pathogenic antigen, disease, etc. A subject may be immunocompromised as a consequence of taking one or more immunosuppressive agents, or by being afflicted with a disease or pathology that affects the subject’s immune system, such as certain congenital diseases.

Immunocompromised patients include for example AIDS patients; patients on chronic immunosuppressive treatment regimens, such as organ transplant patients; cancer patients, such as Hodgkin's disease or lymphoma; and patient suffering from an autoimmune disease, such as those being treated with mycophenolate mofetil or a biologic such as natalizumab, rituximab, or efalizumab. Such autoimmune conditions include, but are not limited to multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosis (SLE). Elderly patients, such as those beyond 60 years, 70 years, or 80 years with weakened immune systems are also understood as immunocompromised patients. The term “immunosuppressed” refers to a subject whose immune system and associated immune response to pathogens, pathogenic antigens, disease, etc. is partially or completely suppressed, for example, by a reduction in the activity or efficiency in the immune system.

Immunosuppression of a subject’s immune system or immune response may occur naturally due to a disease or disorder in the subject, or may be induced in the subject by the administration of immunosuppressive agents, drugs, e.g., anti-cancer drugs, compounds, and the like. In some cases, a subject who is immunosuppressed or is undergoing immunosuppression, or who has a weakened immune system due to a disease or condition (e.g., chemotherapy or an immune deficiency disease) is said to be immunocompromised.

As used herein, the term “cancer” has its general meaning in the art and includes, in particular, solid tumors and blood borne tumors. The term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels. The term “cancer” further encompasses both primary and metastatic cancers. Examples of cancers that may treated by the uses of the invention include, but are not limited to, cancer of cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.

As used herein the term “immunosuppressive agent” refers to any agent that inhibits or prevents an activity of the immune system of a subject. Examples of immunosuppressive agents include antibodies that specifically bind to CD20, CD25, such as basiliximab or daclizumab, or CD3, such as muromonab; calcineurin inhibitors, such as pimecrolimus, tacrolimus, sirolimus, and/or cyclosporine; interferons, such as interferon-beta; a glucocorticoid, such as such prednisone, dexamethasone, and hydrocortisone; an IL1-R antagonist; myophenolate mofetil; azathioprine; methotrexate, Actinomycin D; and/or TNF-alpha binding proteins, such as antibodies and/or soluble TNF-alpha receptors, e.g., infliximab, etanercept, and/or adalimumab.

A “pathogenic virus” is understood as virus that is able to cause a disease or disorder upon infection in an animal. In case of a human patient to be treated, the pathogenic virus is able to cause a disease or disorder upon infection in the human. The pathogenic virus is therefore preferably a virus pathogenic for humans. According to one aspect of the invention, the pathogenic virus is selected from a virus of the Paramyxoviridae family. According to another aspect of the invention, the pathogenic virus is selected from a virus of the Paramyxoviridae family or a virus from the Orthomyxoviridae family.

Paramyxoviridae and Orthomyxoviridae viruses that have negative-sense singlestranded RNA genomes. Paramyxoviridae and Orthomyxoviridae are helicalshaped viruses which are enveloped. An Orthomyxoviridae virus has an RNA genome segmented into eight pieces. Therefore, the genome of Orthomyxoviridae is segmented. Moreover, it is an enveloped virus having a lipoprotein outer envelope. Paramyxoviridae have a non-segmented genome.

The multiplication of all Paramyxoviridae is similar to that of Orthomyxoviridae. Paramyxoviridae and Orthomyxoviridae transmit via aerosols. Viruses of Paramyxoviridae and Orthomyxoviridae are therefore known to initially infect humans by entering cells of the respiratory tract, such as cells of the upper respiratory tract and/or lower respiratory tract.

The family Paramyxoviridae consists of three genera: the genera Paramyxovirus, Pneumovirus, and Morbillivirus. The genus Paramyxovirus includes the Parainfluenza viruses and Mumps virus. The genus Pneumovirus includes Respiratory Syncytial Virus (RSV) and Metapneumovirus. The genus Morbillivirus includes the Measles virus.

The Paramyxoviridae can be distinguished by the gene order for the viral proteins and by the biochemical properties for their viral attachment proteins. In Parainfluenza viruses, the viral protein spikes have hemagglutinating and neuraminidase activities (HN). Respiratory Syncytial Virus (RSV) lacks both these activities and Measles virus lacks neuraminidase but has hemagglutinating activity.

Accordingly, preferably, the virus of the Paramyxoviridae family is selected from a Pneumovirus, a Paramyxovirus or a Morbillivirus.

In another preferred embodiment, the virus of the Orthomyxoviridae family is selected from an Influenza virus.

The Orthomyxoviridae family is also known as family of “Influenza viruses” and constitutes the genus Orthomyxovirus, which consists of three types or species: Influenza Type A, Influenza Type B, and Influenza Type C. The Influenza viruses cause the disease influenza, an acute respiratory disease with prominent systemic symptoms. Classic influenza is a febrile illness of the upper and lower respiratory tract, characterized by sudden onset of fever, cough, myalgia, malaise, and other symptoms. Many patients do not exhibit the full syndrome. Pneumonia may develop as a complication and may be fatal, particularly in elderly persons with underlying chronic disease.

Type A Influenza viruses cause periodic worldwide epidemics and both Influenza Types A and B cause recurring regional and local epidemics. In Types A and B, the hemagglutinin and neuraminidase antigens undergo genetic variation, which is the basis for the emergence of new strains. Influenza Type C is antigenically stable.

Influenza viruses are spherical or filamentous enveloped particles 80 to 120 nm in diameter. The helically symmetric nucleocapsid consists of a nucleoprotein and a multipartite genome of single-stranded antisense RNA in seven or eight segments. The envelope carries a hemagglutinin attachment protein and a neuraminidase.

Therefore, preferably, the virus of the Orthomyxoviridae family is selected from an Influenza virus. In a preferred embodiment, the disease or disorder caused by an infection with a virus of the Orthomyxoviridae family is influenza.

As described above, the hemagglutinin and neuraminidase antigens undergo genetic variation in Type A or Type B Influenza virus, which is the basis for the emergence of new strains. Accordingly, the use of A1AT for treatment, amelioration and/or prophylaxis of an infection with Type A or Type B Influenza virus is preferred.

In one preferred embodiment, the Influenza virus is a Type A or Type B Influenza virus.

Laboratory diagnosis of Influenza virus infections can be made by methods well- known in the art, such as by detecting viral antigen, by isolating the virus, or by detecting a rise in antibody titer or elevated IgG- and IgA- (IgM-) antibodies in a single serum.

In one preferred embodiment, the Pneumovirus is selected from Respiratory Syncytial Virus (RSV) and Metapneumovirus. In one further preferred embodiment, the Pneumovirus is selected from Respiratory Syncytial Virus (RSV).

An infection with Respiratory Syncytial Virus (RSV) causes upper and lower respiratory tract disease. The lower respiratory tract disease latter is most frequent in young children and is also significant in the elderly. Accordingly, the disease or disorder caused by a Respiratory Syncytial Virus (RSV) includes upper and lower respiratory tract disease. The symptoms caused by a Respiratory Syncytial Virus (RSV) infection include cold-like signs including congested or runny nose, dry cough, fever, sore throat, sneezing, headache, pneumonia, bronchiolitis (i.e. inflammation of the small airway passages entering the lungs), rapid breathing or difficulty breathing, cyanosis and lethargy.

Respiratory Syncytial Viruses are divided into types A and B. Accordingly, in a more preferred embodiment, the Respiratory syncytial virus is selected from Type A and Type B RSV.

The Respiratory syncytial virus has a linear single-stranded RNA of about 5 x 10⁶ Da, which encodes at least 10 proteins, including 7-8 structural and 2 non-structural proteins. The RNA is surrounded by a helical nucleocapsid, which in turn is surrounded by an envelope of pleomorphic structure. RSV Virions range from 120 to 300 nm in diameter. The Respiratory syncytial virus has neither hemagglutinin nor neuraminidase activity.

After absorption of RSV to cells to be infected, penetration, and uncoating, the Respiratory Syncytial Virus genome serves as a template for the production of 10 different mRNA species and a full-length, positive-sense complementary RNA (cRNA). The mRNAs serve as the template for translation of viral proteins. The full- length, cRNA serves as a template for transcription of virion RNA. Within 10 to 24 h after infection, projections of viral proteins appear on the cell surface, and virions bud through the cell membrane incorporating part of the cell membrane into their envelope.

Respiratory syncytial virus in general initiates a localized infection in the upper respiratory tract, or in the lower respiratory tract, or in the upper and lower respiratory tract. Initially, the virus infects the ciliated mucosal epithelial cells of the nose, eyes, and mouth. Infection generally is confined to the epithelium of the upper respiratory tract, but may involve the lower respiratory tract. The virus spreads both extracellularly and by fusion of cells to form syncytia. The virus is shed in respiratory secretions usually for about 5 days and sometimes for as long as 3 weeks. Shedding begins with the onset of symptoms and declines with the appearance of local antibody.

