WO2021207662A1

WO2021207662A1 - Use of il-22fc for the treatment or prevention of pneumonia, acute respiratory distress syndrome, or cytokine release syndrome

Info

Publication number: WO2021207662A1
Application number: PCT/US2021/026666
Authority: WO
Inventors: Joseph Haw-Ling LIN; Melicent Clare PECK; Joseph R. Arron
Original assignee: Genentech, Inc.
Priority date: 2020-04-10
Filing date: 2021-04-09
Publication date: 2021-10-14

Abstract

The invention relates to methods, uses, and compositions (e.g., articles of manufacture and kits) for the treatment or prevention of respiratory diseases, including pneumonia and acute respiratory distress syndrome (ARDS), using IL-22 Fc fusion proteins. The respiratory disease may be associated with a viral infection, e.g., a coronavirus infection such as COVID-19. The present invention also relates to methods of treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR T-cell-induced CRS).

Description

USE OF IL-22FC FOR THE TREATMENT OR PREVENTION OF PNEUMONIA, ACUTE RESPIRATORY DISTRESS SYNDROME, OR CYTOKINE RELEASE

SYNDROME

CROSS-REFERENCE TO RELATED APPLICATIONS

The instant application claims the benefit of priority to U.S. Provisional Application No.

63/008,432, filed on April 10, 2020, the contents of which are incorporated herein by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under HHS0100201800036C awarded by the Department of Health and Human Services. The government has certain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 9, 2021 , is named 50474-223WO2_Sequence_Listing_4_9_21_ST25 and is 116,753 bytes in size.

FIELD OF THE INVENTION

The present invention relates, inter alia, to methods of treating or preventing respiratory diseases, including pneumonia and acute respiratory distress syndrome (ARDS). The respiratory disease may be associated with a viral infection, e.g., a coronavirus infection such as COVID-19. The present invention also relates, inter alia, to methods of treating or preventing cytokine release syndrome (CRS).

BACKGROUND OF THE INVENTION

Coronaviruses (CoV) are positive-stranded RNA viruses with a crown-like appearance under an electron microscope due to the presence of spike glycoproteins on the envelope. They are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS CoV) and severe acute respiratory syndrome (SARS-CoV).

COVID-19, which is the acronym of “coronavirus disease 2019,” is caused by a new coronavirus strain that has not been previously identified in humans and was newly named on 11 February 2020 by the World Health Organization (WHO). An epidemic of cases with unexplained lower respiratory tract infections was first detected in Wuhan, the largest metropolitan area in China's Hubei province, and was reported to the WHO Country Office in China on 31 December 2019. A pandemic was subsequently declared by the WHO on 11 March 2020.

According to the WHO, as of 6 April 2020, over 1 ,210,000 cases of COVID 19 were reported in over 200 countries and territories worldwide, with over 67,500 deaths. Up to -20% of infected patients experienced complications related to a severe form of interstitial pneumonia, which may progress towards acute respiratory distress syndrome (ARDS) and/or multi-organ failure (MOF) and death. To date, there is no vaccine and no specific anti-viral medicine shown to be effective in preventing or treating COVID-19. Most patients with mild disease recover with symptomatic treatment and supportive care. However, those patients with more severe illness require hospitalization (WHO 2020).

There remains a need for improved therapies for respiratory diseases such as pneumonia and acute respiratory distress syndrome (ARDS), including respiratory diseases associated with a viral infection, e.g., a coronavirus infection such as COVID-19. There also remains a need for improved therapies for CRS.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, methods of treating or preventing respiratory diseases, including pneumonia and acute respiratory distress syndrome (ARDS), as well as related compositions, uses, and kits. The respiratory disease may be associated with a viral infection, e.g., a coronavirus infection such as COVID-19. The present invention also provides, inter alia, methods of treating or preventing CRS (including CRS caused by a viral infection (e.g., a coronavirus infection such as COVID- 19) or chimeric antigen receptor (CAR)-T-cell-induced CRS)).

