WO2023067348A1 - Traitement de la pneumonie induite par un virus - Google Patents

Traitement de la pneumonie induite par un virus Download PDF

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Publication number
WO2023067348A1
WO2023067348A1 PCT/GB2022/052682 GB2022052682W WO2023067348A1 WO 2023067348 A1 WO2023067348 A1 WO 2023067348A1 GB 2022052682 W GB2022052682 W GB 2022052682W WO 2023067348 A1 WO2023067348 A1 WO 2023067348A1
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subject
antagonist
free
amount
blood
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PCT/GB2022/052682
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English (en)
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Syed Muhammad Tahir NASSER
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Biosirius Ltd
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Priority claimed from GBGB2115113.9A external-priority patent/GB202115113D0/en
Priority claimed from GBGB2202301.4A external-priority patent/GB202202301D0/en
Application filed by Biosirius Ltd filed Critical Biosirius Ltd
Publication of WO2023067348A1 publication Critical patent/WO2023067348A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to pharmaceutical compositions and methods for the treatment of viral respiratory infections, e.g. virally-induced pneumonia. More specifically, the present invention relates to IL-18 antagonists and their use in the treatment of viral respiratory infections, e.g. virally-induced pneumonia, particularly COVID-19. BACKGROUND TO THE INVENTION Numerous viral infections affect the upper or lower respiratory tract. Respiratory infections can be classified by the causative virus (e.g., coronavirus, influenza virus) or according to syndrome caused (e.g., the common cold, bronchiolitis, croup, pneumonia).
  • the causative virus e.g., coronavirus, influenza virus
  • syndrome caused e.g., the common cold, bronchiolitis, croup, pneumonia.
  • viral pathogens typically cause characteristic clinical manifestations (e.g., rhinovirus typically causes the common cold, respiratory syncytial virus (RSV) typically causes bronchiolitis), each can cause many of the viral respiratory syndromes.
  • RSV respiratory syncytial virus
  • the severity of viral respiratory illness can vary widely depending on the viral pathogen and patient characteristics, e.g. age, gender, health status etc. For many infections, severe disease is more likely in older patients and infants. Morbidity may result directly from the viral infection or may be indirect, due to exacerbation of underlying conditions, such as cardiopulmonary conditions, or subsequent bacterial superinfection of the lung, paranasal sinuses, or middle ear.
  • CAP Community-acquired pneumonia
  • SARS-CoV2 severe acute respiratory syndrome coronavirus 2
  • Infection with SARS-CoV2 has been described as having two phases, with the majority of individuals experiencing only the first phase.
  • the first phase consists of a flu-like illness, with sufferers describing intermittent fevers, lethargy and a new onset continuous cough.
  • the second phase starting at around day 10 of symptoms is characterised by sudden onset shortness of breath that becomes progressively worse. It is at this stage that patients usually present in the hospital and a significant proportion of those patients require invasive ventilation and intensive care support. In the absence of an effective treatment that can prevent the transition to the second phase of the disease and/or relieve the acute respiratory symptoms of those patients in the second phase, there has been a relatively high proportion of patients requiring invasive ventilation.
  • the data also indicates that free IL-18 may be protective in at least the first 10 days of the illness and that elevated levels of free IL-18, relative to a healthy subject but below those observed in patients with a severe form of the illness, may be beneficial to patient survival.
  • the study data indicates that while the reduction of IL-18 levels in patients severely affected by COVID-19 may represent an effective treatment, the timing and intensity of the reduction is critical to achieving a positive outcome.
  • the data suggests that reduction of free IL-18 levels too early or to a level typical of healthy subjects may be detrimental to patient survival. It is these unexpected findings that underlie the present invention. While the study was conducted on COVID-19 patients, it will be appreciated that the findings may be extrapolated to viral respiratory diseases in general, particularly virally-induced pneumonias.
  • the invention provides an IL-18 antagonist for use in treating a viral respiratory infection (e.g. virally-induced pneumonia) in a subject, wherein the IL-18 antagonist is first administered to the subject: (a) at about day 10 of one or more symptoms of the viral respiratory infection or after, wherein the one or more symptoms are selected from: (i) a fever; (ii) a cough (e.g. a continuous cough); and (iii) a loss or change to sense of taste and/or smell; and (b) wherein the subject has a PaO 2 /FiO 2 ratio (partial pressure of oxygen in arterial blood divided by the fraction of inspired oxygen) of less than 300 mmHg.
  • a viral respiratory infection e.g. virally-induced pneumonia
  • the IL-18 antagonist is first administered to the subject: (a) at about day 10 of one or more symptoms of the viral respiratory infection or after, wherein the one or more symptoms are selected from: (i) a fever; (ii) a cough (e.g. a continuous cough);
  • the invention provides a method of treating a viral respiratory infection (e.g. virally-induced pneumonia) in a subject in need thereof comprising administering an effective amount of an IL-18 antagonist to the subject, thereby treating the subject, wherein the IL-18 antagonist is first administered to the subject: (a) at about day 10 of one or more symptoms of the viral respiratory infection or after, wherein the one or more symptoms are selected from: (i) a fever; (ii) a cough (e.g.
  • the invention provides the use of an IL-18 antagonist in the manufacture of a medicament for treating a viral respiratory infection (e.g. virally-induced pneumonia) in a subject, wherein the medicament is first administered to the subject: (a) at about day 10 of one or more symptoms of the viral respiratory infection or after, wherein the one or more symptoms are selected from: (i) a fever; (ii) a cough (e.g.
  • a viral respiratory infection e.g. virally-induced pneumonia
  • the invention provides an IL-18 antagonist for use in treating a viral respiratory infection (e.g.
  • the invention provides a method of treating a viral respiratory infection (e.g.
  • the invention provides the use of an IL-18 antagonist in the manufacture of a medicament for treating a viral respiratory infection (e.g.
  • the medicament is administered to the subject in an amount effective to reduce the amount of free IL-18 in the blood of the subject to a reference amount, wherein the reference amount is the amount of free IL-18 in the blood of a reference subject or a group of reference subjects, and wherein: (i) a reference subject is a subject that has a less severe manifestation of the same viral respiratory infection; and (ii) the reference amount is the amount of free IL-18 in the blood of the reference subject or group of reference subjects at the same or a similar time point of the infection.
  • viral respiratory infections such as COVID-19
  • COVID-19 may expose an inherent weakness in the innate immune system of subjects who are elderly (e.g.65 years of age or older), or suffer from metabolic syndrome and associated disorders.
  • natural killer cell dysfunction or deficiencies in such subjects may result in poor viral control early in the disease, resulting in excessive inflammasome activation in the later stage of the disease (after day 10) due to unchecked viral spread, resulting in uncontrolled cleavage of IL-18 to its active form (free IL-18), which goes on to drive a multi-system inflammatory state.
  • the excessive inflammatory response prevents viral clearance, resulting in further poor control of viral load.
  • blockade of IL-18 in accordance with the invention described herein may be particularly effective in patients who are elderly (e.g.65 years of age or older) or who suffer from metabolic syndrome and associated disorders, such as coronary artery disease, hypertension and diabetes, particularly hypertension.
  • the subject to be treated has metabolic syndrome, coronary artery disease, hypertension, atherosclerosis, type II diabetes or a combination thereof (i.e. in addition to the viral respiratory infection, e.g. virally-induced pneumonia).
  • viral respiratory infection refers to an infection of the lower and optionally the upper respiratory tract with a viral pathogen, i.e. an infection with a viral respiratory pathogen.
  • a viral respiratory infection is an infection of the bronchial tubes and/or lungs with a viral pathogen.
  • viral respiratory syndrome refers to a set of medical signs (e.g. patient temperature, blood pressure etc.) and symptoms (e.g. cough, shortness of breath etc.) associated with a particular viral respiratory infection and/or a disease or disorder caused or triggered by the viral respiratory infection, e.g. viral pneumonia or virally-induced pneumonia.
  • the inventor has determined that viral respiratory infections, such as SARS-CoV2 infection, can trigger a systemic increase in levels of free IL-18 in the infected subject, and that the controlled reduction of IL-18 levels at an appropriate time point of the infection provides an effective treatment of the infection/syndrome.
  • the viral respiratory infection may be viewed as an infection by a viral pathogen that can trigger a systemic increase in levels of free IL-18 in the infected subject, i.e. an increase in the blood levels of free IL-18.
  • the increase may be an increase relative to the level of free IL-18 in the subject prior to infection.
  • the increase may be determined by comparing the blood level of free IL-18 in the infected subject with the blood level of free IL-18 a subject that is not infected with the viral pathogen.
  • the skilled person readily would be able to determine the characteristics of a suitable uninfected subject for the comparison, e.g. age, gender, ethnic/racial background, health status etc.
  • a suitable uninfected subject may be of the same gender, ethnicity and same age bracket as the infected subject, e.g.40- 49, 50-59, 60-69 years old etc.
  • Numerous viral pathogens are known to infect the respiratory tract and any such viral pathogen may result in a viral respiratory infection as defined above.
  • the viral respiratory infection is an infection by a coronavirus, influenza virus, human parainfluenza virus, respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus or adenovirus.
  • influenza virus is an influenza A virus or an influenza B virus.
  • viral respiratory infection is an infection by a coronavirus.
  • the coronavirus is a severe acute respiratory syndrome (SARS) coronavirus (e.g. SARS-CoV or SARS-CoV2) or a Middle East respiratory syndrome (MERS) coronavirus.
  • SARS severe acute respiratory syndrome
  • SARS-CoV severe acute respiratory syndrome
  • SARS-CoV2 Middle East respiratory syndrome
  • MERS Middle East respiratory syndrome
  • the coronavirus is SARS coronavirus 2 (SARS-CoV2).
  • the viral respiratory infection is Coronavirus Disease 2019 (COVID-19), SARS or MERS.
  • the viral respiratory infection causes a viral respiratory syndrome, such as viral pneumonia, viral bronchitis or viral bronchiolitis.
  • a viral respiratory syndrome such as viral pneumonia, viral bronchitis or viral bronchiolitis.
  • viral respiratory infection causes a viral pneumonia.
  • the invention involves treating viral pneumonia, viral bronchitis or viral bronchiolitis in a subject, preferably viral pneumonia.
  • the invention provides an IL-18 antagonist for use in treating a viral pneumonia caused by a viral respiratory infection in a subject, wherein the IL-18 antagonist is first administered to the subject: (a) at about day 10 of one or more symptoms of the viral respiratory infection or after, wherein the one or more symptoms are selected from: (i) a fever; (ii) a cough (e.g. a continuous cough); and (iii) a loss or change to sense of taste and/or smell; and (b) wherein the subject has a PaO2/FiO2 ratio (partial pressure of oxygen in arterial blood divided by the fraction of inspired oxygen) of less than 300 mmHg.
  • the term “subject” refers to a mammal, preferably a human.
  • subject to be treated and “patient” are used interchangeably herein and refer to a human having a viral respiratory infection and/or a viral respiratory syndrome, as defined herein, in need of treatment.
  • subjects may also have another disease or disorder, i.e. a comorbidity (e.g. an underlying disease or disorder that makes them particularly susceptible to having a severe form of a viral respiratory infection or syndrome), such as metabolic syndrome, coronary artery disease, hypertension, atherosclerosis, diabetes (e.g. type 2 diabetes) or a combination thereof.
  • first administered refers to the time point of administration of the first dose of the IL-18 antagonist (medicament) in the course of the viral respiratory infection being treated.
  • second and subsequent doses of the IL-18 antagonist may be administered after the first dose.
  • the level of free IL-18 in the subject to be treated is reduced to a reference amount and thus administration of the IL-18 antagonist may involve one or more doses of the same or different amounts needed to reduce the level of free IL-18 to the reference amount, e.g. over the course of the treatment.
  • the term “first administered” does not preclude the possibility that the subject may be have been administered an IL-18 antagonist previously, i.e. in the course of treating a different disease (e.g. Adult Onset Still’s Disease, Macrophage Activation Syndrome etc.) or a previous viral respiratory infection.