The most important clinical syndromes caused by Respiratory Syncytial Virus are bronchiolitis and pneumonia, in particular in infants, croup and tracheobronchitis, in particular in young children, and tracheobronchitis and pneumonia, in particular in elderly subjects. Further symptoms of RSV which may occur, include conjunctivitis, otitis media, and exanthems involving the trunk or face, or both.

“Bronchiolitis” is understood as blockage of the small airways in the lungs. Acute bronchiolitis is due to a viral infection, and is typically affecting children younger than two years of age. Symptoms of bronchiolitis may include fever, cough, runny nose, wheezing, and breathing problems, and severe cases may be associated with nasal flaring, grunting, or the skin between the ribs pulling in with breathing, and if the child has not been able to feed properly, signs of dehydration may be present. Acute bronchiolitis is typically the result of infection by Respiratory Syncytial Virus (about 72% of cases) or human rhinovirus (about 26% of cases).

“Pneumonia” is understood as an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include combination of two or more of productive or dry cough, chest pain, fever, and difficulty breathing. The severity of pneumonia may be variable. Pneumonia is typically caused by infection with viruses or bacteria, and less commonly by other microorganisms.

In pneumonia caused by RSV or Metapneumovirus, the pneumonia is preferably interstitial.

The pathogenesis of bronchiolitis caused by RSV or Metapneumovirus may be immunologic or directly due to viral cytopathology. Respiratory Syncytial Virus bronchiolitis during the first year of life may be a risk factor for the later development of asthma and sensitization to common allergens. Laboratory diagnosis of an RSV infection can be made by methods well-known in the art, such as by detecting viral antigen, by isolating the virus or by detecting RNA with polymerase chain reaction (PCR), or by detecting a rise in antibody titer or elevated IgM antibodies in a single serum.

Metapneumovirus (human metapneumovirus; HMPV) is a negative-sense singlestranded RNA virus of the family Pneumoviridae and was isolated for the first time in 2001 in the Netherlands by using the RAP-PCR (RNA arbitrarily primed PCR) technique for identification of unknown viruses growing in cultured cells. It is the second most common cause after Respiratory syncytial virus (RSV) of lower respiratory tract infection in young children.

The genomic organisation of HMPV is similar to RSV, however, HMPV lacks the non-structural genes, NS1 and NS2, and the HMPV antisense RNA genome contains eight open reading frames in slightly different gene order than RSV.

HPMV includes subtype A and B and subgroups A1 and A2 and B1 and B2.

HMPV infects airway epithelial cells in the nose and lung.

The peak age of hospitalization for infants with HMPV occurs between 6-12 months of age, slightly older than the peak of RSV, which is around 2-3 months. The clinical symptoms and the severity of disease of HMPV are similar to those of an RSV infection. HMPV is also an important cause of disease in older adults.

Methods for diagnosing an HMPV infection are well known in the art and include reverse-transcriptase polymerase chain reaction (RT-PCR) technology to amplify directly from RNA extracted from respiratory specimens, the detection of hMPV antigens in nasopharyngeal secretions by immunofluorescent-antibody test, the immunofluorescence staining with monoclonal antibodies to detect HMPV in nasopharyngeal secretions, shell vial cultures immunofluorescence assays for detection of hMPV-specific antibodies and the use of polyclonal antibodies and direct isolation in cultured cells.

In another preferred embodiment, the Paramyxovirus is selected from a Parainfluenza virus and Mumps virus. Human Parainfluenza viruses are divided into types 1 , 2, 3, and 4; type 4 consists of A and B subtypes. Accordingly, in a more preferred embodiment, the Parainfluenza virus is selected from Parainfluenza virus Type 1 , Parainfluenza virus Type 2, Parainfluenza virus Type 3, Parainfluenza virus Type 4A and Parainfluenza virus Type 4B.

The transmission of Parainfluenza viruses is by droplets or direct contact. The virus disseminates locally in the ciliated epithelial cells of the respiratory mucosa. Parainfluenza virus infections occur worldwide. The Parainfluenza virus infections are usually endemic but sometimes epidemic. Primary infections may occur in particular young children. Moreover, reinfection may occur and is described common but results in milder disease.

Parainfluenza viruses cause mild or severe upper and lower respiratory tract infections, particularly in children. Symptoms caused by Parainfluenza viruses include croup, bronchiolitis, bronchitis, pneumonia, otitis media, pharyngitis, conjunctivitis, and tracheobronchitis. Further less common respiratory symptoms include apnea, bradycardia, parotitis, and respiratory distress syndrome.

Laboratory diagnosis of Parainfluenza virus infections can be made by methods well-known in the art, such as by detecting viral antigen, by isolating the virus, or by detecting a rise in antibody titer or elevated IgG- and IgA- (IgM-) antibodies in a single serum.

The Mumps virus is a virus well-known in the art. The single serotype of Mumps virus shares antigens with Parainfluenza viruses, particularly type 1 .

The disease or disorder caused by the Mumps virus is known as mumps. Mumps is a systemic febrile infection of children and young adults. Mumps is characterized by the symptoms of swelling of the salivary glands, especially the parotid glands. Further symptoms of mumps that may occur including meningitis, which is common, and pancreatitis, encephalitis, and hearing loss may occur. Yet further symptoms include, in particular in young adults, orchitis and oophoritis.

The single serotype of Mumps virus shares antigens with parainfluenza viruses, particularly type 1 . The Mumps virus is spread in droplets. The primary infection with Mumps virus consists of viremia and involvement of glandular and nervous tissue, resulting in inflammation and cell death.

In typical cases of mumps, the clinical picture is diagnostic and Mumps may be diagnosed accordingly. Atypical cases of a Mumps virus infection may be diagnosed with methods known in the art, such as by isolating the virus in cell culture, or by detecting viral antigen or RNA, and by detecting specific IgM in the first serum sample soon after onset of symptoms or by a rise of IgG antibodies.

In another preferred embodiment, the Morbillivirus is the Measles virus.

As to date, a single antigenic type is known for the Measles virus.

The disorder or disease caused by the Measles virus is known as measles. Measles sets in abruptly with coryza, conjunctivitis, fever, and rash. The typical maculopapular rash appears 1 to 3 days later. The symptoms of the initial viremia phase of measles therefore include coryza, conjunctivitis, fever, rash maculopapular rash. Complications of measles include otitis, pneumonia, and encephalitis. Subacute sclerosing panencephalitis is a rare late sequela. Therefore, further symptoms of measles include otitis, pneumonia, encephalitis and subacute sclerosing panencephalitis. The virus causes viremia with wide dissemination and multiplies in cells of the lymphatic, respiratory, intestinal and urinary system, the skin, and sometimes the brain. These are further symptoms of measles.

Methods for diagnosing measles are known in the art and include determining the clinical picture. Atypical cases or cases following previous vaccination may be diagnosed by isolating the virus in cell culture by direct smear of cell-containing specimen, by detection of RNA with the polymerase chain reaction (by RT-PCR) or detecting specific IgM in the first serum at the time of rash with a rising titer of IgG antibodies in the second serum.

In a more preferred embodiment herein, the disease or disorder is caused by an infection with a pathogenic virus in a human patient, which is an infection with Respiratory Syncytial Virus (RSV) or Metapneumovirus. In a further more preferred embodiment herein, the disease or disorder is caused by an infection with a pathogenic virus in a human patient, which is an infection with Respiratory Syncytial Virus (RSV).

As shown in Figure 1 and Example 1 , it was surprisingly found in the examples that human alpha-1 -antitrypsin of commercially available Prolastin® effectively prevented various RSV strains, including commercially available strains RSV A2 and RSV-long, from entering human epithelial cells HEp-2 in vitro. Thereby, it could be shown that human alpha-1 -antitrypsin effectively prevents RSV viruses from entering those cells of a human patient which are initially infected: epithelial cells of the respiratory tract, in particular epithelial cells of the nose, eyes, and mouth and/or epithelial cells of the nose, eyes, and mouth of the upper respiratory tract or upper airways.

Therefore, it is expected that administering human alpha-1 -antitrypsin or derivative thereof in a therapeutically or prophylactically effective amount to the human patient allows treatment and/or amelioration of the disease or disorder caused by an infection with RSV, and allows prophylaxis of an infection with RSV.

Moreover, symptoms are observed very quickly observed initial viremia in RSV infections. In the initial viremia phase, RSV is spread and amplified in the patient’s body, including infection of further cells in the human body. Administering human alpha-1 -antitrypsin or derivative thereof in a therapeutically effective amount to the human patient upon occurrence of one or more disease symptoms thereby is expected to allow treatment and/or amelioration of the disease or disorder caused by an infection with RSV.