In one aspect, the invention features a method of treating or preventing pneumonia in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of treating or preventing acute respiratory distress syndrome (ARDS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of reducing disease progression to ARDS in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of promoting convalescence of a patient having pneumonia or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving interferon (IFN)- mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In another aspect, the invention features a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an effective amount of an IL-22 Fc fusion protein to the patient. In some aspects, the patient has a viral infection.

In some aspects, the viral infection is a coronavirus infection.

In some aspects, the coronavirus infection is with SARS-CoV-2, MERS-CoV, or SARS-CoV.

In some aspects, the coronavirus infection is with SARS-CoV-2.

In some aspects, the patient has a positive polymerase chain reaction (PCR) test for SARS-CoV- 2 from a biological sample obtained from the patient.

In some aspects, the patient has been admitted to a hospital.

In some aspects, the patient has pneumonia or ARDS or is at risk of developing pneumonia or

ARDS.

In some aspects, the ARDS is caused by a primary pulmonary infection, a systemic infection that spreads to the lungs, or a non-infectious cause.

In some aspects, the non-infectious cause is trauma or hypotensive shock.

In some aspects, the ARDS has progressed from pneumonia.

In some aspects, the pneumonia is viral pneumonia.

In some aspects, the pneumonia is moderate, severe, or critical pneumonia.

In some aspects, the pneumonia is severe pneumonia.

In some aspects, the pneumonia is coronavirus pneumonia.

In some aspects, the coronavirus pneumonia is COVID-19 pneumonia, Middle East respiratory syndrome pneumonia, or severe acute respiratory syndrome pneumonia.

In some aspects, the coronavirus pneumonia is COVID-19 pneumonia.

In some aspects, the COVID-19 pneumonia is severe COVID-19 pneumonia.

In some aspects, the IL-22 Fc fusion protein is administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In some aspects, the IL-22 Fc fusion protein is administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

In some aspects, the IL-22 Fc fusion protein is administered at a dose of about 90 pg/kg.

In some aspects, the IL-22 Fc fusion protein is administered at a dose of about 60 pg/kg.

In some aspects, the method comprises administering at least a first dose and a second dose of the IL-22 Fc fusion protein to the patient.

In some aspects, the second dose is administered to the patient about 7 to about 21 days after the first dose.

In some aspects, the patient experiences improvement of clinical status after the first dose.

In some aspects, the patient experiences no improvement or worsening of clinical status after the first dose.

In some aspects, the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of treating or preventing pneumonia in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen. In another aspect, the invention features a method of treating or preventing ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of promoting convalescence of a patient having pneumonia or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In some aspects, the second dose is administered to the patient 14 days after the first dose. In some aspects, the first dose is between about 30 pg/kg to about 120 pg/kg.

In some aspects, the first dose is about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

In some aspects, the first dose is about 90 pg/kg.

In some aspects, the first dose is about 60 pg/kg.

In some aspects, the second dose is between about 30 pg/kg to about 120 pg/kg.

In some aspects, the second dose is about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

In some aspects, the second dose is about 90 pg/kg.

In some aspects, the second dose is about 60 pg/kg.

In some aspects, the method achieves a greater improvement in clinical outcome compared to standard of care (SOC).

In another aspect, the invention features a method of treating or preventing pneumonia in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of treating or preventing ARDS in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of reducing disease progression to ARDS in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of promoting convalescence of a patient having pneumonia or ARDS comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status. In another aspect, the invention features a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In some aspects, the clinical outcome is measured on an ordinal scale of clinical status.

In some aspects, the ordinal scale is a 7-category ordinal scale.

In some aspects, the clinical outcome is measured on the ordinal scale of clinical status at Day 28 following treatment on Day 1 .

In some aspects, the clinical outcome is time to clinical improvement (TTCI) defined as a National Early Warning Score 2 (NEWS2) of < 2 maintained for 24 hours.

In some aspects, the clinical outcome is time to improvement of at least 2 categories relative to baseline on the ordinal scale of clinical status.

In some aspects, the clinical outcome is incidence of mechanical ventilation.

In some aspects, the clinical outcome is ventilator-free days to Day 28 following treatment on

Day 1 .

In some aspects, the clinical outcome is organ failure-free days to Day 28 following treatment on

Day 1 .