  • the IL-18 antagonist (medicament) is first administered to the subject at about day 10 of one or more symptoms of the viral respiratory infection or after, wherein the one or more symptoms are selected from: (i) a fever; (ii) a cough (e.g. a continuous cough); and (iii) a loss or change to sense of taste or smell.
  • the term “at about day 10 of one or more symptoms of the viral respiratory infection or after” defines the time point of administration of the first dose of the IL- 18 antagonist. In particular it refers to the number of days the subject to be treated has had one or more symptoms. In other words, day 10 of one or more symptoms refers to the tenth day the subject has had one or more symptoms.
  • the IL-18 antagonist (medicament) is first administered to the subject at least about 10 days after the subject develops (i.e. after the onset of) of one or more symptoms of the viral respiratory infection.
  • the terms “develops symptoms” and “onset of symptoms” are used interchangeably herein to refer to the first appearance or initial existence of symptoms of the viral respiratory infection, as reported by the patient themselves.
  • the day on which the onset of symptoms occurs may be viewed as “Day 1” and thus the IL-18 antagonist may be first administered to the subject on Day 10 or after (e.g. at least 9 days after the end of the day on which one or more symptoms first occurred).
  • any subject in need of treatment with an IL-18 antagonist will require at least a first dose between days 10-20 of symptoms, e.g. between 10-20 days after the onset of symptoms.
  • second and subsequent doses may be administered outside of this window, i.e. treatment may continue after day 20 of symptoms, e.g. after 20 days after the onset of symptoms.
  • treatment may continue until amelioration of one or more of the symptoms of the viral respiratory infection (e.g. COVID-19), related conditions and/or complications arising from same or manifestations thereof, e.g. until one or more symptoms has improved or abated, such as until the subject has recovered.
  • treatment may continue until the PaO 2 /FiO 2 ratio increases to 300 mmHg or more, preferably at least 350 mmHg or more.
  • the treatment may continue after day 25, 30, 35, 40, 45, 50 or more of symptoms, e.g.
  • the IL-18 antagonist is first administered between about day 10-20 of symptoms, such as about day 10-18 of symptoms, about day 10-16 of symptoms or about day 10-14 of symptoms.
  • the IL-18 antagonist is first administered between about 10-20 days after the onset of symptoms, such as about 10-18, 10-16 or 10-14 days after the onset of symptoms.
  • the IL-18 antagonist is first administered between about day 12-20 of symptoms, such as about day 13-20, 14-20 or 15-20 of symptoms.
  • the IL-18 antagonist is first administered between about 12-20 days after the onset of symptoms, such as about 13-20, 14-20 or 15-20 days after the onset of symptoms.
  • the study in the Examples shows that in patients with COVID-19 there is a key divergence in free IL-18 beyond day 14 of the illness, between those with severe disease and those with mild disease.
  • the viral respiratory infection is severe acute respiratory syndrome (SARS) coronavirus infection (e.g. SARS-CoV2, i.e. COVID-19)
  • the IL-18 antagonist may be first administered between about day 12-20 of symptoms, such as about day 13-20, 14- 20 or 15-20 of symptoms, e.g. at least day 13, 14 or 15 of symptoms, e.g. day 14- 19 or 15-19 of symptoms.
  • SARS severe acute respiratory syndrome
  • the IL-18 antagonist may be first administered between about 12-20 days after the onset of symptoms, such as about 13-20, 14-20 or 15-20, e.g. at least about 13, 14 or 15, days after the onset of symptoms.
  • the IL-18 antagonist may be first administered earlier, such as between about day 10-14 of symptoms, preferably at least day 11, 12, 13 or 14 of symptoms.
  • the IL-18 antagonist may be first administered between about 10-14 days after the onset of symptoms, preferably at least 11, 12, 13 or 14 days after the onset of symptoms.
  • the IL-18 antagonist is first administered on or after Day 14 of the disease, e.g. at least 14 days after the onset of symptoms.
  • a fever refers to a temporary increase in body temperature to 38°C or greater, e.g.38.5°C, 39°C, 39.5°C, 40°C, 40.5°C or greater.
  • a cough refers to an involuntary act of expelling air through the large breathing passages, e.g. to help clear them of fluids, irritants, foreign particles etc.
  • a cough can be classified as acute, subacute or chronic, in addition to productive (with sputum expectoration) or dry.
  • the subject to be treated has developed an acute cough, particularly an acute dry cough.
  • the cough is a continuous cough, meaning that at onset coughing occurs frequently for a prolonged period of time, e.g.
  • the cough is a continuous dry cough or an acute continuous dry cough.
  • a “loss of sense of taste and/or smell” refers to the onset of anosmia, ageusia, hyposmia, hypogeusia or a combination thereof, i.e. the absolute loss of taste and/or smell, or a reduced ability to taste and/or smell.
  • a “change to sense of taste and/or smell” typically refers to a change in the way odours, tastes or flavours are perceived, i.e. odours, tastes or flavours may be misread or distorted. For instance, something that is normally pleasant to taste or smell may taste or smell unpleasant.
  • the subject to be treated develops a loss of sense of taste or smell, i.e. anosmia, ageusia, hyposmia, hypogeusia or a combination thereof, e.g. hyposmia and ageusia, anosmia and ageusia, or hyposmia and hypogeusia.
  • the subject to be treated develops more than one symptom described above, e.g. a fever and a cough, particularly a continuous cough (e.g. a continuous dry cough). In some embodiments, the subject to be treated develops all three symptoms, i.e. a fever, a cough, particularly a continuous cough (e.g. a continuous dry cough), and a loss or change of taste and/or smell, particularly a loss of taste and/or smell.
  • a “PaO 2 /FiO 2 ratio” is the ratio of the partial pressure of arterial oxygen in the blood (PaO 2 in mmHg) divided by the fraction of inspired oxygen (FiO 2 is expressed as a fraction, not a percentage).
  • the “Horowitz index”, the “Carrico index”, the “P/F ratio” and “PFR” may be used interchangeably herein.
  • the PaO 2 /FiO 2 ratio may be determined using any suitable means known in the art and unless stated otherwise, the values stated herein refer to the PaO 2 /FiO 2 ratio at sea level or equivalent.
  • the skilled person would understand that, in practice, if the PaO 2 /FiO 2 ratio is measured at an altitude significantly above sea level, the measured PaO 2 /FiO 2 ratio of the subject to be treated may be adjusted to provide the equivalent value at sea level.
  • the PaO2/FiO2 ratio may be used to categorise the severity of the viral respiratory infection, wherein subjects suffering from a severe form of the infection or syndrome may benefit from treatment according to the invention to a greater extent than subjects with a less severe manifestation of the infection.
  • Subjects suffering from a severe form of the infection or syndrome may be viewed as subjects with a PaO2/FiO2 ratio of less than 300 mmHg, particularly less than 150 mmHg.
  • the subject to be treated has a PaO2/FiO2 ratio of less than 300 mmHg, which relates to a subject with Acute Respiratory Distress Syndrome (ARDS) in the Berlin definition.
  • the subject to be treated has a PaO2/FiO2 ratio of less than 250 mmHg, 200 mmHg, 150 mmHg or 100 mmHg.
  • the subject to be treated has a PaO2/FiO2 ratio of less than 200 mmHg or 100 mmHg.
  • the observational study described in the Examples below shows that subjects with mild or moderate forms of a viral respiratory disease (e.g. COVID-19), i.e.
  • the IL-18 antagonist is administered to the subject in an amount effective to reduce the amount of free IL-18 in the blood of the subject to that of an uninfected subject (e.g. a healthy subject), e.g.
  • the IL-18 antagonist is administered to the subject in an amount effective to reduce the amount of free IL-18 in the blood of the subject to a reference amount, wherein the reference amount is the amount of free IL-18 in the blood of a reference subject or a group of reference subjects, and wherein: (i) a reference subject is a subject that has a less severe manifestation of the same viral respiratory infection; and (ii) the reference amount is the amount of free IL-18 in the blood of the reference subject or group of reference subjects at the same or a similar time point of the infection.
  • a “reference subject” that has a less severe manifestation of the same viral respiratory infection refers to a subject that has milder symptoms of the viral respiratory syndrome associated with the infection at the same or a similar time point of the infection.
  • the reference subject has milder impairment of respiratory function in comparison to the subject to be treated.
  • respiratory function may be assessed by measuring the PaO2/FiO2 ratio and thus, in some embodiments, the reference subject has a PaO2/FiO2 ratio of 300 mmHg or higher, such as a PaO2/FiO2 ratio of about 300-400 mmHg, e.g. about 300-375 mmHg or 300-350 mmHg.
  • a reference subject that has a less severe manifestation of the same viral respiratory infection may be defined as a subject that survived to at least day 30, 45 or 60 (preferably day 60) of the infection (i.e. without treatment with an IL-18 antagonist as defined herein).
  • the reference amount does not need to be determined at the time of treatment, i.e. it may be a pre-determined amount.
  • the “time point of infection” refers to the number of days of symptoms, e.g. after the onset of symptoms as defined above.
  • a reference amount of free IL- 18 in the blood of the reference subject means that the reference amount is measured in a blood sample obtained from the reference subject on the same number of days of symptoms, e.g.
  • the reference amount may be the amount of free IL-18 in a blood sample obtained from a reference subject at any one of days 7-13 of the infection, preferably any one of days 8-12 or 9-11.
  • the reference amount is the amount of free IL-18 in a blood sample obtained from a reference subject at the same time point of infection as the subject to be treated. As the reference amount (i.e.
  • the reference amount may be a range calculated from the amount of free IL-18 in blood samples obtained from a group of reference subjects.
  • the blood samples may be obtained from the reference subjects in the group at a similar time point of infection to the subject to be treated, i.e. references subjects within the group may be at different time points of infection when the blood samples were obtained.
  • the reference amount is calculated from samples that were all obtained from reference subjects at a time point of infection within 3 days of the subject to be treated, preferably within 2 or 1 days of the subject to be treated.
  • the reference amount is calculated from samples that were all obtained from reference subjects at the same time point of infection as the subject to be treated.
  • the reference amount of free IL-18 in the blood of the reference subject or group of reference subjects is about 40-80 pg/ml, about 45-75 pg/ml or about 50-70 pg/ml.
  • the reference amount of free IL-18 in the blood of the reference subject or group of reference subjects is about 60-80 pg/ml, about 65-80 pg/ml or about 70-80 pg/ml.
  • the “amount effective to reduce the amount of free IL-18 in the blood of the subject to a reference amount”, i.e. the “therapeutically effective amount” refers to the amount of IL-18 antagonist needed to reduce the amount of free IL-18 in the blood of the subject to be treated to about 40-80 pg/ml, e.g. about 45-75 pg/ml or about 50-70 pg/ml. In some embodiments, it refers to the amount of IL-18 antagonist needed to reduce the amount of free IL-18 in the blood of the subject to be treated to about 60-80 pg/ml, about 65-80 pg/ml or about 70-80 pg/ml.
  • the therapeutically effective amount may result in the amelioration of the symptoms of the viral respiratory infection (e.g. COVID-19), related conditions and/or complications arising from same or manifestations thereof.
  • Undesirable effects e.g. side effects, may sometimes manifest along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "therapeutically effective amount”.
  • the absolute amount of IL-18 antagonist to be administered to the subject to be treated will vary from subject to subject and will depend on several factors.
  • the clinical study shows that there is a correlation between the amount of free IL-18 in the blood of the infected subject (e.g. COVID-19 subject) and their PaO2/FiO2 ratio.
  • the PaO2/FiO2 ratio may be used as a marker to indicate (i.e. as a surrogate or proxy for) the amount of IL-18 antagonist to be administered, i.e. the amount by which the blood amount of free IL-18 should be reduced in the subject.
  • the upper level of free IL-18 in the blood of the subject may be up to about 120 pg/ml.
  • the therapeutically effective amount of IL-18 antagonist is the amount needed to reduce the amount free IL-18 in the blood of the subject to be treated to the reference amount defined above, e.g.
  • the amount free IL-18 in the blood of the subject by about 40-80 pg/ml, such as about 45-75 pg/ml or about 50-70pg/ml, e.g. about 40-60 pg/ml, about 40-55 pg/ml or about 40-50 pg/ml.