As RSV and MPV or hMPV are similar in genomic structure and symptoms, it is expected that human alpha-1 -antitrypsin or a derivative thereof is also particularly suitable for the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with Metapneumovirus.

In another more preferred embodiment herein, the disease or disorder is caused by an infection with a pathogenic virus in a human patient, which is an infection with an Influenza virus.

As shown in Figure 2, Table 1 and Example 2, it was surprisingly found in the examples that human alpha-1 -antitrypsin of commercially available Prolastin® effectively prevented an Influenza strain (H1 N1 ) from entering human epithelial Caco-2 in vitro. Thereby, it could be shown that human alpha-1 -antitrypsin effectively prevents epithelial cells from being infected.

Therefore, it is expected that administering human alpha-1 -antitrypsin or derivative thereof in a therapeutically or prophylactically effective amount to the human patient allows treatment and/or amelioration of the disease or disorder caused by an infection with Influenza viruses, and allows prophylaxis of an infection with Influenza viruses.

Moreover, symptoms are observed very quickly observed initial viremia in Influenza virus infections. In the initial viremia phase, Influenza is spread and amplified in the patient’s body, including infection of further cells in the human body. Administering human alpha-1 -antitrypsin or derivative thereof in a therapeutically effective amount to the human patient upon occurrence of one or more disease symptoms thereby is expected to allow treatment and/or amelioration of the disease or disorder caused by an infection with an Influenza virus.

In another more preferred embodiment herein, the disease or disorder is caused by an infection with a pathogenic virus in a human patient, which is an infection with the Measles virus.

As shown in Figure 3, Table 2 and Example 3, it was surprisingly found in the examples that human alpha-1 -antitrypsin of commercially available Prolastin® effectively prevented the Measles from entering human epithelial A549 cells in vitro. Thereby, it could be shown that human alpha-1 -antitrypsin effectively prevents epithelial cells from being infected.

Therefore, it is expected that administering human alpha-1 -antitrypsin or derivative thereof in a therapeutically or prophylactically effective amount to the human patient allows treatment and/or amelioration of the disease or disorder caused by an infection with the Measles virus, and allows prophylaxis of an infection with the Measles virus.

In another preferred embodiment, at least one symptom of the disease or disorder herein is/are treated, ameliorated or prevented. For example, 1 symptom, or 2, 3, 4, 5, 6, 7, 8, 9, 10 or more symptoms of the disease or disorder herein is/are treated, ameliorated or prevented. For example, all symptoms of the disease or disorder herein is/are treated, ameliorated or prevented, or less than all symptoms of the disease or disorder herein is/are treated, ameliorated or prevented.

The at least one symptom of the disease or disorder herein that can be treated, ameliorated or prevented depends on the pathogenic virus.

For example, in case of the Pneumovirus, which is preferably selected from Respiratory Syncytial Virus (RSV) and Metapneumovirus, the at least one symptom of the disease or disorder herein that is/are treated, ameliorated or prevented preferably includes one or more of bronchiolitis, pneumonia, croup, and tracheobronchitis, and combinations thereof such as croup and tracheobronchitis, in particular in children, and tracheobronchitis and pneumonia, in particular in elderly subjects.

For example, in case of the Orthomyxoviridae family, preferably selected from Influenza type A and Influenza type B, the at least one symptom of the disease or disorder herein that is/are treated, ameliorated or prevented preferably includes one or more of acute respiratory disease symptom(s), febrile illness of the upper and lower respiratory tract, fever, cough, myalgia, malaise, and pneumonia.

For example, in case of the Parainfluenza viruses, the at least one symptom of the disease or disorder herein that is/are treated, ameliorated or prevented preferably includes one or more of croup, bronchiolitis, bronchitis, pneumonia, otitis media, pharyngitis, conjunctivitis, and tracheobronchitis.

For example, in case of the Mumps virus, the at least one symptom of the disease or disorder herein that is/are treated, ameliorated or prevented preferably includes one or more of symptoms of fever, swelling of the salivary glands, especially the parotid glands, meningitis, pancreatitis, encephalitis, hearing loss, orchitis and oophoritis.

For example, in case of the Morbillivirus, preferably the Measles virus, the at least one symptom of the disease or disorder herein that is/are treated, ameliorated or prevented preferably includes one or more of symptoms of coryza, conjunctivitis, fever, rash, maculopapular rash, otitis, pneumonia, encephalitis and subacute sclerosing panencephalitis. The human alpha-1 -antitrypsin or derivative thereof herein may be administered in any manner including, but not limited to, orally, parenterally, sublingually, transdermally, transmucosally, topically, via inhalation, via buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intra-peritoneal, subcutaneous and intramuscular.

It is preferred that the human alpha-1 -antitrypsin or derivative thereof is administered intranasally and/or via inhalation and/or transmucosally or systemically.

Intranasal administration, administration via inhalation and/or transmucosal administration may be advantageous to locally deliver the active agent to the initial site(s) of viral entry into the subject, in particular the respiratory tract, including the lower respiratory tract and/or the upper respiratory tract, such as the larynx, nose, nasal mucosa, mouth, mouth mucosa, the trachea, the bronchi and the lungs, the and/or the epithelial cells of the respiratory tract, including the lower respiratory tract and/or the upper respiratory tract.

The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory mucosa or respiratory epithelium (see e.g. https://en.wikipedia.org/wiki/Respiratory_tract; entry of March 2022). The respiratory tract includes the “upper airways” also termed “upper respiratory tract”, including the oropharynx and larynx, followed by the “lower airways” also termed “lower respiratory tract”, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conductive airways. The terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, the alveoli, or deep lung. The lungs are part of the lower respiratory tract, which is also termed lower airways or lower respiratory airways.

Alternatively, the human alpha-1 -antitrypsin or derivative thereof may be delivered systemically, such as intravenously, e.g. by infusion.

For example, approved formulations for intravenous administration comprising human alpha-1 -antitrypsin be used. Such formulations are safe and exhibit an advantageous side effect profile. Accordingly, in a more preferred embodiment herein, the human alpha-1 -antitrypsin or derivative is selected from human plasma-derived human alpha-1 -antitrypsin, recombinant human alpha-1 -antitrypsin, and derivatives thereof with engineered glycan content, and/or an N- and/or C-terminally modified human alpha-1 - antitrypsin.

In the examples, it is demonstrated that human plasma-derived human alpha-1 - antitrypsin from an approved medicinal product is effective as anti-viral agent. Accordingly, the use of human plasma-derived human alpha-1 -antitrypsin is particularly preferred. Any of the approved human alpha-1 -antitrypsin products and proteins therein may preferably be used according to the invention.

Alternatively, recombinantly produced human alpha-1 -Antitrypsin may be used as well as derivatives thereof with engineered glycan content. Suitable recombinant alpha-1 -antitrypsin proteins with modified, engineered glycoprotein are disclosed in WO201 9/177982. Further, the human alpha-1 -antitrypsin may be the N- and/or C- terminally modified human alpha-1 -antitrypsin. For example, a derivative of human alpha-1 -Antitrypsin encompasses a human alpha-1 -Antitrypsin further comprising one or more moieties linked to the N-terminus, C-terminus or an internal amino acid side chain. For example, an N-terminal peptide tag and/or a C-terminal peptide tag may be linked to the human alpha-1 -Antitrypsin protein. For example, such tag may have a length of 1 to 5, 1 to 10 or 1 to 100 amino acids. Alternatively, the N-terminal and/or C-terminal 1 to 5, such as 1 to 4, 1 to 3, 1 to 2 amino acids may be deleted from human alpha-1 -antitrypsin. The term “human alpha-1 -antitrypsin” therefore encompasses human alpha-1 -antitrypsin protein in which the C-terminal Lysine (Lys394) is deleted, or is present, or is deleted in part of a human alpha-1 -antitrypsin protein population comprising 2 or more human alpha-1 -antitrypsin proteins.

In any preferred human alpha-1 -antitrypsin for use in the invention, the C-terminal Lysine (Lys394) may be deleted, or may be present, or may be deleted in part of a human alpha-1 -antitrypsin protein population comprising 2 or more human alpha-1 - antitrypsin proteins, such as in an approved product.

The administration of human alpha-1 antitrypsin as antiviral agent provides an alternative prophylactic approach for pathogenic viruses for which no vaccine is available or for population groups for which the benefits of vaccination are limited. Such patients include immunosuppressed patients, immunocompromised patients, elderly patients, cancer patients, premature infants, patients which do not respond to vaccines, patients suffering from an autoimmune disease, patients suffering from a chronic pulmonary disease, patients suffering from a cardiac disease, asthma patients, and/or patients suffering from a neurological disease. For example, cancer patients and patients suffering from an autoimmune disease may be treated with chemotherapeutic and/or immunosuppressive agents resulting in immunosuppression and/or an immunocompromised status. Further, premature infants or elderly patients may be immunocompromised or vaccination may not be possible.