In some aspects, the clinical outcome is incidence of intensive care unit (ICU) stay.

In some aspects, the clinical outcome is duration of ICU stay.

In some aspects, the clinical outcome is time to clinical failure defined as the time to death, mechanical ventilation, ICU admission, or withdrawal, whichever occurs first.

In some aspects, the clinical outcome is mortality rate at Days 7, 14, 21 , 28, and 60 following treatment on Day 1 .

In some aspects, the clinical outcome is time to hospital discharge; or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or < 2L supplemental oxygen.

In some aspects, the clinical outcome is duration of supplemental oxygen.

In some aspects, the clinical outcome is selected from the group consisting of incidence of vasopressor use, duration of vasopressor use, incidence of extracorporeal membrane oxygenation (ECMO), incidence of starting dialysis, SARS-CoV-2 viral load on Day 15 or day of hospital discharge (whichever occurs first), and proportion of patients with secondary bacterial infections.

In some aspects, the method is associated with an acceptable safety outcome compared with standard of care (SOC).

In some aspects, the safety outcome is selected from the group consisting of: incidence and severity of adverse events; incidence and severity of adverse events with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0; change from baseline in targeted vital signs; and change from baseline in targeted clinical laboratory test results.

In some aspects, the SOC comprises supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s).

In some aspects, the anti-bacterial epithelial factors comprise one or more of REG3A, Lipocalin 2, INFAR1 , INFA11 , CXCL10, DEFA1 , DEFB14, MDK, PTN, and CRP.

In another aspect, the invention features a method of treating or preventing cytokine release syndrome (CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

In some aspects, the IL-22 Fc fusion protein is administered at a dose of about 30 pg/kg, about

60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

In some aspects, the CRS is caused by a viral infection (e.g., COVID-19) or is chimeric antigen receptor (CAR) T cell-induced CRS.

In some aspects, the CRS is caused by a viral infection.

In some aspects, the viral infection is COVID-19.

In some aspects, the IL-22 Fc fusion protein comprises an IL-22 polypeptide linked to an Fc region by a linker.

In some aspects, the IL-22 polypeptide is glycosylated and/or the Fc region is not glycosylated.

In some aspects: (i) the amino acid residue at position 297 as in the EU index of the Fc region is

Gly or Ala; and/or (ii) the amino acid residue at position 299 as in the EU index of the Fc region is Ala,

Gly, or Val.

In some aspects, the Fc region is an IgG 1 Fc region, an lgG2 Fc region, or an lgG4 Fc region.

In some aspects, the Fc region comprises the CH2 and CH3 domain of lgG4.

In some aspects, the Fc region is an lgG4 Fc region.

In other aspects, the Fc region is an lgG2 Fc region.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:8.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:8.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:8.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8. In some aspects, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16.

In some aspects, the IL-22 Fc fusion protein comprises or consists of the amino acid sequence of SEQ ID NO:8.

In some aspects, the IL-22 Fc fusion protein is efmarodocokin alfa.ln some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:12.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:12.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:12.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:12.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:12.

In some aspects, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:12, SEQ ID NO:14, or SEQ ID NO:20.

In some aspects, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:81 , SEQ ID NO:82, or SEQ ID NO:83.

In some aspects, the IL-22 Fc fusion protein is eflepedocokin alfa.

In some aspects, the IL-22 Fc fusion protein is a dimeric IL-22 Fc fusion protein.

In some aspects, the IL-22 Fc fusion protein is a monomeric IL-22 Fc fusion protein.

In some aspects, the IL-22 polypeptide is a human IL-22 polypeptide.

In some aspects, the IL-22 polypeptide comprises the amino acid sequence of SEQ ID NO:4.

In some aspects, the linker comprises or consists of the amino acid sequence RVESKYGPP (SEQ ID NO: 44).

In some aspects, the IL-22 Fc fusion protein binds to IL-22 receptor.

In some aspects, the IL-22 receptor is human IL-22 receptor.

In some aspects, the IL-22 Fc fusion protein is administered to the patient in a pharmaceutical composition.