  • the PaO 2 /FiO 2 ratio of the subject to be treated is 100 ⁇ 200 mmHg (i.e.100 or more mmHg and less than 200 mmHg)
  • the upper level of free IL-18 in the blood of the subject may be about 150 pg/ml.
  • the therapeutically effective amount of IL-18 antagonist is the amount needed to reduce the amount free IL-18 in the blood of the subject to be treated to the reference amount defined above, e.g. to reduce the amount free IL-18 in the blood of the subject by about 70-110 pg/ml, such as about 75-105 pg/ml or about 80-100pg/ml, , e.g. about 70-90 pg/ml, about 70-85 pg/ml or about 70-80 pg/ml.
  • the upper level of free IL-18 in the blood of the subject may be about 160 pg/ml.
  • the therapeutically effective amount of IL-18 antagonist is the amount needed to reduce the amount free IL-18 in the blood of the subject to be treated to the reference amount defined above, e.g. to reduce the amount free IL-18 in the blood of the subject by about 80-120 pg/ml, such as about 85-115 pg/ml or about 90-110pg/ml, e.g.
  • the amount of free IL-18 in the blood of the subject is at least about 80 pg/ml, such as about 80-300 pg/ml, 80-250 pg/ml or 80- 200 pg/ml. In some embodiments, the amount of free IL-18 in the blood of the subject is at least about 90 pg/ml, 95pg/ml, 100 pg/ml, 105 pg/ml, 110 pg/ml or 120 pg/ml, e.g. above 120 pg/ml.
  • the amounts specified above are based on data from a particular time point in the context of a specific infection (i.e. COVID-19) it is expected that the values are applicable to all viral respiratory infections and time points of infection. However, in some particular embodiments, the amounts specified are particularly applicable to the treatment of subjects with COVID-19 and/or wherein the IL-18 antagonist is first administered at least about 10 days after the subject develops one or more symptoms of the viral respiratory infection, e.g. wherein the IL-18 antagonist is first administered at least about 14 days (e.g.14-20 days) after the subject develops one or more symptoms of the viral respiratory infection. While the amount of IL-18 antagonist to be administered may be based on the PaO 2 /FiO 2 ratio (e.g.
  • the amount of free IL-18 may be measured prior to administration of the IL-18 antagonist and used to calculate the amount of IL-18 antagonist to be administered to the subject to reduce the level of free IL-18 to the reference amount.
  • the amount of free IL-18 may be measured after administration of the IL-18 antagonist to determine whether the level of free IL-18 is within the required range, i.e. within the reference amount range defined herein.
  • the amount of free IL-18 may be measured prior to and after administration of the IL-18 antagonist, e.g. to monitor the subject.
  • the invention involves: (i) assaying the amount of free IL-18 in a blood sample obtained from the subject to be treated; (ii) comparing the amount of free IL-18 in the blood sample to the reference amount; and (iii) administering the IL-18 antagonist to the subject to be treated when the amount of free IL-18 in the blood sample obtained from the subject to be treated is above the reference amount, e.g. at least about 20%, 30%, 40% or more above the reference amount (e.g. the upper limit of the reference amount defined herein, such as above about 70 pg/ml, preferably above about 80 pg/ml).
  • the amount of free IL-18 in the blood of a subject may be determined using assays, e.g.
  • the method for assaying the amount of free IL-18 in a sample from a subject is an immunoassay, such as an enzyme-linked immunosorbent assay (ELISA) and radio-immunoassay (RIA), which are routinely used in laboratories.
  • an immunoassay such as an enzyme-linked immunosorbent assay (ELISA) and radio-immunoassay (RIA)
  • ELISA enzyme-linked immunosorbent assay
  • RIA radio-immunoassay
  • the amount of free IL-18 in a sample may be determined by separately measuring the levels of total IL-18, IL-18BP and IL-18-BP-Complex (e.g. as described in the Examples, i.e. by ELISA) followed by calculating the levels of free IL-18 as per the law of Mass Action.
  • the level of free IL-18 may be calculated from the levels of total IL-18, IL-18BP and IL-18-BP-Complex on the basis that IL-18 and IL-18BP bind with a 1:1 stoichiometry with a dissociation constant (K d ) of 0.05nM.
  • K d dissociation constant
  • a dissociation constant (K d ) of 0.4nM may be used, although this is less preferred.
  • Values of free IL-18 determined using this method may be viewed as “calculated values” or “calculated amounts” of free IL-18 and may differ from amounts measured using other means.
  • all amounts of free IL-18 specified herein refer to the calculated amounts, which have been calculated using the dissociation constant (K d ) of 0.05nM in accordance with the latest experimental evidence of the dissociation constant (Girard C, Rech J, Brown M, Allali D, Roux-Lombard P, Spertini F, Schiffrin EJ, Schett G, Manger B, Bas S, Del Val G. Elevated serum levels of free interleukin-18 in adult-onset Still’s disease.
  • the absolute free IL-18 amounts recited herein refer to amounts calculated per the law of Mass Action using a dissociation constant (K d ) for IL-18 binding to IL-18BP of 0.05nM, e.g. using the method described in the Examples.
  • K d dissociation constant
  • IL-18BP IL-18 binding protein
  • a therapeutically effective amount readily may be determined based on the reference amounts described above, the body surface area (BSA) of the subject to be treated and the molecular weight of the antagonist.
  • BSA Body surface area
  • Mosteller formula ⁇ ([height(cm) x weight(kg)]/3600)
  • treatment may involve administration of one or more doses of the IL-18 antagonist, i.e. to reduce the level of free IL-18 to the reference amount and optionally maintain the level of free IL-18 at the reference amount, e.g. over the course of the treatment.
  • each dose may be a different amount based on the level of free IL-18 in the blood of the subject to be treated and thus the specific dosage regimen of the IL-18 antagonist will be determined by the attending physician.
  • the PaO2/FiO2 ratio conveniently may be used as a proxy (i.e. indicator) for the level of free IL-18 in the blood of the subject, especially between days 15-19 of symptoms (disease course).
  • each dose may be based on the PaO 2 /FiO 2 ratio of the subject to be treated, wherein a decrease in the PaO 2 /FiO 2 ratio may prompt the administration of second or subsequent dose, optionally wherein the dose is higher than the previous dose.
  • an increase in the PaO 2 /FiO 2 ratio may preclude the administration of second or subsequent dose or prompt the administration of a lower second or subsequent dose relative to the previous dose.
  • administration of the IL-18 antagonist may continue until amelioration of one or more of the symptoms of the viral respiratory infection (e.g. COVID-19), related conditions and/or complications arising from same or manifestations thereof, e.g. until one or more symptoms has improved or abated, such as until the subject has recovered.
  • administration of the IL-18 antagonist may continue until the PaO 2 /FiO 2 ratio of the subject being treated increases to 300 mmHg or more, preferably at least 350 mmHg or more.
  • administration of the IL-18 antagonist may continue after day 25, 30, 35, 40, 45 or 50 of symptoms.
  • administration of the IL- 18 antagonist may continue after 25, 30, 35, 40, 45, 50 or more days after the onset of symptoms.
  • a viral respiratory infection such as SARS CoV2
  • may exhibit only symptoms associated with the first phase of the infection e.g. intermittent fevers, lethargy and a new onset continuous cough, and may be characterised as having a “mild” infection, e.g. mild COVID-19.
  • Such patients may recover without the need for treatment.
  • the present invention therefore finds particular utility in the treatment of subjects having a severe form of the viral respiratory syndrome caused by the viral respiratory infection.
  • the subject to be treated has a severe form of the viral respiratory syndrome caused by the viral respiratory infection as defined above.
  • the subject to be treated has severe manifestation of COVID-19, i.e. a PaO2/FiO2 ratio of less than 300 mmHg.
  • a subject with a severe form of the viral respiratory syndrome caused by the viral respiratory infection may be defined as having a blood amount (concentration) of free IL-18 of at least about 80pg/ml, such as at least about 90pg/ml, 100pg/ml, 110pg/ml or 120pg/ml.
  • the amount of free IL-18 in the blood of the subject to be treated is 100-300pg/ml, 120- 300pg/ml or 140-300pg/ml.
  • the viral respiratory infection is severe Coronavirus Disease 2019 (COVID-19).
  • the subject to be treated may have other characteristics associated with an increased risk of developing a severe form of a viral respiratory syndrome caused by the viral respiratory infection.
  • subjects above the age of 65, with hypertension, type II diabetes, metabolic syndrome, coronary artery disease, atherosclerosis or a combination thereof may have amount of free IL-18 in their blood that is higher than the level in a healthy subject or may be more susceptible to developing high levels of free IL-18, e.g.
  • the subject to be treated may be above 65 years of age and have hypertension, type II diabetes, metabolic syndrome, coronary artery disease, atherosclerosis or a combination thereof, preferably wherein the subject is above 65 years of age and has hypertension and/or type II diabetes and optionally one or more of metabolic syndrome, coronary artery disease and atherosclerosis.
  • the term metabolic syndrome typically refers to subjects having more than one condition, e.g. at least three conditions, selected from abdominal obesity, high blood pressure (hypertension), high blood sugar (e.g. diabetes), high serum triglycerides, and low serum high-density lipoprotein (HDL).
  • the subject to be treated has more than one condition selected from abdominal obesity, high blood pressure, high blood sugar (e.g. diabetes), high serum triglycerides, and low serum high-density lipoprotein (HDL).
  • abdominal obesity is a key sign of metabolic syndrome
  • the subject to be treated has abdominal obesity and one or more conditions (e.g.2, 3 or 4 conditions) selected from high blood pressure, high blood sugar (e.g. diabetes), high serum triglycerides, and low serum high-density lipoprotein (HDL).
  • the subject to be treated has high blood pressure and one or more conditions (e.g.2, 3 or 4 conditions) selected from abdominal obesity, high blood sugar (e.g.
  • the term “abdominal obesity” refers to a condition where excessive abdominal fat around the stomach and abdomen has built up to the extent that it is likely to have a negative impact on health. This is also known as central obesity and truncal obesity.
  • the terms “high blood pressure” and “hypertension” are used interchangeably herein and refer to a long-term medical condition in which the blood pressure in the arteries is persistently elevated. For adults, high blood pressure is present if the resting blood pressure is persistently at or above 130/80 mmHg or 140/90 mmHg. High blood pressure may be classified as primary (essential) hypertension or secondary hypertension.
  • Primary hypertension refers to high blood pressure due to nonspecific lifestyle factors (e.g. excess salt in the diet, excess body weight, smoking, and alcohol use) and genetic factors. Secondary hypertension refers to high blood pressure due to an identifiable cause, such as chronic kidney disease, narrowing of the kidney arteries, an endocrine disorder, or the use of birth control pills.
  • the subject to be treated has primary hypertension.
  • Subjects with metabolic syndrome have an increased risk of various disorders, particularly hypertension, diabetes mellitus type 2 and coronary artery disease. However, subjects with hypertension, diabetes mellitus type 2 and/or coronary artery disease do not necessarily also have metabolic syndrome.
  • the subject to be treated has hypertension, diabetes mellitus type 2, atherosclerosis and/or coronary artery disease without metabolic syndrome.
  • the subject to be treated has metabolic syndrome and optionally one or more other conditions selected from hypertension, diabetes mellitus type 2, coronary artery disease, atherosclerosis and a combination thereof.
  • Atherosclerosis is a disease in which the inside of an artery narrows due to the build-up of plaque and can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected.
  • CAD Coronary artery disease
  • CAD is also known as atherosclerotic heart disease, coronary heart disease (CHD) or ischemic heart disease (IHD).
  • CHD coronary heart disease
  • IHD ischemic heart disease
  • Diabetes mellitus type 2 also known as “type 2 diabetes” (T2D) and adult- onset diabetes, is a form of diabetes that is characterized by high blood sugar, insulin resistance, and relative lack of insulin.
  • Other characteristics associated with an increased risk of developing a severe form of a viral respiratory syndrome e.g. COVID-19
  • SARS CoV2 may include the age, ethnicity and/or gender of the subject, particularly in combination with an underlying condition as described above.