In a yet further preferred embodiment, the human patient is selected from an immunosuppressed patient, an immunocompromised patient, an elderly patient, a cancer patient, a premature infant, a patient which does not respond to vaccines, and/or a patient suffering from an autoimmune disease.

Preferred immunocompromised patients include AIDS patients; patients on chronic immunosuppressive treatment regimens, such as organ transplant patients; cancer patients, such as Hodgkin's disease or lymphoma; and patients suffering from an autoimmune disease, such as those being treated with mycophenolate mofetil or a biologic such as natalizumab, rituximab, or efalizumab.

Suitable patients suffering from an autoimmune disease include, for example, patients suffering from multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosis (SLE).

Suitable elderly patients are for example those beyond 60 years, 70 years, or 80 years, preferably wherein the elderly patient has a weakened immune system and/or is suffering from an autoimmune disease or cancer.

The immunosuppressed patient is a subject whose immune system and associated immune response to pathogens, pathogenic antigens, disease, etc. is partially or completely suppressed, for example, by a reduction in the activity or efficiency in the immune system. In a preferred embodiment, immunosuppression in the patient occurs naturally due to a disease or disorder in the subject, or is be induced in the subject by the administration of immunosuppressive agents, anti-cancer drugs, corticosteroids and the like. In some cases, a subject who is immunosuppressed or is undergoing immunosuppression, or who has a weakened immune system due to a disease or condition (e.g., chemotherapy or an immune deficiency disease) is said to be immunocompromised.

A cancer patient may suffer from any cancer, including solid tumors and blood borne tumors, and including cancer of the skin, tissues, organs, bone, cartilage, blood and vessels. The cancer patient may suffer from a primary or metastatic cancer. Examples of cancers include cancer of cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.

A premature infant is an infant born before 37 completed weeks of gestation, such as before 35, 32, 30, 28, 27, or 26 completed weeks of gestation. The premature infant to be treated may have an age of 0 to 5 years, 0 to 3 years, 0 to 2 years, 0 to 1 year, or 0 to 1 , 2, 3, 4, 5, or 6 months.

Pathogenic Paramyxoviridae viruses and Orthomyxoviridae typically initially infect patients by entering human cells of the respiratory tract, in particular cells of the upper respiratory tract and/or lower respiratory tract. It is expected that, by preventing pathogenic Paramyxoviridae viruses or Orthomyxoviridae from entering human epithelial cells, human alpha-1 antitrypsin (A1AT) and derivatives thereof can effectively prevent, ameliorate and treat infections with these viruses in the phase of initial viremia. In this phase, initial occurrence of symptom(s) of the disease or disorder caused by the respective virus are typically observed.

Accordingly, in another preferred embodiment, the human alpha-1 -antitrypsin or derivative thereof is administered between day 0 and day 7 of initial viremia with the pathogenic virus and/or between day 0 and day 7 of initial occurrence of symptom(s) of the disease or disorder.

Viremia is understood as the medical condition where the virus enters the blood of the patient and thereby has access to the rest of the body. The presence of the virus in the blood can be determined using assays for detecting the virus which are known in the art.

“Initial viremia” and “primary viremia” are synonyms and refer to the initial spread of virus in the blood from the first site of infection. For example, the human alpha-1 -antitrypsin or derivative thereof is administered between day 0 (dO) and day 6 (d6), dO and d5, dO and d4, dO and d3, dO and d2, dO and d1 , d1 and d7, d1 and d6, d1 and d5, d1 and d4, d1 and d3 or d1 and d2, of initial viremia with the pathogenic virus, such as at dO, d1 , d2, d3, d4, d5, d6 and/or d7.

In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family or of the Orthomyxoviridae family. In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family.

For example, the human alpha-1 -antitrypsin or derivative thereof is administered between day 0 (dO) and day 6 (d6), dO and d5, dO and d4, dO and d3, dO and d2, dO and d1 , d1 and d7, d1 and d6, d1 and d5, d1 and d4, d1 and d3 or d1 and d2, of initial occurrence of symptom(s) of the disease or disorder, such as at dO, d1 , d2, d3, d4, d5, d6 and/or d7.

For example, the initial occurrence of symptom(s) of the disease or disorder may be diagnosed by a physician. The presence of the virus may be detected using suitable laboratory tests known in the art and as described herein.

As described above human alpha-1 -antitrypsin or derivative thereof is suitable both for treatment and prophylactic purposes. For treating or ameliorating the disease or disorder, the human alpha-1 -antitrypsin or derivative thereof is administered to a human patient who is already infected with the pathogenic virus. Typically, the patient is diagnosed to be infected with the pathogenic virus, or is suspected to be infected with the pathogenic virus.

Accordingly, in a yet further preferred embodiment, the human alpha-1 -antitrypsin or derivative thereof is administered to a human patient infected with the pathogenic virus, and the human alpha-1 -antitrypsin or derivative thereof is for treatment, and/or amelioration of the disease or disorder. In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family or of the Orthomyxoviridae family. In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family. In another preferred embodiment, the human alpha-1 -antitrypsin is administered to a patient at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family. In yet another preferred embodiment, the human alpha-1 -antitrypsin is administered to a patient at risk of having an infection with a pathogenic virus of the Paramyxoviridae family. In such embodiments, the human alpha-1 -antitrypsin or derivative thereof can be used for preventing an infection with the virus and/or for corresponding prophylaxis. Such human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a human alpha-1 -antitrypsin virus from the Orthomyxoviridae family may be a healthy person or a person suffering from further diseases or disorders. For example, a human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family may be a person that was, is or will be in contact with a another human infected or suspected to be infected with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family or a sample containing or suspected to contain a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family. Further, a human at risk of having an infection with a pathogenic virus of the Paramyxoviridae family or a pathogenic virus from the Orthomyxoviridae family may be a hospitalized human, and/or a human selected from an immunosuppressed patient, an immunocompromised patient, an elderly patient, a cancer patient, a premature infant, a patient which does not respond to vaccines, a patient suffering from an autoimmune disease, a patient suffering from a chronic pulmonary disease, a patient suffering from a cardiac disease, an asthma patient, and/or a patient suffering from a neurological disease.

Accordingly, in a yet further preferred embodiment, the patient is not infected with the virus, and the human alpha-1 -antitrypsin or derivative thereof is for prophylaxis of the disease or disorder caused by the infection with the pathogenic virus.

It was surprisingly found in the examples that human alpha-1 antitrypsin protein from commercially available Prolastin® effectively prevented various RSV, Influenza and Measles strains from entering human epithelial cells in vitro. The cells used in the Examples are human epithelial cells. The cells are therefore a model for epithelial cells of the respiratory tract, in particular the upper respiratory tract, such as the nose, mouth or larynx, or the lower respiratory tract such the lungs or bronchi. Accordingly, it could be shown that human alpha-1 antitrypsin protein blocks or reduces entry of the pathogenic virus into epithelial cells. For example, human alpha-1 antitrypsin protein blocks or reduces entry of the pathogenic viruses herein into epithelial cells in vitro or in vivo.

Methods for determining whether human alpha-1 antitrypsin protein blocks or reduces entry of the pathogenic viruses into epithelial cells in vitro are known in the art and are described in detail in the Examples. In particular, the % value of infection of a human epithelial cell population infectable by a pathogenic virus can be determined in the presence of human alpha-1 antitrypsin as compared to a control in absence of human alpha-1 antitrypsin (normalized to control). For example, a suitable cell line can be used. The %- value of infection in the presence of human alpha-1 antitrypsin may be reduced for example by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 98%, or 99%, or by 100% as compared to the control.

Accordingly, in a yet further preferred embodiment, the administration of human alpha-1 -antitrypsin or the derivative thereof:

(i) blocks or reduces entry of the pathogenic virus into epithelial cells,

(iii) reduces the severity of co-infections with one or more further pathogens.

In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family. In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family or of the Orthomyxoviridae family.

In an embodiment of any of the aspects herein, the administration of human alpha- 1 -antitrypsin or the derivative thereof:

(i) blocks or reduces entry of the pathogenic virus into epithelial cells,

(iii) reduces the severity of co-infections with one or more further pathogens.

In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family. In an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family or of the Orthomyxoviridae family. In a preferred embodiment, the administration of human alpha-1 -antitrypsin or the derivative thereof reduces the severity of co-infections with one or more further pathogens. Such co-infection with one or more further pathogens may be coinfection with a further pathogenic virus. This further pathogenic virus may be a different virus of the Paramyxoviridae family or the Orthomyxoviridae family, such as a co-infection with RSV and Influenza, or Influenza and Measles virus, or Measles virus and RSV, or RSV and Parainfluenza virus, or may be an infection with a pathogenic virus from a virus family different from the Paramyxoviridae family or the Orthomyxoviridae family. Accordingly, in an embodiment, the one or more further pathogens are virus(es) of the Paramyxoviridae or Orthomyxoviridae family.

In embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. In embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) are selected from a Pneumovirus selected from Respiratory Syncytial Virus (RSV) and Metapneumovirus, a Paramyxovirus selected from a Parainfluenza virus and mumps virus; and the measles virus.

For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) are selected from a Pneumovirus selected from Respiratory Syncytial Virus (RSV) and Metapneumovirus. For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) is selected from Respiratory Syncytial Virus (RSV). For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) is selected from a Metapneumovirus. For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) are selected from a Paramyxovirus selected from a Parainfluenza virus and mumps virus. For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) is selected from a Parainfluenza virus. For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) is selected from a mumps virus. For example, in embodiments, the disease or disorder is caused by an infection with an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus, and the one or more further virus(es) or pathogen(s) are selected from the measles virus.

Further, in an embodiment, the pathogenic virus is a virus of the Paramyxoviridae family and the one or more further pathogens are virus(es) of the Paramyxoviridae or Orthomyxoviridae family.

Accordingly, in one embodiment, Human alpha-1 -antitrypsin or a derivative thereof is for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family, and wherein the administration of human alpha-1 -antitrypsin or the derivative thereof

(i) reduces the severity of a co-infection with one or more further virus(es) selected from viruses of the Paramyxoviridae and Orthomyxoviridae family; and/or

In an embodiment, the virus of the Orthomyxoviridae family is an Influenza virus. The Influenza virus may for example be a Type A or Type B Influenza virus. The Influenza virus may for example be a Type A Influenza virus. The Influenza virus may for example be a Type B Influenza virus.

In certain embodiments, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV). In embodiments, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and the one or more further virus(es) or pathogen(s) are selected from a Metapneumovirus, a Paramyxovirus selected from a Parainfluenza virus and mumps virus; the measles virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. For example, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and the one or more further virus(es) or pathogen(s) are selected from a Metapneumovirus. Alternatively, for example, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and the one or more further virus(es) or pathogen(s) are selected from an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Alternatively, for example, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and the one or more further virus(es) or pathogen(s) are selected from a measles virus. Alternatively, for example, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and the one or more further virus(es) or pathogen(s) are selected from a Parainfluenza virus. Alternatively, for example, the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and the one or more further virus(es) or pathogen(s) are selected from a mumps virus.

In certain embodiments, the disease or disorder is caused by an infection with a Metapneumovirus. In embodiments, the disease or disorder is caused by an infection with a Metapneumovirus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV), a Paramyxovirus selected from a Parainfluenza virus and mumps virus, the measles virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus.

For example, the disease or disorder is caused by an infection with a Metapneumovirus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV). Alternatively, for example, the disease or disorder is caused by an infection with a Metapneumovirus and the one or more further virus(es) or pathogen(s) are selected from an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Alternatively, for example, the disease or disorder is caused by an infection with a Metapneumovirus and the one or more further virus(es) or pathogen(s) are selected from the measles virus. Alternatively, for example, the disease or disorder is caused by an infection with a Metapneumovirus and the one or more further virus(es) or pathogen(s) are selected from a Parainfluenza virus. Alternatively, for example, the disease or disorder is caused by an infection with a Metapneumovirus and the one or more further virus(es) or pathogen(s) are selected from a mumps virus. In certain embodiments, the disease or disorder is caused by an infection with a Parainfluenza virus. In embodiments, the disease or disorder is caused by an infection with a Parainfluenza virus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV), a Metapneumovirus, a mumps virus, the measles virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus.

For example, the disease or disorder is caused by an infection with a Parainfluenza virus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV). Alternatively, for example, the disease or disorder is caused by an infection with a Parainfluenza virus, and the one or more further virus(es) or pathogen(s) are selected from an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Alternatively, for example, the disease or disorder is caused by an infection with Parainfluenza virus and the one or more further virus(es) or pathogen(s) are selected from a measles virus. Alternatively, for example, the disease or disorder is caused by an infection with Parainfluenza virus and the one or more further virus(es) or pathogen(s) are selected from a Metapneumovirus. Alternatively, for example, the disease or disorder is caused by an infection with Parainfluenza virus and the one or more further virus(es) or pathogen(s) are selected from a mumps virus.

In certain embodiments, the disease or disorder is caused by an infection with a mumps virus. In embodiments, the disease or disorder is caused by an infection with mumps virus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV), a Metapneumovirus, a Parainfluenza virus, the measles virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus.

For example, the disease or disorder is caused by an infection with a mumps virus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV). Alternatively, for example, the disease or disorder is caused by an infection with a mumps virus, and the one or more further virus(es) or pathogen(s) are selected from an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Alternatively, for example, the disease or disorder is caused by an infection with a mumps virus and the one or more further virus(es) or pathogen(s) are selected from a measles virus. Alternatively, for example, the disease or disorder is caused by an infection with a mumps virus and the one or more further virus(es) or pathogen(s) are selected from a Metapneumovirus. Alternatively, for example, the disease or disorder is caused by an infection with a mumps virus and the one or more further virus(es) or pathogen(s) are selected from a Parainfluenza virus.

In certain embodiments, the disease or disorder is caused by an infection with the measles virus. In embodiments, the disease or disorder is caused by an infection with the measles virus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV), a Metapneumovirus, a Parainfluenza virus, a mumps virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus.

For example, the disease or disorder is caused by an infection with the measles virus and the one or more further virus(es) or pathogen(s) are selected from a Respiratory Syncytial Virus (RSV). Alternatively, for example, the disease or disorder is caused by an infection with the measles virus, and the one or more further virus(es) or pathogen(s) are selected from an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Alternatively, for example, the disease or disorder is caused by an infection with the measles virus and the one or more further virus(es) or pathogen(s) are selected from a mumps virus. Alternatively, for example, the disease or disorder is caused by an infection with the measles virus and the one or more further virus(es) or pathogen(s) are selected from a Metapneumovirus. Alternatively, for example, the disease or disorder is caused by an infection with the measles virus and the one or more further virus(es) or pathogen(s) are selected from a Parainfluenza virus.

Alternatively, in any of the aspects herein, the one or more further pathogen may be a bacterial, protozoan, fungal or parasitic pathogen. Exemplary other viruses from families different from the Paramyxoviridae family or the Orthomyxoviridae family include a Herpes simplex virus, HIV, hepatitis A, hepatitis B, hepatitis C, FSME and other pathogenic flaviviruses, cytomegalovirus, Epstein-Barr virus, and Herpes zoster virus. An exemplary pathogenic bacterium includes for example Helicobacter pylori, E. coli, Pseudomonas strains, including aeruginosa, Staphylococcus, Proteus vulgaris, and Candida albicans. An exemplary fungus includes for example Aspergillus. Typical parasites include for example Amoeba, Plasmodium, Leishmania, Mycosus profundus, Trypanosoma, Spirochete, and Arbovirus. Preferably, the human alpha-1 -antitrypsin or derivative thereof is in pharmaceutical composition comprising human alpha-1 -antitrypsin or derivative thereof and at least one pharmaceutically acceptable excipient, carrier or diluent.

Pharmaceutical compositions for can be formulated in conventional manners using at least one physiologically acceptable excipient, carrier or diluent. The pharmaceutical compositions can include formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, colour, isotonicity, odour, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. Suitable formulation materials include, but are not limited to: amino acids (for example, glycine, glutamine, asparagine, arginine and lysine); antimicrobials; antioxidants (for example, ascorbic acid, sodium sulfite and sodium hydrogen-sulfite); buffers (for example, borate, bicarbonate, Tris-HCI, citrates, phosphates and other organic acids); bulking agents (for example, mannitol and glycine); chelating agents (for example, ethylenediamine tetraacetic acid (EDTA)); complexing agents (for example, caffeine, polyvinylpyrrolidone, betacyclodextrin, and hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides, disaccharides, and other carbohydrates (for example, glucose, mannose and dextrins); proteins (for example, serum albumin, gelatin and immunoglobulins); coloring, flavoring, and diluting agents; emulsifying agents; hydrophilic polymers (for example, polyvinylpyrrolidone); low molecular weight polypeptides; salt forming counterions (for example, sodium); preservatives (for example, benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and hydrogen peroxide); solvents (for example, glycerol, propylene glycol and polyethylene glycol); sugar alcohols (for example, mannitol and sorbitol); suspending agents; surfactants or wetting agents (for example, pluronics, PEG, sorbitan esters, polysorbates (for example, polysorbate 20 and polysorbate 80), triton, tromethamine, lecithin, cholesterol, and tyloxapal); stability enhancing agents (for example, sucrose and sorbitol); tonicity enhancing agents (for example, alkali metal halides (for example, sodium or potassium chloride), mannitol, and sorbitol); delivery vehicles; diluents; excipients; and recognized pharmaceutical adjuvants. Additionally, the described protein can be linked to a half-life extending vehicle. Certain exemplary half-life extending vehicles are known in the art, and include, but are not limited to, the Fc domain, polyethylene glycol, and dextran. A preferred excipient or diluent herein is water, in particular sterile water. Further suitable excipients or diluents are saline solution, in particular in a buffered saline or phosphate-buffered saline (PBS).