In some aspects, the pharmaceutical composition has an average sialic acid content in the range of 8 to 12 moles of sialic acid per mole of the IL-22 Fc fusion protein.

In some aspects, the pharmaceutical composition has an average sialic acid content in the range of 8 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein.

In some aspects, the pharmaceutical composition has an average sialic acid content in the range of 8 to 9 moles of sialic acid per mole of the IL-22 Fc fusion protein.

In some aspects, the pharmaceutical composition has an average sialic acid content in the range of 9 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein.

In some aspects, the IL-22 Fc fusion protein is administered to the patient as a monotherapy. In some aspects, the IL-22 Fc fusion protein is administered to the patient as a combination therapy.

In some aspects, the combination therapy comprises administering tocilizumab, hydroxychloroquine, azithromycin, or a combination thereof.

In some aspects, the combination therapy comprises administering tocilizumab.

In some aspects, the IL-22 Fc fusion protein is administered to the patient in combination with

SOC.

In some aspects, the IL-22 Fc fusion protein is administered to the patient prior to, concurrently with, or after the SOC.

In some aspects, the supportive care comprises oxygen therapy.

In some aspects, the one or more anti-viral agent(s) comprise alpha-interferon, lopinavir, ritonavir, lopinavir/ritonavir, remdesivir, ribavirin, hydroxychloroquine, chloroquine, umifenovir, favipiravir, or a combination thereof.

In some aspects, the administering is by intravenous infusion.

In some aspects, the patient is a human.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient having or at risk of developing pneumonia in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient having or at risk of developing ARDS in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to reduce disease progression to ARDS in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to promote convalescence of a patient having pneumonia or ARDS in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to reduce lung inflammation in the patient without compromising antiviral host defense in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to reduce maladaptive hyper- inflammatory responses in the patient without inhibiting development of protective adaptive immunity and viral clearance in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to promote epithelial lung repair, improve lung epithelial barrier integrity, improve lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reduce pulmonary edema in accordance with any one of the methods disclosed herein. In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to induce expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient having a viral infection to provide prophylaxis against secondary bacterial and/or fungal infection of the lung in accordance with any one of the methods disclosed herein.

In another aspect, the invention features a kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to treat or prevent CRS in a patient in accordance with any one of the methods disclosed herein.

In another aspect, the invention features an IL-22 Fc fusion protein for use in treating or preventing pneumonia in a patient.

In another aspect, the invention features an IL-22 Fc fusion protein for use in treating or preventing ARDS in a patient.

In another aspect, the invention features an IL-22 Fc fusion protein for use in reducing disease progression to ARDS in a patient.

In another aspect, the invention features an IL-22 Fc fusion protein for use in promoting convalescence of a patient having pneumonia or ARDS.

In another aspect, the invention features an IL-22 Fc fusion protein for use in reducing lung inflammation in a patient without compromising antiviral host defense.

In another aspect, the invention features an IL-22 Fc fusion protein for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance.

In another aspect, the invention features an IL-22 Fc fusion protein for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, IFN- mediated antiviral responses, and/or reducing pulmonary edema in a patient.

In another aspect, the invention features an IL-22 Fc fusion protein for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS.

In another aspect, the invention features an IL-22 Fc fusion protein for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection.

In some aspects, the patient has a viral infection.

In some aspects, the viral infection is a coronavirus infection.

In some aspects, the coronavirus infection is with SARS-CoV-2.

In some aspects, the patient has a positive PCR test for SARS-CoV-2 from a biological sample obtained from the patient.

In some aspects, the patient has been admitted to a hospital.

ARDS. In some aspects, the ARDS is caused by a primary pulmonary infection, a systemic infection that spreads to the lungs, or a non-infectious cause.

In some aspects, the non-infectious cause is trauma or hypotensive shock.

In some aspects, the ARDS has progressed from pneumonia.

In some aspects, the pneumonia is viral pneumonia.

In some aspects, the pneumonia is moderate, severe, or critical pneumonia.

In some aspects, the pneumonia is severe pneumonia.

In some aspects, the pneumonia is coronavirus pneumonia.

In some aspects, the coronavirus pneumonia is COVID-19 pneumonia.