  • subjects with a high risk of developing a severe form of a viral respiratory syndrome include subjects with one or more of the following characteristics: (i) male; (ii) aged 50 years old or above, e.g.55, 60, 65 years old or above; and/or (iii) African or Indo-Pakistani Asian ethnicity. These characteristics, particularly age, are associated with increased levels of free IL-18, principally due to worsening innate immune system function.
  • the subject to be treated is at least 50 years old, e.g. 55, 60, 65 years old or above (i.e. an elderly subject).
  • treating“ or “treatment” as used herein refer broadly to any effect or step (or intervention) beneficial in the management of a clinical condition or disorder. Treatment therefore may refer to reducing, alleviating, ameliorating, slowing the development of, or eliminating one or more symptoms of the viral respiratory infection or syndrome that is being treated, relative to the symptoms prior to treatment, or in any way improving the clinical status of the subject.
  • a treatment may include any clinical step or intervention which contributes to, or is a part of, a treatment programme or regimen.
  • a treatment may include delaying, limiting, reducing or preventing the onset of one or more symptoms of the viral respiratory infection or syndrome, for example relative to the symptom prior to the treatment.
  • treatment explicitly includes both absolute prevention of occurrence or development of symptoms of the viral respiratory infection or syndrome, and any delay in the development of the viral respiratory infection or syndrome or symptom thereof, or reduction or limitation on the development or progression of the viral respiratory infection or syndrome or symptom thereof.
  • treatment refers to improving or increasing the PaO2/FiO2 ratio of the subject being treated to 300 mmHg or more, preferably at least 350 mmHg or more.
  • blockade of free IL- 18 functions to rebalance the inflammatory state of the patient as well as the innate immune system, thereby enabling the body to clear the viral infection.
  • treating the subject may be viewed as treating the immunopathology in the subject with a viral respiratory infection.
  • the term “blood sample” as used herein may refer to whole blood or a component or derivative thereof, e.g. peripheral whole blood or a component or derivative thereof.
  • the blood sample may be whole blood, serum or plasma.
  • the blood sample is diluted whole blood, which is a derivative of whole blood.
  • the blood sample may be maintained in the presence of an anticoagulant such as heparin, sodium citrate or ethylene diamine tetra acetic acid (EDTA).
  • an anticoagulant such as heparin, sodium citrate or ethylene diamine tetra acetic acid (EDTA).
  • IL-18 also known as interferon-gamma inducing factor, is a cytokine produced by activated macrophages, Kupffer cells and other cells.
  • IL-18 binds to the IL-18 receptor (IL-18R) and induces cell-mediated immunity. Defects (e.g. knock-out) of the IL-18 receptor or IL-18 lead to impaired natural killer (NK) cells activity and impaired Th1 responses.
  • IL-18 as used herein typically refers to human IL-18.
  • IL-18 antagonist or “IL-18 inhibitor” are used interchangeably herein and refer to agents capable of directly or indirectly inhibiting, reducing or blocking the activity or function of IL-18, e.g. IL-18 signalling.
  • direct inhibitors include agents that interact directly with IL-18 to inhibit, reduce or block the activity or function of IL-18. Such agents may work via competitive inhibition, uncompetitive inhibition, on-competitive inhibition or mixed inhibition.
  • the IL-18 antagonist disrupts the interaction between IL-18 and its receptor.
  • an IL-18 antagonist may interact with the IL- 18 receptor.
  • indirect inhibitors do not interact directly with IL-18.
  • indirect inhibitors may inhibit, reduce or block the activity or function of IL-18 by reducing the expression of the gene encoding the IL-18.
  • the IL-18 antagonist may interfere with the processing of IL-18 precursor into its active form, e.g.
  • the IL-18 antagonist may be a caspase-I inhibitor, such as the oral prodrug VX-765.
  • the IL-18 antagonist directly inhibits, reduces or blocks the activity or function of IL-18.
  • the IL-18 antagonist binds to free IL-18 to inhibit the activity or function of IL-18.
  • a combination of IL-18 antagonists may be used to effect inhibition or blockage of IL-18 activity or signalling.
  • agent may be used interchangeably herein to refer to a substance that induces a desired pharmacological and/or physiological effect. The terms also encompass pharmaceutically acceptable and pharmacologically active forms thereof, including salts.
  • Proteinaceous, non-proteinaceous (e.g. chemical entities) and nucleic acid molecule IL-18 antagonists may be used in treatments described herein.
  • Proteinaceous molecules include peptides, polypeptides and proteins. The terms polypeptide and protein are used interchangeably herein.
  • Non-proteinaceous molecules include small, intermediate or large chemical molecules as well as molecules identified from natural product screening or the screening of chemical libraries.
  • Natural product screening includes the screening of extracts or samples from any suitable source of natural products including plants, microorganisms, soil, river beds, coral and aquatic environments for molecules or groups of molecules which have an effect on IL-18 activity or the level of IL-18 gene expression.
  • Nucleic acid molecule agents include RNA, cDNA, genomic DNA, synthetic forms and mixed polymers, both sense and antisense strands, and may be chemically or biochemically modified or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those skilled in the art.
  • synthetic molecules that mimic polynucleotides in their ability to bind to a designated sequence via hydrogen binding and other chemical interactions. Such molecules are known in the art and include, for example, those in which peptide linkages substitute for phosphate linkages in the backbone of the molecule.
  • the IL-18 antagonist is a proteinaceous agent, e.g. a protein.
  • the IL-18 antagonist is a protein that binds selectively to IL-18 or the IL-18 receptor, preferably a protein that binds selectively to IL-18, preferably free IL-18.
  • Proteins that bind to and inhibit IL-18 are well-known in the art.
  • IL-18 Binding Protein IL-18BP
  • IL-18BP IL-18 Binding Protein
  • numerous antibodies that bind to IL-18 have been developed and any such antibody may find utility in the treatments described herein.
  • IL-18 antibodies are described in WO 2012/085015 and WO 2016/139297 (both incorporated herein by reference, particularly with respect to the IL-18 antibodies described therein) and may find utility in the treatments described herein.
  • methods for producing antibodies that specifically bind to a target protein are well-known in the art and described further below.
  • native mammalian IL-18 binding proteins e.g. human isoforms a-d, SEQ ID NOs: 1-4
  • numerous infectious agents e.g. viruses, have evolved IL-18 binding proteins.
  • IL-18 binding proteins have been identified in Molluscum contagiosum virus subtype 1 (MC51L, MC53L, and MC54L, e.g. GenBank accession number CAB89814.1, SEQ ID NO: 5), Vaccinia virus (e.g. GenBank accession number CAB89842.1, SEQ ID NO: 6), Ectromelia virus (e.g. GenBank accession number CAB89805.1, SEQ ID NO: 7), Lumpy skin disease virus (e.g. GenBank accession number AAK43555.1, SEQ ID NO: 8) and Cowpox virus (e.g. GenBank accession number ARB50252.1, SEQ ID NO: 9).
  • Vaccinia virus e.g. GenBank accession number CAB89842.1, SEQ ID NO: 6
  • Ectromelia virus e.g. GenBank accession number CAB89805.1, SEQ ID NO: 7
  • Lumpy skin disease virus e.g. GenBank accession number AAK43555.1
  • the IL-18 antagonist is a mammalian IL-18 binding protein (IL-18BP), preferably a human IL-18 binding protein, or an IL-18- binding fragment or variant thereof (e.g. an isoform of IL-18BP).
  • IL-18BP mammalian IL-18 binding protein
  • the IL-18 antagonist is recombinant human IL-18BP (e.g. Tadekinig alfa ).
  • the IL-18 antagonist is a viral IL-18 binding protein or an IL-18-binding fragment or variant thereof.
  • the IL-18 antagonist is an IL-18 binding protein comprising: (i) an amino acid sequence as set forth in any one of SEQ ID NOs: 1-9, preferably any one of SEQ ID NOs: 1-4; (ii) an amino acid sequence with at least 70% sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs: 1-9, preferably any one of SEQ ID NOs: 1-4; or (iii) a IL-18 binding fragment of (i) or (ii).
  • a "fragment" may comprise at least 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98 or 99% of the amino acids of the protein from which it is derived.
  • Said fragment may be obtained from central, N-terminal or C-terminal portions of the sequence. Whilst the size of the fragment will depend on the size of the original protein, in some embodiments the fragments may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40 or more amino acid residues shorter than the sequence from which it is derived, e.g.1-40, 2-35, 3-30, 4-25 amino acid residues shorter than the sequence from which it is derived. As referred to herein a “variant” or “derivative” of a sequence is at least 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical to the sequence to which it is compared. Sequence identity may be determined by, e.g.
  • sequence identity related proteins i.e. variants or derivatives
  • the proteins with sequences as set forth in the SEQ ID NOs. may be modified without affecting the sequence of the polypeptide.
  • fragments as described herein are functional equivalents. Preferably these fragments satisfy the identity (relative to a comparable region) conditions mentioned herein.
  • the protein fragment and/or variant may show some reduced efficacy in performing the function relative to the parent molecule (i.e. the molecule from which it was derived, e.g. by amino acid substitution), but preferably is as efficient or is more efficient.
  • functional equivalence refers to a protein that is effective at binding selectively to, and antagonising the function of, IL-18, preferably free IL-18.
  • the fragment or variant is at least 30, 50, 70 or 90% as effective as the parent protein.
  • Functionally-equivalent proteins which are related to or derived from the parent protein may be obtained by modifying the parent amino acid sequence by single or multiple amino acid substitution, addition and/or deletion (providing they satisfy the above-mentioned sequence identity requirements), but without destroying the molecule's function.
  • the parent sequence has less than 60 substitutions, additions or deletions, e.g.
  • any substitutions that are present in the variant protein relative to the parent protein may be conservative amino acid substitutions.
  • a conservative amino acid substitution refers to the replacement of an amino acid by another which preserves the physicochemical character of the polypeptide (e.g. D may be replaced by E or vice versa, N by Q, or L or I by V or vice versa).
  • D may be replaced by E or vice versa, N by Q, or L or I by V or vice versa
  • the substituting amino acid has similar properties, e.g. hydrophobicity, hydrophilicity, electronegativity, bulky side chains etc. to the amino acid being replaced.
  • Isomers of the native L-amino acid e.g. D-amino acids may be incorporated.
  • the proteins that bind to IL-18 e.g. IL-18 binding proteins, antibodies
  • IL-18 bind selectively to IL-18, preferably free IL-18.
  • the term “binds selectively” refers to the ability of the protein to bind non-covalently (e.g. by van der Waals forces and/or hydrogen-bonding) to IL-18 with greater affinity and/or specificity than to other components, e.g. other components in the sample (e.g. blood, tissue) in which the IL-18 is present.
  • the IL-18 binding protein may alternatively be viewed as binding specifically and reversibly to IL-18, preferably free IL-18, under suitable conditions.
  • the term free IL-18 refers to IL-18 that is not already bound to its respective IL-18 binding protein or IL-18 receptor. Binding to IL-18 may be distinguished from binding to other molecules (e.g. peptides or polypeptides) present in a sample.
  • the protein that binds to IL-18 e.g. IL-18 binding protein, antibody
  • the protein that binds to IL-18 either does not bind to other molecules (e.g. peptides or polypeptides) present in a sample or does so negligibly or non- detectably that any such non-specific binding, if it occurs, readily may be distinguished from binding to IL-18.
  • the protein that binds to IL-18 binds to molecules other than IL-18
  • binding affinity must be less than the binding affinity of the IL-18 binding protein for IL-18.
  • the binding affinity of a protein that binds to IL-18 (e.g. an IL-18 binding protein, antibody) for IL-18 should be at least an order of magnitude more than the other molecules (i.e. non-cognate molecules) present in a sample.
  • the binding affinity of the protein that binds to IL-18 e.g.
  • IL-18 binding protein, antibody for IL-18 should be at least 2, 3, 4, 5, or 6 orders of magnitude more than the binding affinity for other molecules (e.g. peptides or polypeptides).