For example, the human alpha-1 -antitrypsin or derivative thereof may be lyophilized or a solution comprising or containing human alpha-1 -antitrypsin or derivative thereof. Suitable human alpha-1 -antitrypsin products containing or consisting of lyophilized human alpha-1 -antitrypsin or a solution of human alpha-1 -antitrypsin in sterile water are commercially available and are approved for administration to humans.

In a further preferred embodiment, the human alpha-1 -antitrypsin or derivative thereof is formulated for administration as an aerosol or for intravenous administration, and/or the pharmaceutical composition comprises or consists of lyophilized human alpha-1 -antitrypsin or a derivative thereof, or human alpha-1 - antitrypsin or a derivative thereof in water or aqueous solution.

Suitable human alpha-1 -antitrypsin products comprising or consisting of lyophilized human alpha-1 -antitrypsin or a solution of human alpha-1 -antitrypsin in sterile water are commercially available and are approved for administration to humans. Such products are suitable for administration as an aerosol or for intravenous administration. In case of lyophilized human alpha-1 -antitrypsin, this applies upon dissolving the protein in water or in another aqueous solution such as saline.

For example, lyophilized human alpha-1 -antitrypsin may be used. Such lyophilized human alpha-1 -antitrypsin may be dissolved in sterile water. For example, singleuse vials containing approximately 1000 mg, 4000 mg, or 5000 mg of alpha-1 - antitrypsin as lyophilized powder for reconstitution with 20 mL, 76 mL, or 95 mL of sterile water, for injection, are currently approved as Zemaira®. For example, lyophilized human alpha-1 -antitrypsin may be dissolved in sterile water to a suitable concentration of human alpha-1 -antitrypsin. In Zemaira® according to the package insert, the concentration is not less than 16 mg/mL and the specific activity is not less than 0.55 mg active human alpha-1 -antitrypsin/mg total protein.

Therefore, preferably the pharmaceutical composition comprises or consists of lyophilized human alpha-1 -antitrypsin or a derivative thereof, or human alpha-1 - antitrypsin or a derivative thereof in sterile water or an aqueous solution, more preferably in sterile water. In yet another preferred embodiment, the pharmaceutical composition is for administration of human alpha-1 -antitrypsin or a derivative thereof in a dosage of between about 20 and 500 mg/kg/day of body weight, and/or the single unit dose comprises between about 20 mg and 20 g of human alpha-1 -antitrypsin or a derivative thereof.

Preferably, the pharmaceutical composition is for administration of human alpha-1 - antitrypsin or a derivative thereof in a dosage of between about 20 and 500 mg/kg/day of body weight. For example, the pharmaceutical composition is for administration of human alpha-1 -antitrypsin or a derivative thereof in a dosage of between about 20 and 500, 30 to 400, 50 to 200, 50 to 500, 100 to 500, 20 to 100, or 50 to 400 mg/kg/day of body weight of human alpha-1 -antitrypsin or a derivative thereof.

For example, a ready-to-use liquid formulation consisting of alpha-1 -antitrypsin in sterile water may be used. Such formulation is approved as Prolastin-C Liquid®. The recommended dose of Prolastin-C Liquid® is 60 mg/kg of body weight infused intravenously once per week.

Preferably, the single unit dose or the single dose unit comprises between about 20 mg and 20 g of human alpha-1 -antitrypsin or a derivative thereof. For example, the single unit dose or the single dose unit comprises between about 20 mg and 20 g, 20 mg and 10 g, 20 and 1 g, 50 mg and 10 g, 50 mg and 1 g, or any other combination of ranges of these values, of human alpha-1 -antitrypsin or a derivative thereof.

The human alpha-1 -antitrypsin or derivative thereof herein may be administered in any manner including, but not limited to, orally, parenterally, sublingually, transdermally, transmucosally, topically, via inhalation, via buccal or intranasal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intra-peritoneal, subcutaneous and intramuscular.

Preferably, the human alpha-1 -antitrypsin or derivative thereof is formulated for administration as an aerosol or for intravenous administration. For example, in one preferred embodiment, the pharmaceutical composition may be delivered as an aerosol. For example, the aerosol formulation may be administered intranasally or via inhalation. Thereby, the human alpha-1 -antitrypsin is delivered locally and/or topically to the respiratory tract, such as the mucosa of the mouth or the nose.

For example, a suitable aerosol formulation is described in Gaggar A et al. (Journal of Cystic Fibrosis 15 (2016) 227-233). A 50 mg/ml solution of human alpha-1 - antitrypsin in water may delivered once, in a dose of 100 mg or 200 mg daily via the AKITA2 nebulizer system. Accordingly, an aerosol formulation for use according to the invention may comprise or consist of a solution of human alpha-1 -antitrypsin in water.

Accordingly, preferably, the human alpha-1 -antitrypsin for use of the invention is comprised in a pharmaceutical composition formulated as aerosol and is formulated for intranasal administration and/or for administration via inhalation. The human alpha-1 -antitrypsin formulated as aerosol and/or for intranasal administration and/or for administration via inhalation can be administered to the human subject intranasally or via inhalation. Thereby, the human alpha-1 -antitrypsin is delivered locally and topically to the respiratory tract, such as to upper respiratory tract and/or lower respiratory tract, in particular the epithelial cells of the upper respiratory tract and/or lower respiratory tract.

For example, suitable formulations for human alpha-1 -antitrypsin are known in the art and are described above, and include lyophilized human alpha-1 -antitrypsin, which is approved for administration to humans. The human alpha-1 -antitrypsin may be reconstituted in sterile water and may be administered as aerosol and/or intranasally and/or via inhalation.

Further, suitable formulations for human alpha-1 -antitrypsin are known in the art and/or are approved for administration to humans for systemic administration, preferably intravenous administration, such as intravenous injection.

For example, a ready-to-use liquid formulation consisting of human alpha-1 - antitrypsin in sterile water may be used. Such formulation is approved as Prolastin- C Liquid®. The recommended dose of Prolastin-C Liquid® is 60 mg/kg of body weight infused intravenously once per week. Further suitable formulations as an aerosol are known in the art and are described e.g. in U.S. Patent Nos. 4,044,126, 4,414,209 and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma. These pharmaceutical compositions for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflations, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will have diameters of less than 50 microns or less than 10 microns. US 5,474,759 discloses aerosol formulations that are substantially free of chlorofluorocarbons. The formulations contain a propellant (such as 1 ,1 , 1 ,2, 3, 3, 3, -heptafluoropropane), a medium-chain fatty acid propylene glycol diester, a medium-chain triglyceride, optionally a surfactant, and optionally auxiliary agents such as antioxidants, preservatives, buffers, sweeteners and taste masking agents.

Preferably, the pharmaceutical composition formulated for administration as an aerosol or for intravenous administration is for administration of human alpha-1 - antitrypsin or a derivative thereof in a dosage of between about 20 and 500 mg/kg/day of body weight. For example, the pharmaceutical composition is for administration of human alpha-1 -antitrypsin or a derivative thereof in a dosage of between about 20 and 500, 30 to 400, 50 to 200, 50 to 500, 100 to 500, 20 to 100, or 50 to 400 mg/kg/day of body weight.

Preferably, the pharmaceutical composition formulated for administration as an aerosol or for intravenous administration is administered in a dosage of between about 20 and 500 mg/kg/day of body weight of human alpha-1 -antitrypsin or a derivative thereof. For example, the pharmaceutical composition is administered in a dosage of between about 20 and 500, 30 to 400, 50 to 200, 50 to 500, 100 to 500, 20 to 100, or 50 to 400 mg/kg/day of body weight of human alpha-1 -antitrypsin or a derivative thereof.

Preferably, the single unit dose or the single dose unit formulated for administration as an aerosol or for intravenous administration comprises between about 20 mg and 20 g of human alpha-1 -antitrypsin or a derivative thereof. For example, the single unit dose or the single dose unit comprises between about 20 mg and 20 g, 20 mg and 10 g, 20 and 1 g, 50 mg and 10 g, 50 mg and 1 g, or any other combination of ranges of these values, of human alpha-1 -antitrypsin or a derivative thereof. For example, the dose administered to the patient is between about 20 mg and 20 g of human alpha-1 -antitrypsin or a derivative thereof, such as between about 20 mg and 20 g, 20 mg and 10 g, 20 and 1 g, 50 mg and 10 g, 50 mg and 1 g, or any other combination of ranges of these values, of human alpha-1 -antitrypsin or a derivative thereof.