In some aspects, the COVID-19 pneumonia is severe COVID-19 pneumonia.

In some aspects, the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In some aspects, the IL-22 Fc fusion protein is to be administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

In some aspects, the IL-22 Fc fusion protein is to be administered at a dose of about 90 pg/kg.

In some aspects, the IL-22 Fc fusion protein is to be administered at a dose of about 60 pg/kg.

In some aspects, the IL-22 Fc fusion potein is to be administered to the patient in at least a first dose and a second dose.

In some aspects, the second dose is to be administered to the patient about 7 to about 21 days after the first dose.

In some aspects, the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of treating or preventing pneumonia in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of treating or preventing ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of promoting convalescence of a patient having pneumonia or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another aspect, the invention features an IL-22 Fc fusion protein for use in a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In some aspects, the second dose is to be administered to the patient 14 days after the first dose.

In some aspects, the first dose is between about 30 pg/kg to about 120 pg/kg.

In some aspects, the first dose is about 90 pg/kg.

In some aspects, the first dose is about 60 pg/kg. In some aspects, the second dose is between about 30 pg/kg to about 120 pg/kg.

In some aspects, the second dose is about 90 pg/kg.

In some aspects, the second dose is about 60 pg/kg.

In some aspects, the use achieves a greater improvement in clinical outcome compared to SOC.

In another aspect, the invention features an IL-22 Fc fusion protein for use in treating or preventing pneumonia in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in promoting convalescence of a patient having pneumonia or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another aspect, the invention features an IL-22 Fc fusion protein for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status. In another aspect, the invention features an IL-22 Fc fusion protein for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL- 22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In some aspects, the ordinal scale is a 7-category ordinal scale.

In some aspects, the clinical outcome is TTCI defined as a NEWS2 of < 2 maintained for 24 hours.

In some aspects, the clinical outcome is incidence of mechanical ventilation.

Day 1 .

In some aspects, the clinical outcome is incidence of ICU stay.

In some aspects, the clinical outcome is duration of ICU stay.

In some aspects, the clinical outcome is duration of supplemental oxygen.

In some aspects, the clinical outcome is selected from the group consisting of incidence of vasopressor use, duration of vasopressor use, incidence of ECMO, incidence of starting dialysis, SAFtS- CoV-2 viral load on Day 15 or day of hospital discharge (whichever occurs first), and proportion of patients with secondary bacterial infections.

In some aspects, the use is associated with an acceptable safety outcome compared with SOC.

In some aspects, the safety outcome is selected from the group consisting of: incidence and severity of adverse events; incidence and severity of adverse events with severity determined according to NCI CTCAE v5.0; change from baseline in targeted vital signs; and change from baseline in targeted clinical laboratory test results.

In some aspects, the SOC comprises supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s). In some aspects, the anti-bacterial epithelial factors comprise one or more of REG3A, Lipocalin 2, INFAR1 , INFA11 , CXCL10, DEFA1 , DEFB14, MDK, PTN, and CRP.

In another aspect, the invention features an IL-22 Fc fusion protein for use in treating or preventing CRS in a patient.

In some aspects, the CRS is caused by a viral infection (e.g., COVID-19) or is CAR T cell- induced CRS.

In some aspects, the CRS is caused by a viral infection (e.g., COVID-19).

In some aspects, the viral infection is COVID-19.

Gly, or Val.

In some aspects, the Fc region comprises the CH2 and CH3 domain of lgG4.

In some aspects, the Fc region is an lgG4 Fc region.

In other aspects, the Fc region is an lgG2 Fc region.

In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8.

In some aspects, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16.

In some aspects, the IL-22 Fc fusion protein is efmarodocokin alfa. In some aspects, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:12.

In some aspects, the IL-22 Fc fusion protein is eflepedocokin alfa.

In some aspects, the IL-22 polypeptide is a human IL-22 polypeptide.

In some aspects, the IL-22 Fc fusion protein binds to IL-22 receptor.

In some aspects, the IL-22 receptor is human IL-22 receptor.

In some aspects, the IL-22 Fc fusion protein is to be administered to the patient as a monotherapy.