  • selective or specific binding refers to affinity of the protein that binds to IL-18 (e.g. IL-18 binding protein, antibody) for IL-18 where the dissociation constant of the protein that binds to IL-18 (e.g. IL-18 binding protein, antibody) for IL-18 is less than about 10 -3 M.
  • the dissociation constant of the protein that binds to IL-18 e.g.
  • IL-18 binding protein, antibody) for IL-18 is less than about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M or 10 -9 M.
  • the IL-18 binding protein fragments and variants described above compete with the parent protein from which they are derived for binding to IL-18, preferably free IL-18.
  • the IL-18 binding protein fragments and variants may be viewed as "competing IL-18 binding protein fragments and variants", which term refers to proteins that bind to about, substantially or essentially the same, or even the same, epitope as the parent protein.
  • “Competing IL-18 binding protein fragments and variants” include proteins with overlapping epitope specificities.
  • polypeptides described herein may be an isolated, purified, recombinant or synthesised polypeptides.
  • polypeptide is used herein interchangeably with the term "protein".
  • polypeptide or protein typically includes any amino acid sequence comprising at least 40 consecutive amino acid residues, e.g. at least 50, 60, 70, 80, 90, 100, 150 amino acids, such as 40-1000, 50-900, 60-800, 70-700, 80-600, 90-500, 100-400 amino acids.
  • the IL-18 antagonist is an antibody that binds selectively (as defined above) to IL-18, preferably free IL-18.
  • the IL-18 antagonist is an antibody that effectively competes with IL-18 binding protein (e.g. any one of the IL-18 binding proteins described herein, preferably one or more (e.g. all) of SEQ ID NOs: 1-4) for binding to IL-18, i.e. free IL-18.
  • the antibody binds to about, substantially or essentially the same, or even the same, epitope as IL-18 binding protein, preferably the same epitope as any one of SEQ ID NOs: 1-4.
  • the immunological binding reagents encompassed by the term "antibody” extend to all antibodies and antigen binding fragments thereof, including whole antibodies, dimeric, trimeric and multimeric antibodies; bispecific antibodies; chimeric antibodies; recombinant and engineered antibodies, and fragments thereof.
  • antibody is thus used to refer to any antibody-like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabody; kappa(lambda) bodies (scFv-CL fusions); Bispecific T-cell Engager (BiTE) (scFv- scFv tandems to attract T cells); dual variable domain (DVD)-Ig (bispecific format); small immunoprotein (SIP) (kind of minibody); SMIP ("small modular immunopharmaceutical" scFv-
  • Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab fragments.
  • Papain digestion can lead to the formation of Fab fragments.
  • Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well-known and described in the art. The antibodies or antibody fragments can be produced naturally or can be wholly or partially synthetically produced. Thus, the antibody may be from any appropriate source, for example recombinant sources and/or produced in transgenic animals or transgenic plants, or in eggs using the IgY technology.
  • the antibody molecules can be produced in vitro or in vivo.
  • the antibody or antibody fragment comprises an antibody light chain variable region (VL) that comprises three CDR domains and an antibody heavy chain variable region (VH) that comprises three CDR domains.
  • VL and VH generally form the antigen binding site.
  • An "Fv" fragment is the minimum antibody fragment that contains a complete antigen-recognition and binding site. This region has a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. It is in this configuration that the three hypervariable regions (CDRs) of each variable domain interact to define an antigen-binding site on the surface of the VH- VL dimer.
  • CDRs hypervariable regions confer antigen-binding specificity to the antibody.
  • constructs smaller than the above classical antibody fragment are known to be effective.
  • camelid antibodies have an extensive antigen binding repertoire but are devoid of light chains.
  • results with single domain antibodies comprising VH domains alone or VL domains alone show that these domains can bind to antigen with acceptably high affinities.
  • three CDRs can effectively bind antigen.
  • a single CDR, or two CDRs can effectively bind antigen.
  • two CDRs can effectively bind antigen, and even confer superior properties than possessed by the parent antibody.
  • two CDRs from a parent antibody may retain the antigen recognition properties of the parent molecule but have a superior capacity to penetrate tumours.
  • Joining these CDR domains with an appropriate linker sequence e.g., from VH FR2 to orientate the CDRs in a manner resembling the native parent antibody produced even better antigen recognition.
  • antigen binding antibody mimetics comprising two CDR domains (preferably one from a VH domain and one from a VL domain, more preferably, with one of the two CDR domains being a CDR3 domain) orientated by means of an appropriate framework region to maintain the conformation found in the parent antibody.
  • preferred antibodies of the invention might comprise six CDR regions (three from a light chain and three from a heavy chain), antibodies with fewer than six CDR regions and as few as one or two CDR regions are encompassed by the invention.
  • antibodies with CDRs from only the heavy chain or light chain are also contemplated.
  • the antibody or antibody fragment comprises all or a portion of a heavy chain constant region, such as an IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgE, IgM or IgD constant region.
  • a heavy chain constant region such as an IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgE, IgM or IgD constant region.
  • the heavy chain constant region is an IgG1 heavy chain constant region, or a portion thereof.
  • the antibody or antibody fragment can comprise all or a portion of a kappa light chain constant region or a lambda light chain constant region, or a portion thereof. All or part of such constant regions may be produced naturally or may be wholly or partially synthetic. Appropriate sequences for such constant regions are well known and documented in the art.
  • the antibodies of the invention are typically referred to herein as “full length” antibodies or “whole” antibodies.
  • Antibodies containing an Fc region are preferred for therapeutic uses in vivo.
  • the antibodies of the invention are monoclonal antibodies, which may be humanised or human monoclonal antibodies.
  • human or humanised antibodies generally have at least three potential advantages for use in human therapy. First, the human immune system should not recognize the antibody as foreign. Second, the half-life in the human circulation will be similar to naturally occurring human antibodies, allowing smaller and less frequent doses to be given. Third, because the effector portion is human, it will interact better with the other parts of the human immune system.
  • Non-human antibodies may be humanised in known ways, for example by inserting the CDR regions of said non-human antibodies into the framework of human antibodies.
  • Humanised antibodies can be made using the techniques and approaches described in Verhoeyen et al (1988) Science, 239, 1534-1536, and in Kettleborough et al, (1991) Protein Engineering, l4(7), 773-783.
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • the humanised antibody will contain variable domains in which all or most of the CDR regions correspond to those of a non-human immunoglobulin, and framework regions which are substantially or completely those of a human immunoglobulin consensus sequence.
  • Completely human antibodies may be produced using recombinant technologies. Typically large libraries comprising billions of different antibodies are used. In contrast to the previous technologies employing chimerisation or humanisation of e.g. murine antibodies this technology does not rely on immunisation of animals to generate the specific antibody. Instead the recombinant libraries comprise a huge number of pre-made antibody variants wherein it is likely that the library will have at least one antibody specific for any antigen. Thus, in the context of the present invention, a competing antibody having the desired binding characteristics can be identified using such libraries. In order to find the good binder in a library in an efficient manner, various systems where phenotype i.e. the antibody or antibody fragment is linked to its genotype i.e.
  • phage display system where antibody fragments are expressed, displayed, as fusions with phage coat proteins on the surface of filamentous phage particles, while simultaneously carrying the genetic information encoding the displayed molecule.
  • Phage displaying antibody fragments specific for a particular antigen may be selected through binding to the antigen in question. Isolated phage may then be amplified and the gene encoding the selected antibody variable domains may optionally be transferred to other antibody formats, such as e.g. full-length immunoglobulin, and expressed in high amounts using appropriate vectors and host cells well known in the art.
  • the “human” antibodies can be made by immunising transgenic mice which contain, in essence, human immunoglobulin genes (Vaughan et al (1998) Nature Biotechnol.16, 535-539).
  • the "human” and “humanised” antibodies of the invention may include amino acid residues not encoded by human sequences, e.g., mutations introduced by random or site directed mutations in vitro, for example mutations introduced by in vitro cloning or PCR.
  • Such mutations are mutations that involve conservative substitutions or other mutations (non-conservative substitutions, additions and/or deletions) in a small number of residues of the antibody, e.g., in up to 5, 4, 3, 2 or 1 of the residues of the antibody, preferably e.g., in up to 5, 4, 3, 2 or 1 of the residues making up one or more of the CDRs of the antibody.
  • Certain examples of such "human” and “humanised” antibodies include antibodies and variable regions that have been subjected to standard modification techniques to reduce the amount of potentially immunogenic sites.
  • the "human” and “humanised” antibodies of the invention include sequences derived from and related to sequences found in humans, but which may not naturally exist within the human antibody germline repertoire in vivo.
  • human and humanised antibodies of the present invention include proteins comprising human consensus sequences identified from human sequences, or sequences substantially homologous to human sequences.
  • the human and humanised antibodies of the present invention are not limited to combinations of VH, VL, CDR or FR regions that are themselves found in combination in human antibody molecules.
  • the human and humanised antibodies of the invention can include or correspond to combinations of such regions that do not necessarily exist naturally in humans.
  • the human antibodies may be fully human antibodies.
  • "Fully human" antibodies, as used herein are antibodies comprising "human" variable region domains and/or CDRs, as defined above, without substantial non-human antibody sequences or without any non-human antibody sequences.
  • antibodies comprising human variable region domains and/or CDRs "without substantial non-human antibody sequences” are antibodies, domains and/or CDRs in which only up to 5, 4, 3, 2 or 1 amino acids are amino acids that are not encoded by human antibody sequences.
  • "fully human” antibodies are distinguished from “humanised” antibodies, which are based on substantially non-human variable region domains, e.g., mouse variable region domains, in which certain amino acids have been changed to better correspond with the amino acids typically present in human antibodies.
  • the "fully human” antibodies of the invention may be human variable region domains and/or CDRs without any other substantial antibody sequences, such as being single chain antibodies.
  • the "fully human” antibodies of the invention may be human variable region domains and/or CDRs integral with or operatively attached to one or more human antibody constant regions.
  • Certain preferred fully human antibodies are IgG antibodies with the full complement of IgG constant regions.
  • "human” antibodies of the invention will be part- human chimeric antibodies.
  • Part-human chimeric antibodies are antibodies comprising "human” variable region domains and/or CDRs operatively attached to, or grafted onto, a constant region of a non-human species, such as rat or mouse. Such part-human chimeric antibodies may be used, for example, in pre- clinical studies, wherein the constant region will preferably be of the same species of animal used in the pre-clinical testing.
  • part-human chimeric antibodies may also be used, for example, in ex vivo diagnostics (e.g. in the method for selecting a subject for treatment described above), wherein the constant region of the non-human species may provide additional options for antibody detection.
  • proteinaceous IL-18 antagonists are preferred, the skilled person will understand that other antagonists may find utility in the treatment of the invention.
  • nucleic acid molecules can be used to inhibit IL-18 activity and/or signalling indirectly.
  • sense and/or antisense nucleic acid molecules directed to the IL-18 or IL-18 receptor (IL-18R) gene or mRNA are contemplated as IL-18 antagonists.
  • Such sense or antisense molecules include molecules that hybridise to any portion of the coding or non-coding regions including leader sequence and selected introns or exons of the IL-18 or IL18R gene or mRNA.
  • Sense and antisense molecules of 20 to 30 nucleotide basis in length are particularly contemplated, e.g. siRNA molecules directed to IL-18 or IL18R encoding nucleic acids.
  • Small interfering RNA is a class of double-stranded RNA non- coding RNA molecules, 20-25 base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway.
  • the IL-18 antagonist is a nucleic acid molecule.
  • the IL-18 antagonist is a nucleic acid, e.g. an siRNA, that interferes with the expression of IL-18 or IL-18R, preferably IL-18.
  • the treatment described herein may utilize a combination of IL-18 antagonists, e.g. an IL-18 binding protein and an antibody to IL-18 or IL-18R. The amounts described above may be used for each antagonist agent in such combination therapies.
  • the IL-18 antagonist may be provided in pharmaceutical composition, which may be formulated according to any of the conventional methods known in the art and widely described in the literature. Thus, IL-18 antagonist may be incorporated, optionally together with other active substances, with one or more conventional carriers, diluents and/or excipients.