In general, the precise dose to be employed in a composition will also depend on the route of administration, and the seriousness of the infection, disorder or disease caused by it, and should be decided according to the judgment of the practitioner and each subject's circumstances. For example, effective doses may also vary depending upon means of administration, target site, physiological state of the subject (including age, body weight and health), other medications administered, or whether treatment is preventive or therapeutic. Usually, the patient is a human but non-human mammals can also be treated. Treatment dosages are optimally titrated to optimize safety and efficacy.

For example, it is possible that 1 single dose unit of human alpha-1 -antitrypsin or a derivative thereof or pharmaceutical composition is administered, e.g. intranasally or via inhalation or systemically, such as by intravenous administration, to the subject. Alternatively, the human alpha-1 -antitrypsin or a derivative thereof, or pharmaceutical composition, is administered in multiple doses, e.g. intranasally or via inhalation, or systemically, such as by intravenous administration. Preferably, in case multiple doses are administered, these are administered at least 2 hours apart from each other. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more single unit doses may be administered. For example, the single unit doses may be administered daily, twice daily, every 2, 3 or 4 days, weekly or monthly.

The human alpha-1 -antitrypsin or a derivative thereof or pharmaceutical composition may be administered only once to the subject. Alternatively, the human alpha-1 -antitrypsin or a derivative thereof or pharmaceutical composition may be administered to the subject repeatedly, for example 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times.

Moreover, it is possible to administer the human alpha-1 -antitrypsin or a derivative thereof or pharmaceutical composition continuously to the subject, for example over a period of 10 minutes or more, 30 minutes or more, or 1 hour or more, e.g. by intravenous administration. Preferably, the pharmaceutical composition is comprised (i) in a pulmonary drug delivery kit comprising: a) an inhaler; and b) the pharmaceutical composition; or (ii) in a pharmaceutical package comprising: a) the pharmaceutical composition; and b) a nebulizer.

Examples of pharmaceutical devices for administration via inhalation or intranasal administration, as well as corresponding methods and uses, include metered dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers. Exemplary delivery systems by inhalation which can be adapted for delivery of human alpha-1 - antitrypsin or a derivative thereof, to the subject are described in, for example, US 5,756,353; US 5,858,784; WO98/31346; WO98/10796; WOOO/27359;

WO01/54664; and W002/060412. Other aerosol pharmaceutical compositions and devices that may be used for delivering the human alpha-1 -antitrypsin or a derivative thereof via inhalation or intranasal administration are described in US 6,294,153; US 6,344,194; US 6,071 ,497, W002/066078; W002/053190; W001/60420; and WO00/66206.

Pressurized metered dose inhalers (pMDIs) are the most commonly used inhaler worldwide (see e.g. W02006/122257 for details). The aerosol is created when a valve is opened (usually by pressing down on the propellant canister), allowing liquid propellant to spray out of a canister. Typically, a drug or therapeutic is contained in small particles (usually a few microns in diameter) suspended in the liquid propellant, but in some formulations, the drug or therapeutic may be dissolved in the propellant. The propellant evaporates rapidly as the aerosol leaves the device, resulting in small drug or therapeutic particles that are inhaled. Propellants typically used in such pMDIs include but are not limited to hydrofluoroalkanes (HFAs). A surfactant may also be used, for example, to formulate the drug or therapeutic, with pMDIs. Other solvents or excipients may also be employed with pMDIs, such as ethanol, ascorbic acid, sodium metabisulfate, glycerin, chlorobutanol, and cetylpyridium chloride. Such pMDIs may further include add-on devices such as, for example, spacers, holding chambers and other modifications.

Nebulizers produce a mist of drug-containing liquid droplets for inhalation (see e.g. for details W02006/122257). They are usually classified into two types: ultrasonic nebulizers and jet nebulizers. A type of nebulizer is also available which does not require ultrasound or air pressure to function. Single breath atomizers have also been developed (e.g., Respimat®), which is used to deliver a drug in a single inhalation and may be preferred because of less contamination. Jet nebulizers use a source of pressurized air to blast a stream of air through a drug-containing water reservoir, producing droplets in a complex process involving a viscosity-induced surface instability that leads to nonlinear phenomena in which surface tension and droplet breakup on baffles play a role. Ultrasonic nebulizers produce droplets by mechanical vibration of a plate or mesh. In either type of nebulizer, the drug is usually contained in solution in the liquid in the nebulizer and so the droplets being produced contain drug in solution. However, for some formulations (e.g., Pulmicort) the drug is contained in small particles suspended in the water, which are then contained as particles suspended inside the droplets being produced. Certain excipients are usually included in formulations suitable for nebulization, such as sodium chloride (e.g., to maintain isotonicity), mineral acids and bases (e.g., to maintain or adjust pH), nitrogen headspace sparging, benzalkonium chloride, calcium chloride, sodium citrate, disodium edetate, and polysorbate 80.

Another type of inhaler is the dry powder inhaler (DPI) (see e.g. WO2006/122257 for details). In DPIs, the aerosol is usually a powder, contained within the device until it is inhaled. The therapeutic or drug is manufactured in powder form as small powder particles (usually a few millionths of a meter, or micrometers, in diameter). In many DPIs, the drug or therapeutic is mixed with much larger sugar particles (e.g., lactose monohydrate), that are typically 50-100 micrometers in diameter. The increased aerodynamic forces on the lactose/drug agglomerates improve entrainment of the drug particles upon inhalation, in addition to allowing easier filling of small individual powder doses. Upon inhalation, the powder is broken up into its constituent particles with the aid of turbulence and/or mechanical devices such as screens or spinning surfaces on which particle agglomerates impact, releasing the small, individual drug powder particles into the air to be inhaled into the lung. The sugar particles are usually intended to be left behind in the device and/or in the mouth-throat.

The human alpha-1 -antitrypsin or a derivative thereof may be administered as single antiviral treatment, or in combination with other treatments for treating or ameliorating disorders caused by the viruses or symptom(s) thereof, such as treatments targeting single-stranded RNA viruses and/or broad-spectrum antiviral agents, such as nucleoside analogues, e.g. ribavirin, antibodies or binding proteins directed against a viral epitope, such as palivizumab, which is directed against RSV, corticosteroids, including inhaled corticosteroids, or an agent targeting IL-6R, such as Tocilizumab which is a recombinant humanized antibody directed against anti- IL-6 receptor. When used in combination with one or other treatments, the one or other treatments may be administered spatially and/or temporally separate from human alpha-1 - antitrypsin or spatially and/or temporally together with human alpha-1 -antitrypsin.

The term “treatment” or “treating” may be understood in the broadest sense that the subject treated with the human alpha-1 -antitrypsin or a derivative thereof described herein, has already been infected with a virus. The treatment may be performed at any stage of the infection, e.g. during incubation time or when symptoms of an infection the virus are visible or the disease is ongoing or when the infection is nearly defeated or has become chronic.

The terms “prophylaxis”, “prophylactic treatment”, “preventing” and “prevention” are used interchangeably and may be understood in the broadest sense that the subject treated with the human alpha-1 -antitrypsin or a derivative thereof described herein is not infected with the virus. The intention of the prophylaxis or prevention may be to prevent an infection and/or to prevent at least one symptom of the disease or disorder caused by the virus.

The term “amelioration” or “ameliorating” may be understood in the broadest sense as any improvement of the condition of an infected subject, e.g. a reduction of one or more symptoms or a reduction of the viral load of the respective virus in the treated subject.

In a yet further aspect, the present invention relates to a method of treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, the method comprising administering to the patient an effective amount of human alpha-1 -antitrypsin or a derivative thereof, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family or a virus from the Orthomyxoviridae family.

The preferred embodiments disclosed for the use of the invention above also apply to this aspect of the invention.

As used herein, the term “effective amount” in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired preventive or prophylactic, ameliorating or therapeutic effect. For achieving an ameliorating or therapeutic effect, a “therapeutically effective amount” is administered. For achieving an ameliorating effect, a “prophylactically effective amount” is administered.

For example, typical a “therapeutically effective amount” or “prophylactically effective amount” of human alpha-1 -antitrypsin or a derivative thereof is typically between about 20 and 500, 30 to 400, 50 to 200, 50 to 500, 100 to 500, 20 to 100, or 50 to 400 mg/kg/day of body weight, or is between about 20 mg and 20 g, 20 mg to 10 g, 20 to 1 g, 50 mg to 10 g, 50 mg to 1 g of human alpha-1 -antitrypsin or a derivative thereof.

As used herein, the terms “patient” and “subject” are used interchangeably and includes any human or non-human mammalian animal. Preferably, the patient is a human.

In general, the disclosure is not limited to the particular methodology, protocols, and reagents described herein because they may vary. Further, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure. As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Similarly, the words "comprise", "contain" and "encompass" are to be interpreted inclusively rather than exclusively.

Unless defined otherwise, all technical and scientific terms and any acronyms used herein have the same meanings as commonly understood by one of ordinary skill in the art in the field of the disclosure.

The term “about” in the context of a value refers to the value ± 10%, preferably the value ± 5%.