  • the pharmaceutical composition described herein may be administered systemically or locally to the subject using any suitable means and the route of administration will depend on formulation of the pharmaceutical composition. In some embodiments, systemic administration may particularly useful. “Systemic administration” includes any form administration in which the agent (i.e. IL-18 antagonist) is administered to the body resulting in the whole body receiving the administered agent. Conveniently, systemic administration may be via enteral delivery (e.g. oral) or parenteral delivery (e.g.
  • “Local administration” refers to administration of the agent at the primary site of infection (e.g. the respiratory tract) or in the local vicinity of the primary site of infection, e.g. via inhalation. However, it will be evident that some forms of local administration may result in the whole body receiving the administered agent (e.g. inhalation). Thus, in some embodiments, the agent may be administered to provide an initial local effect and subsequent systemic effect.
  • systemic administration includes intra-articular, intravenous, intraperitoneal, and subcutaneous injection, infusion, as well as administration via oral, rectal and nasal routes, or via inhalation.
  • the IL-18 antagonist may be provided and/or formulated for intranasal, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, intraurinary tract, intrarectal, intravaginal, sublingual, intrabronchial, intrapulmonary, transdermal or intramuscular administration.
  • the IL-18 antagonist i.e. pharmaceutical composition
  • the pharmaceutical composition may be provided as a liquid, liquid spray, microspheres, semisolid, gel, or powder for transmucosal administration, e.g.
  • compositions intranasal, buccal, oral transmucosal, intratracheal, intraurinary tract, intravaginal, sublingual, intrabronchial, intrapulmonary and/or transdermal administration.
  • the composition may be in a solid dosage form for buccal, oral transmucosal and/or sublingual administration.
  • Intranasal, buccal, oral intratracheal, intraurinary tract, intravaginal, transmucosal and sublingual administrations lead to the disintegration of the composition as described herein in an oral cavity at body temperature and optionally may adhere to the body tissue of the oral cavity.
  • composition as disclosed herein further may include one or more excipient, diluent, binder, lubricant, glidant, disintegrant, desensitizing agent, emulsifier, mucosal adhesive, solubilizer, suspension agent, viscosity modifier, ionic tonicity agent, buffer, carrier, surfactant, flavor, or mixture thereof.
  • the composition is formulated as a parenteral, intravenous, tablet, pill, bioadhesive patch, drops, sponge, film, lozenge, hard candy, wafer, sphere, lollipop, disc-shaped structure, suppository or spray.
  • Transmucosal administration is generally rapid because of the rich vascular supply to the mucosa and the lack of a stratum corneum in the epidermis. Such drug transport typically provides a rapid rise in blood concentrations, and similarly avoids the enterohepatic circulation and immediate destruction by gastric acid or partial first-pass effects of gut wall and hepatic metabolism. Drugs typically need to have prolonged exposure to a mucosal surface for significant drug absorption to occur. Transmucosal routes can also be more effective than the oral route in that these routes can provide for relatively faster absorption and onset of therapeutic action.
  • the transmucosal routes can be preferred for use in treating patients who have difficulty in swallowing tablets, capsules, or other oral solids, or those who have disease-compromised intestinal absorption.
  • drug absorption can be delayed or prolonged.
  • the sublingual route can provide a rapid onset of action where uptake may be almost as rapid as if an intravenous bolus were administered because of the high permeability of the rich blood supply.
  • the intranasal compositions can be administered by any appropriate method according to their form.
  • a composition including microspheres or a powder can be administered using a nasal insufflator device.
  • An insufflator produces a finely divided cloud of the dry powder or microspheres.
  • the insufflator is preferably provided with a mechanism to ensure administration of a substantially fixed amount of the composition.
  • the powder or microspheres can be used directly with an insufflator, which is provided with a bottle or container for the powder or microspheres.
  • the powder or microspheres can be filled into a capsule such as a gelatin capsule, or other single dose device adapted for nasal administration.
  • the insufflator preferably has a mechanism to break open the capsule or other device.
  • the composition can provide an initial rapid release of the active ingredient followed by a sustained release of the active ingredient, for example, by providing more than one type of microsphere or powder.
  • alternative methods suitable for administering a composition to the nasal cavity are well-known by the person of ordinary skill in the art. Any suitable method may be used. For a more detailed description of suitable methods reference is made to EP2112923, EP1635783, EP1648406, EP2112923 (the entire contents of which are incorporated by reference herein).
  • the pharmaceutical composition may be administered intranasally, i.e. by inhalation and, thus, may be formulated in a form suitable for intranasal administration, i.e. as an aerosol, dry powder formulation or a liquid preparation.
  • Suitable pharmaceutical carriers, excipients and/or diluents include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, or mixtures thereof.
  • Pharmaceutically acceptable carriers for liquid formulations are aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • oils are those of animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, olive oil, sunflower oil, fish-liver oil, another marine oil, or a lipid from milk or eggs.
  • the present invention also relates to transpulmonary administration by inhalation of the pharmaceutical composition as dry powder, gaseous or volatile formulations into systemic circulation via the respiratory tract. Absorption is virtually as rapid as the formulation can be delivered into the alveoli of the lungs, since the alveolar and vascular epithelial membranes are quite permeable, blood flow is abundant and there is a very large surface for adsorption.
  • aerosols may be delivered from pressure-packaged, metered-dose inhalers (MDIs).
  • MDIs metered-dose inhalers
  • the pharmaceutical composition will generally be administered in a mixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the chosen means of inhalation and standard pharmaceutical practice.
  • the IL-18 antagonist is provided as a dry powder composition, optionally together with at least one particulate pharmaceutically acceptable carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol or sorbitol.
  • the carrier is lactose, for example lactose monohydrate or anhydrous lactose.
  • the dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device, preferably in dosage units together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg.
  • a dry powder inhalation device which may be a single dose or multiple dose device, preferably in dosage units together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg.
  • the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation (MDDPI) device adapted to deliver.
  • MDDPI multi-dose dry powder inhalation
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media such as phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc.
  • Compositions comprising such carriers can be formulated by well-known conventional methods.
  • Suitable carriers may comprise any material which, when combined with the IL-18 antagonist, retains the biological activity.
  • Preparations for transmucosal administration may include sterile aqueous or non-aqueous solutions, suspensions, dry powder formulations and emulsions.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Transmucosal vehicles may include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Preservatives and other additives may also be present including, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • the pharmaceutical composition comprise proteinaceous carriers, like, e.g., serum albumin or immunoglobulin, preferably of human origin.
  • the pharmaceutical composition may also be administered as a controlled-release composition, i.e. a composition in which the active ingredient is released over a period of time after administration.
  • Controlled- or sustained-release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils).
  • the composition is an immediate- release composition, i.e. a composition in which all the active ingredient is released immediately after administration. Further examples for suitable formulations are provided in WO 2006/085983, the entire contents of which are incorporated by reference herein.
  • the pharmaceutical composition may be provided as liposomal formulations.
  • the technology for forming liposomal suspensions is well- known in the art.
  • the lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free.
  • the liposomes can be reduced in size, as through the use of standard sonication and homogenization techniques.
  • Liposomal formulations containing the pharmaceutical composition can be lyophilized to produce a lyophilizate which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • the pharmaceutical composition is a "ready to use" formulation that contains the IL-18 antagonist in dissolved or solubilized form and is intended to be used as such or upon further dilution in pharmaceutically acceptable (e.g. intravenous) diluents.
  • the pharmaceutical composition may be provided in a solid form, e.g. as a lyophilizate, to be dissolved in a suitable solvent to provide a liquid formulation.
  • the IL-18 antagonist e.g. protein
  • the IL-18 antagonist may be in the form of a salt, i.e. a pharmaceutically acceptable salt.
  • the IL-18 antagonist may be in the form of an acidic or basic salt.
  • the IL-18 antagonist is in a neutral salt form.
  • Pharmaceutically acceptable salts include pharmaceutical acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts, and sulfonate salts.
  • Acid addition salts include inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate.
  • metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.
  • ammonium salts are ammonium salt and tetramethylammonium salt.
  • organic amine addition salts are salts with morpholine and piperidine.
  • amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine.
  • Sulfonate salts include mesylate, tosylat and benzene sulfonic acid salts.
  • Pharmaceutically acceptable as referred to herein refers to ingredients that are compatible with other ingredients used in the methods or uses of the invention as well as physiologically acceptable to the recipient. In some embodiments of the invention, the patient may be subjected to other treatments prior to, contemporaneously with, or after the treatments of the present invention.
  • the patient may be treated with other procedures for the treatment of symptoms associated with the viral respiratory infection, e.g. assisted ventilation according to procedures known in the art.
  • the IL-18 antagonist may be administered in combination with other therapeutic agents for the treatment of symptoms associated with the viral respiratory disease or other underlying condition/comorbidity, e.g. metabolic syndrome, CAD, hypertension, diabetes etc.
  • the pharmaceutical composition containing the IL-18 antagonist may contain one or more additional therapeutic agents or, preferably, may be for administration with one or more additional therapeutic agents.
  • the pharmaceutical composition containing the IL-18 antagonist may contain or be administered with a further therapeutic agent useful in treating a viral invention, i.e. an antiviral agent.
  • oseltamivir and zanamivir are effective for treating influenza.
  • Ribavirin a guanosine analog that inhibits replication of many RNA and DNA viruses, may find utility in the treatment of patients with lower respiratory tract infection due to RSV.
  • Palivizumab a monoclonal antibody to RSV fusion protein, may be to treat RSV infection.
  • a suitable antiviral agent may be selected based on the viral infection.
  • the pharmaceutical composition containing the IL-18 antagonist may contain or be administered with a further therapeutic agent useful in treating a symptom of the infection, such as shortness of breath.
  • the further therapeutic agent may be an inhaled bronchodilator and/or corticosteroid.
  • the pharmaceutical composition containing the IL-18 antagonist may contain or be administered with a long-acting beta-adrenoceptor agonist (LABA), such as formoterol, and/or a steroid, such as beclomethasone or dexamethasone.
  • LPA beta-adrenoceptor agonist
  • the other therapeutic agents may be part of the same composition already comprising the IL-18 antagonist, in the form of a mixture, wherein the IL-18 antagonist and the other therapeutic agent are intermixed in or with the same pharmaceutically acceptable solvent and/or carrier or may be provided separately as part of a separate compositions, which may be offered separately or together in form of a kit of parts.
  • the IL-18 antagonist may be administered concomitantly with the other therapeutic agent separately, simultaneously or sequentially.
  • the IL-18 antagonist may be administered simultaneously with a first additional therapeutic agent or sequentially after or before administration of said first additional therapeutic agent. If the treatment regimen or schedule utilizes more than one additional therapeutic agent, the various agents may be partially administered simultaneously, partially sequentially in various combinations.
  • the therapeutic agents for use in combination with the IL-18 antagonist may be provided in pharmaceutical compositions as defined above and may be administered as defined above.
  • the compositions comprising additional therapeutic agents may comprise pharmaceutically acceptable excipients, solvents and diluents suitable for such formulations. The skilled person will be aware of suitable dosage ranges for any given additional therapeutic agent.
  • the additional therapeutic agent is administered to the subject in its typical dose range.
  • Figure 1 shows Free IL18 Levels Longitudinally against 60-day Mortality. In particular it shows free IL-18 levels (pg/ml) in subjects who died by day 60 (dotted line) and subjects who survived to day 60 (solid line). The grey band towards the bottom of the graph represents the mean value ⁇ standard error of free IL-18 in healthy controls.
  • Figure 2 shows Free IL18 in patients requiring ventilation, separated by 60- day mortality outcome. In particular it shows free IL-18 levels (pg/ml) in subjects who were ventilated and survived to day 60 (solid line) and subjects who were ventilated and died by day 60 (dotted line).
  • the grey band towards the bottom of the graph represents the mean value ⁇ standard error of free IL-18 in healthy controls.
  • Figure 3 shows Free IL-18 Levels: Ventilated or Died by Day 60 vs Not- Ventilated and Survived to day-60. In particular it shows free IL-18 levels (pg/ml) in subjects who died by day 60 or required ventilation (dotted line) and subjects who survived to day 60 and did not require ventilation (solid line).
  • the grey band towards the bottom of the graph represents the mean value ⁇ standard error of free IL-18 in healthy controls.
  • Figure 4 shows Day 15-19 PFR by Free IL-18 level.
  • PaO 2 /FiO 2 ratio (PFR) as per ARDS categories of severity versus free IL-18 levels (pg/ml) in blood samples taken between days 15-19 of COVID-19 disease.
  • Figure 5 shows age distribution across severity of disease (worst PF ratio).
  • Figure 8 shows the relationship between Hypertension and Day-60 Mortality across different severity levels of COVID-19 disease, as determined by Worst PFR recorded. Fisher’s Exact Test used to examine the significance of difference between those who died and those who survived in proportions of patients with comorbidity of hypertension.
  • Figure 10 shows patient BMI split according to age range (threshold: 60 years of age) against disease severity (worst PFR).
  • Figure 11 shows a Consort Diagram outlining the process of data collection described in Example 4.
  • Inclusion criteria enabled enrolment of 272 eligible patients, from whom 1,732 aliquots of serum and Ethylenediamine tetraacetic acid (EDTA) blood samples were obtained. Discarding of samples due to insufficient volumes for enzyme-linked immunosorbent assay (ELISA) left 1,523 aliquots, of which, 1,228 could be matched to day from symptom onset, from 206 cohort patients.
  • Mean fIL-18 level in 442 healthy, male volunteers is 58.6 pg/ml. Error bars represent standard error of the mean. Survivors (solid line): 499 samples from 165 patients. Non-survivors (dashed line): 162 samples from 40 patients.
  • Figure 13 shows a breakdown of Figure 12 IL-18 Binding Protein and Total IL-18 by Mortality: IL-18 Binding Protein (IL-18bp) (a; top) and Total IL-18 (b; bottom) by 60-day non-survivors (dashed line) and survival (solid line) categories.
  • IL-18bp levels are higher in the mortality group as compared to the survival group in the first two weeks of the disease before merging;
  • Total IL-18 levels are statistically indifferent up to day 14 of the disease, but thereafter diverge, with the mortality group showing higher levels, increasing to days 25-29 of the disease. Error bars represent standard error of the mean.
  • Linear regression adjusted for age, sex and comorbidities (diabetes and hypertension) of unallocated data shows an increase of 37.9 pg/ml highest fIL-18 for each decrease in PFR by 100 mmHg (13.3kPa) (p ⁇ 0.001).
  • Example 1 An immunological model of COVID-19 Infection with SARS-CoV2 has been described as having two phases, 1 with the majority of individuals experiencing only the first phase.
  • the first phase consists of a flu-like illness, with sufferers describing intermittent fevers, lethargy and a new onset continuous cough.
  • the second phase starting at around 10 days of symptoms is characterised by sudden onset shortness of breath that becomes progressively worse. It is at this stage that patients usually present in the hospital.
  • Those patients that require invasive ventilation on Intensive Care have been noted as strikingly similar, not only in demographic characteristics, but also in clinical presentation. In our hospital in East Surrey, UK, patients requiring Intensive Care support are typically middle aged to elderly males, with one or more metabolic syndrome conditions.
  • Ethnicity has also been noted as a common feature, with a disproportionate number being Black and Ethnic Minorities (BAME) 2 .
  • Biochemical presentation includes lymphopenia, hyperferritinemia and unrecordable high CRP levels, with clinical features consisting of spiking fevers, hypothermia and acute respiratory distress syndrome (ARDS). Some patients can develop liver failure, kidney failure or encephalopathy, with many patients showing uncontrolled hypertension. The above observations have been widely recognised, but the underlying reasons for them have not.
  • the model of COVID-19 immunopathology described below is based on major streams of COVID-19 specific data, histopathological autopsy analysis, transcriptomic and immune analysis of bronchoalveolar lavage fluid, and peripheral blood flow cytometric analysis.
  • the second relates to a preponderance of CD8+ T-cells in mild COVID-19 disease as compared to severe disease, with greater activation of CD4+ T-cells (T-regulatory cells, proliferating cells and CCR7+ cells) in severe disease.
  • CD4+ T-cells T-regulatory cells, proliferating cells and CCR7+ cells
  • CD8+ T cells in mild COVID-19 disease were expanded clones, likely representing SARS-CoV2 specific cytotoxic T-cells, due to repeated antigenic presentation.
  • the amplification index of these clonal CD8+ T cells was significantly higher in all three mild COVID- 19 cases, as compared to the severe cases, from which the authors surmised that early and rapid specific CD8+ T cell expansion was key in limiting viral replication and activity.
  • PBMCs peripheral blood mononuclear cells
  • RNA-seq processing to identify up-regulated genes specific to COVID-19 infection, revealed a “cytokine storm” type picture in which, contrary to the autopsy analysis of spleens described above, viral readings were high in BALF but absent in PBMCs. Instead, PBMCs showed evidence of significant upregulation in the p53 apoptotic signalling pathway gene. Taken together, these findings may indicate that programmed cell death, may also be a key cause of clinically observed lymphopenia, predictive of disease severity.
  • CD4+ Th1 cells in patients with severe disease express aberrant co-expression of GM-CSF, IL-6 and IFN- ⁇ , with CD8+ T-cells also demonstrating higher levels of GM-CSF expression.
  • Peripheral blood monocytes in such patients co-expressed CD14 and CD16, the signature of a high inflammatory state, indicating their activation by the cytokine milieu induced by Th1 activation. Of particular note, these monocytes were capable of secreting both GM-CSF and IL-6 too.
  • CD4+ Th1 cells secrete GM-CSF IL-6, attracting peripheral blood mononuclear cells to invade the lung as macrophages, mediating epithelial injury and ARDS
  • monocytes also secrete GM-CSF and IL-6, to stimulate myelopoiesis and attract more mononuclear cells.
  • severe disease is characterised by depletion and functional exhaustion of NK cells and CD8+ T cells, alongside a subsequent Th1 response, while mild disease is characterised by a pivot towards CD8+ T-cell activation with preserved NK cell numbers and function. Since NK cells and CD8+ T cells are critical for viral clearance, this makes sense.
  • NK cell Dysfunction Underpins Poor Viral Control NK cells constitute a first line of defence that even precede the peak of the cytotoxic T-cell response.
  • NK cells are able to directly bind and lyse cells, and are activated to do so through integration of inputs from activating natural killer cell receptors (aNKR) and inhibitory natural killer cell receptors (iNKR), with loss of iNKRs often sufficient to stimulate lysis of a target cell 18 .
  • aNKR natural killer cell receptors
  • iNKR inhibitory natural killer cell receptors
  • iNKRs consist of the subsets of the major histocompatibility class 1 (MHC-I) human leukocyte antigens (HLA) A, B or C, while aNKRs consist of two major groups: NKG2D receptors, such as UL-16 Binding Proteins (ULBP) and the MHC-I related chain (MIC) proteins, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, NKp46.
  • ULBP UL-16 Binding Proteins
  • MIC MHC-I related chain
  • NCRs natural cytotoxicity receptors
  • MAS is a form of secondary Hemophagocytic lymphohistiocytosis (HLH); primary or “familial” HLH is caused by genetic defects in perforin deployment.
  • HLH primary or “familial” HLH is caused by genetic defects in perforin deployment.
  • APCs antigen presenting cells
  • Some genetic defects relate to pore formation (PRF1) while others relate to vesicle priming (UNC13D), vesicle fusing (RAB27A), vesicle docking (STX11), or other functions relating to perforin delivery and release.
  • NK cells and CD8+ T cells are unable to destroy APCs, despite being continuously challenged by antigens.
  • the consequence of super-antigen presentation is activation of the inflammasome, an understanding of which is key to appreciating this model of IL-18 mediated pathogenesis described herein.
  • One of the mortality risk factors associated with severe COVID-19 disease has been demonstrated in one retrospective study 20 as increasing age. This study also demonstrated significant differences between those who did not survive COVID-19 as compared to those who died, in features of the metabolic syndrome, notably in incidence of hypertension (48% vs 23%) diabetes (31% vs 14%) and coronary artery disease (24% vs 1%). NK cells are impaired both with increasing age and in metabolic syndrome conditions.
  • NK cells With increasing age, both the cytotoxic capacity of NK cells and their capability to secrete cytokines, become impaired 21 .
  • metabolic syndrome conditions which are characterised by high levels of circulating free fatty acids, NK cells undergo “re-programming”, as a result of peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation, through disruption of mTOR-mediated glycloysis 22 .
  • PPAR peroxisome proliferator-activated receptor
  • NK cells In addition to direct antiviral actions, NK cells also play an immunomodulatory role in response to viral infection, by acting to sustain CD8+ T cell populations and functions, by preventing rapid burnout. This was demonstrated elegantly in 2012 as a general principle of viral infections, from lymphocytic choriomeningitis virus (LCMV) Arenavirus, Pichinde virus, and Coronavirus mouse hepatitis virus 25 . This team showed that NK cells directly lyse activated CD4+ cells during viral infection. Since CD4+ costimulation is necessary for an effective CD8+ response, the consequence is a weaker CD8+ response.
  • LCMV lymphocytic choriomeningitis virus
  • the viral dose When the viral dose is high, this is important, since it helps to prolong the response to an acute viral infection, helping to ultimately clear it without fatal immunopathology secondary to over-stimulation of CD4+ and CD8+ T-cells, resulting in functional exhaustion and/or a cytokine storm.
  • the viral dose When the viral dose is moderate, this action of NK cells is detrimental to the host response, but the viral dose is not high enough to cause fatality.
  • the NK cell acts to immunomodulate the host innate response, balancing antiviral activity against immunopathology.
  • NK cells are also known to lyse CD8+ T cells directly, especially when the latter become virally infected and downregulate the iNKR interferon I activating receptor (IFNAR), 26 this is unlikely to be the main cause of CD8+ T cell depletion in severe COVID-19, not least because severe COVID-19, as demonstrated, is characterised by early NK cell depletion and failure too. It is more likely therefore that failure of NK cell-CD4+ T cell regulation sits at the heart of CD8+ T cell functional exhaustion and depletion in severe COVID-19. Thus, the result of a deficiency in cytotoxic activity of NK cells due to increasing age or metabolic syndrome conditions is poorer viral control.
  • IFNAR interferon I activating receptor
  • Inflammasome NK Cell Interactions Regulate Free IL-18
  • the inflammasome is a cytosolic multiprotein complex, activated by interferons (IFNs) released from dendritic cells and macrophages upon recognition of bacterial or viral “pathogen-associated molecular patterns” or “danger-associated molecular patterns” released by damaged or dying cells.
  • IFNs interferons
  • Inflammasomes are stimulated by inputs as diverse as ATP, bacterial toxins, viral DNA or RNA, potassium efflux, calcium influx, and even different types of crystals.
  • osmotic stress in the form of hyperosmolality has also been found to trigger both NLRP3 and NLRC4 inflammasomes 28 .
  • the inflammasomes are thus activated by a wide variety of inputs representing a diverse array of cellular stress events.
  • Inflammasomes end with cleavage, by active subunits of caspase 1 (p10 and p20), of IL-18 and IL-1 ⁇ from their pro to active forms, in addition to the insertion of pore-forming gasdermin D (GSDMD), which induces pyroptotic cell death by causing swelling and bursting of the cell.
  • GDMD pore-forming gasdermin D
  • NLRP3 and NLRC4 mutations in NLRC4 having been shown to generate widespread inflammation through the uncontrolled production of free IL-18, through unopposed activation of toll-like receptor 9 (TLR9).
  • IFN- ⁇ release from NK cells under the influence of IL-18 constitutes a negative feedback loop, as IFN- ⁇ is likely an essential promoter of IL-18BP transcription in humans, as it is in murine models 29 .