Examples

Example 1 : Antiviral activity of human alpha-1 -antitrypsin (Prolastin®) against RSV in vitro

15,000 human epithelial (HEp-2) cells per well were seeded in 96-well plate 24 h prior to infection. The next day, cells were treated with either PBS or Prolastin®, which is a formulation of human alpha-1 -antitrypsin, at indicated concentrations for 1 hour and then infected either with RSV-Long strain (A and C) or RSV-A2 strain (B) at MOI of 0.01. Infection rates were analyzed at 2 dpi using ICC-staining with RSV-specific monoclonal antibody. Shown are mean values of triplicates normalized to mock-treated controls ± SD. IC50 values were calculated using nonlinear regression in GraphPad Prism.

Example 2: Antiviral activity of human alpha-1 -antitrypsin (Prolastin®) against Influenza virus in vitro

20,000 Caco-2 cells were seeded in 100 pl Caco2 medium (DMEM 10 % FCS, 2 mM L-Glutamine, 100 ll/rnl Penicillin, 100 mg/ml streptomycin, 1x non-essential amino acid and 1 mM sodium pyruvate) in a 96-well flat bottom plate. The next day, medium was aspirated and cells were washed 2x with PBS before addition of 80 pl of Caco2 medium (without FCS). Cells were infected with Influenza strain A/PR/8/34 (H1 N1 ) at a multiplicity of infection of 0.1. 1 h post infection, the inoculum was removed, cells were washed 2x with PBS and 100 pl Caco2 medium (without FCS) supplemented with serial dilutions of Prolastin® (in PBS) were added. After 24 h, the supernatants were harvested and virus quantified by neuraminidase activity assay. To this end, 90 pl of supernatants were lysed by addition of 50 pl 1 % Triton X-100 in PBS for 30 min at 37°C. Lysed samples were diluted 1 :1 in MES buffer and 20 pl were transferred into an opaque plate and mixed with 30 pl of 10 pM MUNANA substrate (4-methylumbelliferyl N-acetyl-a-D-neuraminic acid). After 4 h of incubation at 37 °C, shaking at 250 rpm, 150 pl of stop solution (0.1 M glycine, 25 % EtOH in PBS) were added and fluorescence was measured at 360 nm excitation and 455 nm emission. Three independent experiments were performed, each in triplicates. The results are shown in Table 1 and Figure 2.

Caco-2 cells are epithelial cells isolated from colon tissue derived from a 72-year- old, White, male with colorectal adenocarcinoma.

It was found that human alpha-1 -antitrypsin exhibits antiviral activity against Influenza virus in vitro. In particular, it was found that It was found that human alpha- 1 -antitrypsin blocks or reduces entry of Influenza virus into human epithelial cells.

Table 1 : %-lnfection of Caco-2 cells by Influenza virus

Example 3: Antiviral activity of human alpha-1 -antitrypsin (Prolastin®) against the Measles virus in vitro

20,000 A549 cells were seeded in 100 pl A549 medium (DMEM 10% FCS, 2 mM L- Glutamine, 100 ll/rnl Penicillin, 100 mg/ml streptomycin) in a 96-well flat bottom plate. The next day, cells were treated with serial dilutions of Prolastin®. After 1 h of incubation, cells were infected with Measles strain Schwarz-ATU eGFP at an MOI of 0.1. After 2 days, cells were trypsinized, fixed in 4% PFA and analysed for expression of virus encoded GFP reporter gene via flow cytometry. Three independent experiments were performed, each in triplicates. The results are shown in Table 2 and Figure 3.

A549 cells are adenocarcinomic human alveolar basal epithelial cells.

Table 2: %-lnfection of A549 cells by Measles virus

Claims

Claims Human alpha-1 -antitrypsin or a derivative thereof for use in the treatment, amelioration and/or prophylaxis of a disease or disorder caused by an infection with a pathogenic virus in a human patient, wherein the pathogenic virus is selected from a virus of the Paramyxoviridae family. Human alpha-1 -antitrypsin or derivative thereof for use of claim 1 , wherein the virus of the Paramyxoviridae family is selected from a Pneumovirus, a Paramyxovirus or a Morbillivirus. Human alpha-1 -antitrypsin or derivative thereof for use of claim 2, wherein

(iii) the Morbillivirus is the measles virus. Human alpha-1 -antitrypsin or derivative thereof for use of any of claims 1 to 3, wherein the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) or Metapneumovirus. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein at least one symptom of the disease or disorder is/are treated, ameliorated or prevented. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein the human alpha-1 -antitrypsin or derivative thereof is administered intranasally and/or via inhalation and/or transmucosally or systemically. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims wherein human alpha-1 -antitrypsin or derivative is selected from human plasma-derived human alpha-1 -antitrypsin, recombinant human alpha-1 - antitrypsin, and derivatives thereof with engineered glycan content, and/or an N- and/or C-terminally modified human alpha-1 -antitrypsin. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein the human patient is selected from an immunosuppressed patient, an immunocompromised patient, an elderly patient, a cancer patient, a premature infant, a patient which does not respond to vaccines, a patient suffering from an autoimmune disease, a patient suffering from a chronic pulmonary disease, a patient suffering from a cardiac disease, an asthma patient, and/or a patient suffering from a neurological disease. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein the human alpha-1 -antitrypsin or derivative thereof is administered between day 0 and day 7 of initial viremia with the pathogenic virus and/or between day 0 and day 7 of initial occurrence of symptom(s) of the disease or disorder. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein the human alpha-1 -antitrypsin or derivative thereof is administered to a human patient infected with the pathogenic virus, and wherein the human alpha-1 -antitrypsin or derivative thereof is for treatment, and/or amelioration of the disease or disorder. Human alpha-1 -antitrypsin or derivative thereof for use of claim 9 or 10, wherein the administration of human alpha-1 -antitrypsin or the derivative thereof:

(i) blocks or reduces entry of the pathogenic virus into epithelial cells,

(iii) reduces the seventy of co-infections with one or more further pathogens, optionally wherein the one or more further pathogens are virus(es) of the Paramyxoviridae or Orthomyxoviridae family. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein the administration of human alpha-1 -antitrypsin or the derivative thereof

(i) reduces the seventy of a co-infection with one or more further virus(es) selected from viruses of the Paramyxoviridae and Orthomyxoviridae family; and/or (ii) treats, ameliorates and/or prevents the co-infection with one or more further virus(es) selected from viruses of the Paramyxoviridae and Orthomyxoviridae family. Human alpha-1 -antitrypsin or derivative thereof for use of claim 11 or 12, wherein the virus of the Orthomyxoviridae family is an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Human alpha-1 -antitrypsin or derivative thereof for use of any of claims 11 to 13, wherein the disease or disorder is caused by an infection with Respiratory Syncytial Virus (RSV) and wherein the one or more further virus(es) or pathogens are selected from a Metapneumovirus, a Paramyxovirus selected from a Parainfluenza virus and mumps virus; the measles virus, and an Influenza virus, optionally wherein the Influenza virus is a Type A or Type B Influenza virus. Human alpha-1 -antitrypsin or derivative thereof for use of any of claims 1 to 8, wherein the patient is not infected with the virus, and wherein the human alpha- 1 -antitrypsin or derivative thereof is for prophylaxis of the disease or disorder caused by the infection with the pathogenic virus. Human alpha-1 -antitrypsin or derivative thereof for use of any of any of the preceding claims, wherein the administration of human alpha-1 -antitrypsin or the derivative thereof:

(ii) blocks or reduces entry of the pathogenic virus into cells of the respiratory tract of the patient. Human alpha-1 -antitrypsin or derivative thereof for use of any of the preceding claims, wherein the human alpha-1 -antitrypsin or derivative thereof is in a pharmaceutical composition comprising human alpha-1 -antitrypsin or derivative thereof and at least one pharmaceutically acceptable excipient, carrier or diluent. Human alpha-1 -antitrypsin or derivative thereof for use of claim 17, wherein the human alpha-1 -antitrypsin or derivative thereof is formulated for administration as an aerosol or for intravenous administration, and/or the pharmaceutical composition comprises or consists of lyophilized human alpha-1 -antitrypsin or a derivative thereof, or human alpha-1 -antitrypsin or a derivative thereof in water or aqueous solution, and/or the pharmaceutical composition is for administration of human alpha-1 - antitrypsin or a derivative thereof in a dosage of between about 20 and 500 mg/kg/day of body weight, and/or the single unit dose comprises between about 20 mg and 20 g of human alpha- 1 -antitrypsin or a derivative thereof. Human alpha-1 -antitrypsin or derivative thereof for use of claim 17 or 18, wherein the pharmaceutical composition is comprised (i) in a pulmonary drug delivery kit comprising: a) an inhaler; and b) the pharmaceutical composition; or (ii) in a pharmaceutical package comprising: a) the pharmaceutical composition; and b) a nebulizer.