  • IFN- ⁇ levels are lower or equivalent in severe cases of COVID-19 as compared to moderate or mild cases 30 , and that, as compared to healthy controls, intracellular IFN- ⁇ levels in NK cells of COVID-19 patients are very significantly collapsed 31 , and that the IL-6/IFN- ⁇ ratio is emerging as a correlative marker of disease severity 32 , we postulate that IFN-gamma is insufficiently stimulated to trigger release of sufficient IL-18BP in severe form of the disease, when IL-18 is released in much larger quantities in severe disease.
  • Natural killer cells act as rheostats modulating antiviral T cells. Nature.2012 Jan;481(7381):394-8. 26. Crouse J, Bedenikovic G, Wiesel M, Ibberson M, Xenarios I, Von Laer D, Kalinke U, Vivier E, Jonjic S, Oxenius A. Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. Immunity.2014 Jun 19;40(6):961-73. 27. Malik A, Kanneganti TD. Inflammasome activation and assembly at a glance. J Cell Sci.2017 Dec 1;130(23):3955-63. 28. Ip WE, Medzhitov R.
  • Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nature communications.2015 May 11;6(1):1-1. 29. Hurgin V, Novick D, Rubinstein M. The promoter of IL-18 binding protein: activation by an IFN- ⁇ -induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein ⁇ . Proceedings of the National Academy of Sciences.2002 Dec 24;99(26):16957-62. 30. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X. Clinical and immunological features of severe and moderate coronavirus disease 2019.
  • Example 2 Assessment of free IL-18 levels in subjects with COVID-19
  • the immunological model of COVID-19 discussed in Example 1 points to free IL-18 as playing an important role in the pathogenesis of the severe form of COVID-19 and forming the basis of a new drug target to treat the severe form of the disease.
  • ISAAC InflammaSome Axis Analysis in COVID-19 Study
  • Free IL-18, total IL-18, IL-18 Binding Protein levels, Disease trajectory (ventilated/not ventilated) and 60-day mortality are presented here for samples from 661 blood taking events from 194 patients, in whom day of symptom the blood test was taken was able to be recorded, enabling time-based characterisation of free IL18 levels.
  • PaO2/FiO2 ratios (PFRs) is also presented, as a marker of real-time oxygen dependency and therefore disease severity throughout the course of the illness, per patient.
  • IL-18 is regulated by an endogenous ligand: IL-18 Binding Protein (IL-18BP).
  • IL-18BP is constitutively produced by mononuclear cells and is found normally in circulation at a concentration of 2.5ng/ml.
  • IL-18BP has a high affinity for IL18 and effectively silences its biological activity. Thus, it is only free-IL18, unbound to its circulation endogenous ligand, that constitutes the biologically active form of this interleukin.
  • Biochemical features of the disease including lymphocyte count, percentage lymphopaenia, neutrophil:lymphocyte ratio, CRP level and Ferritin level for each individual blood-taking event were recorded.
  • Total IL-18 was analysed from EDTA samples (Human total IL-18/IL-1F4 Quantikine ELISA kit, R&D Systems, Minneapolis, MN, USA); IL18BP from EDTA samples (Human IL-18 BPa Quantikine ELISA kit, R&D Systems, Minneapolis, MN, USA) and IL-18BP-Complex from Serum samples (Human IL-18/IL-18 BPa Complex DuoSet ELISA, R&D Systems, Minneapolis, MN, USA; DuoSet ELISA Ancillary Reagent Kit 2, R&D Systems, Minneapolis, MN, USA). EDTA and Serum samples analysed were always from the same blood-taking event.
  • Figure 2 compares levels of free IL-18 in those who require ventilation and survive to day 60, as compared to those who require ventilation and die by day 60. This graph shows that there is a difference in the trajectory of the free IL-18 levels of those who require ventilation but survive to day 60, demonstrating a much higher mean level of free IL-18 (approaching significance) in the earlier part of their disease course which rapidly declines during the course of their illness, but which is still elevated above normal (118 pg/ml) at the day 14 time point.
  • Outcome 1 represents those who require ventilation or die by day 60
  • Outcome 2 represents those who do not require ventilation and survive to day 60 of their disease course.
  • PFR PaO2/FiO2 ratio
  • the aim of free IL-18 blockade should ideally be to reduce its level to that seen in those who survive to day 60, rather than to healthy controls.
  • the threshold that emerges from Figure 1 is 80pg/ml.
  • Healthy controls in whom free IL- 18 was calculated show levels of free IL-18 lower than those who survive to day 60 in the ISAAC study, with mean levels in healthy controls at 58.6pg/ml. Comparing the free IL-18 levels from the lowest day grouping of those who survive to day 60 (days 25-29) to healthy controls, we see a mean difference of 100.83pg/ml (COVID- 19 positive) to 58.6pg/ml (health controls), yielding a p-value difference of ⁇ 0.0001.
  • Example 3 Assessment of free IL-18 levels in subjects with COVID-19 in the context of demographics and comorbidities Further analysis of the data generated in the study described in Example 2 revealed interesting findings that further support the utility of IL-18 antagonists in the treatment of viral respiratory infections and syndromes, such as viral pneumonia, particularly in subjects with comorbidities, such as hypertension and diabetes. Results Firstly, age was relatively evenly distributed between all categories of disease severity (Fig.5). No significant difference was seen in age of males vs females, and so is not shown.
  • Figure 10 reveals the breakdown of BMI by two age categories, with 60 years of age being the threshold. It reveals a large spread of high BMI patients with mild disease (though still hospitalised) who are at a younger age, skewing the average BMI upwards in that category. Comorbidity and Mortality Our data shows, in consonance with existing studies 1 , that comorbidities relating to the metabolic syndrome, hypertension and diabetes, are associated with worse outcomes in COVID-19 disease. In particular, Figure 6 reveals that the percentage of patients without diabetes or hypertension (score 0) falls significantly between those groups with mild disease and those groups with severe disease, as determined by worst PFR, from 45.31% to 18.52%.
  • BMI showed an interesting picture, with BMI increasing steadily between mild to moderate to severe groups in a significant manner, between mild to severe and moderate to severe groups (Fig.9).
  • a closer examination of the BMI by age range showed that BMIs in the mild-severity group were being skewed upwards by a large distribution of younger individuals with high BMI. This indicates the tension that exists between various risk factors such as age and metabolic syndrome; these high BMI patients were at risk of hospitalisation on that account, but were young enough to be protected from severe disease.
  • a closer analysis might reveal, in those under the age of 60 but suffering from severe disease, a difference in their comorbidity profile, to those also under 60 years of age, in the mild-severity group.
  • Example 4 Further analysis of free IL-18 levels in subjects with COVID-19 in the context of COVID-19 severity and mortality The data collected from the observational, prospective, longitudinal cohort study described in Example 2 was subjected to further analysis to investigate the association between IL-18 negative-feedback control and COVID-19 severity and mortality.
  • Ethylenediaminetetraacetic acid (EDTA) and serum blood samples taken for clinical purposes in recruited patients during their inpatient stay were, excess to clinical requirements, centrifuged, aliquoted and stored at -70 to -75°C degrees on the same day of sampling; no extra blood was taken from any patient. Aliquots were matched to “day from symptom onset” in 219 patients for whom date of symptom onset was recorded in clinical notes. The following additional results from each blood sample were recorded: lymphocyte count; neutrophil count; C-reactive protein; ferritin.
  • Organ-dependency parameters of the patient at the time of blood sampling were also recorded, including: fraction of inspired oxygen (Fi02); method of oxygen delivery; partial pressure of oxygen (Pa02) from arterial blood gas sampling or, if not available, derived from oxygen saturations (Sa02) as described in the literature ([Sa02/Fi02]- 29 ⁇ 6/1 ⁇ 09); Pa02/Fi02 ratio (PFR); ventilatory support parameters (peak inspiratory pressure; positive end-expiratory pressure); number of organs supported; days in intensive care.
  • Data Analysis ELISA Analysis and Data Sorting EDTA and serum samples were thawed at room temperature before enzyme-linked immunosorbent assay (ELISA) analysis.
  • IL-18 Human total IL- 18/IL-1F4 Quantikine ELISA kit, R&D Systems, 5 Minneapolis, MN, USA
  • IL-18bp Human IL-18 Binding Protein
  • IL-18 and IL-18bp analysis were always conducted from the same EDTA or serum sample. All ELISA procedures were undertaken at Cambridge University Hospital’s Cytokine Laboratory, Cambridge, UK, in accordance with the manufacturer’s protocol. Data analysis was conducted by Dr A Rana, Dr T Khan, Dr A Kafizas and Dr SMT Nasser.
  • the Consort Diagram ( Figure 11) demonstrates the flow of participants from enrolment to analysis.
  • fIL-18 Calculation of fIL-18 levels were determined from Total IL-18 and IL-18bp using the established 1:1 stoichiometry and dissociation constant (Kd) of 0 ⁇ 05 nM in a law of mass-action calculation as per recent evidence.
  • Kd dissociation constant
  • IL-18 and IL-18bp provided from historical data in 442 non-COVID-19, male individuals were re- analysed using a dissociation constant of 0 ⁇ 05 nM to calculate fIL-18 levels in healthy individuals.
  • Time-series 1 analysed fIL-18 levels by time from symptom onset, separated by 60-day mortality outcome.
  • Time-series 2 analysed the Total IL-18 and IL-18bp breakdown of Time Series 1. Since the Time Series data involved pooling all fIL-18 values per patient into bins, adjustment for per-patient confounders, could not be carried out on the Time-Series data. For this reason, conclusions were only drawn from per patient adjusted regression analyses, instead.
  • Case-Control Analysis Days 10-14 from symptom-onset were selected for comparison as they represented the time of highest tracheal intubation rate (not shown). In addition, at this time point there was no significant difference in fIL-18 levels between survivors and non-survivors, enabling us to treat COVID-19 cases at this time period, as one group.
  • Logistic regression was conducted with COVID-19 infection as the outcome, adjusted for by age and comorbidities (diabetes and hypertension incidence).
  • Disease Severity Analysis Based on Time Series 1, day 15 onwards was selected for linear regression analysis with highest fIL-18 as the response variable with concurrent Pa02/Fi02 ratio (PFR) as the primary outcome.
  • PFR results were categorised into bins enabling comparison with the Berlin criteria of Acute Respiratory Distress Syndrome (ARDS) severity and extended upwards to include patients without formal ARDS.
  • Regression analysis was adjusted for by age, sex and co-morbidities (diabetes and hypertension incidence).
  • Mortality analysis Based on Time Series 1 day 15 onwards was selected for analysis using logistic regression, adjusting for age, sex and comorbidities (diabetes and hypertension incidence) with highest fIL-18 per patient as the exposure variable and 60-day mortality with hypoxaemic respiratory failure as the secondary outcome.60- day mortality with hypoxaemic respiratory failure, rather than from all causes, was used for regression analysis, in recognition of patients admitted for non-COVID-19 pathologies, dying from causes unrelated to COVID-19, but having contracted COVID-19 as inpatients. Exclusion criteria was: no recorded PFR ⁇ 300 mmHg in recorded observations within 24 hours of death. This was conducted blinded to patient fIL-18 values, resulting in the exclusion of 4 out of 22 patients.
  • Time Series 2 presents the Total IL-18 and IL-18bp levels that underlie the fIL-18 profile in Figure 12, showing that the fIL-18 divergence after day 15, is due to increased IL-18 without a commensurate increase in the levels of IL- 18bp.

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Abstract

La présente invention concerne des compositions pharmaceutiques et des procédés pour le traitement d'infections respiratoires virales, par exemple la pneumonie induite par un virus. Plus précisément, la présente invention concerne un antagoniste d'IL-18 destiné à être utilisé dans le traitement d'une infection respiratoire virale chez un sujet, l'antagoniste d'IL-18 étant d'abord administré au sujet : (a) à environ 10 jours d'un ou de plusieurs symptômes de l'infection respiratoire virale ou après, le ou les symptômes étant choisis parmi : (i) une fièvre ; (ii) une toux ; et (iii) une perte ou un changement de goût et/ou d'odeur ; et (b) le sujet ayant un rapport PaO2/FiO2 (pression partielle d'oxygène dans le sang artériel divisé par la fraction d'oxygène inspiré) inférieure à 300 mmHg.
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