In some aspects, the IL-22 Fc fusion protein is to be administered to the patient as a combination therapy.

In some aspects, the combination therapy comprises administering tocilizumab. In some aspects, the IL-22 Fc fusion protein is administered to the patient in combination with

SOC.

In some aspects, the supportive care comprises oxygen therapy.

In some aspects, the one or more anti-viral agent(s) comprise alpha-interferon, lopinavir, ritonavir, lopinavir/ritonavir, remdesivir, ribavirin, hydroxychloroquine, chloroquine, u ifenovir, favipiravir, or a combination thereof.

In some aspects, the administering is to be by intravenous infusion.

In some aspects, the patient is a human.

Each and every embodiment can be combined unless the context clearly suggests otherwise. Each and every embodiment can be applied to each and every aspect of the invention unless the context clearly suggests otherwise.

Specific embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an amino acid sequence alignment of mature IL-22 from different mammalian species: human (GenBank Accession No.Q9GZX6, SEQ ID NO:4, chimpanzee (GenBank Accession No.XP_003313906, SEQ ID NO:48), orangutan (GenBank Accession No. XP_002823544, SEQ ID NO:49), mouse (GenBank Accession No. Q9JJY9, SEQ ID NO:50), and dog (GenBank Accession No.

XP 538274, SEQ ID NO:51).

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Interleukin (IL)-22 is a member of the IL-10 family of cytokines that is produced, e.g., by Th22 cells, natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, dendritic cells, and Th17 cells. IL-22 binds to the IL-22R1 /IL-10R2 receptor complex, which is expressed in innate cells (e.g., epithelial cells, hepatocytes, and keratinocytes) and in barrier epithelial tissues of several organs (e.g., the respiratory system, dermis, pancreas, and intestine).

IL-22 plays an important role in mucosal immunity, e.g., by mediating early host defense against attaching and effacing bacterial pathogens. IL-22 promotes the production of anti-microbial peptides and pro-inflammatory cytokines from epithelial cells and stimulates proliferation and migration of colonic epithelial cells in the gut. Upon bacterial infection, IL-22 knock-out mice displayed impaired gut epithelial regeneration, high bacterial load, and increased mortality. Similarly, infection of IL-22 knock-out mice with influenza virus resulted in severe weight loss and impaired regeneration of tracheal and bronchial epithelial cells. Thus, IL-22 plays a pro-inflammatory role in suppressing microbial infection as well as an anti-inflammatory protective role in epithelial regeneration in inflammatory responses. As described, e.g., in Example 1 , IL-22 can repair the lung epithelial barrier and limit excessive host inflammatory responses to respiratory viral and bacterial pathogens without compromising viral clearance or protective adaptive immunity. In multiple acute lung injury murine models, IL-22 reduced pulmonary edema and increased lung epithelial barrier integrity. IL-22 decreases levels of cytokines (e.g., IL-6, IFN-g, and IL-17A) and chemokines (e.g., MCP-1 , MIP-1a, and MIR-1 b) in bronchoalveolar lavage, which correlates with decreased numbers of lung neutrophils and lymphocytes and reduced alveolitis in viral infection models. IL-22 also protects against influenza virus-bacterial co-infection and coronavirus infection. As discussed herein, IL-22 Fc fusion proteins can be used to treat or prevent respiratory diseases such as severe COVID-19 pneumonia, e.g., by increasing epithelial regeneration and pulmonary function, reducing inflammation, and providing protection against secondary bacterial or fungal infections.

I. DEFINITIONS

Unless otherwise defined, all terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For example, reference to “an isolated peptide” means one or more isolated peptides.

Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

For the purposes herein “inflammation” refers to an immunological defense against infection, marked by increases in regional blood flow, immigration of white blood cells, and release of chemical toxins. Inflammation is one way the body uses to protect itself from infection. Clinical hallmarks of inflammation include redness, heat, swelling, pain, and loss of function of a body part. Systemically, inflammation may produce fevers, joint and muscle pains, organ dysfunction, and malaise.

“Pneumonia” refers to inflammation of one or both lungs, with dense areas of lung inflammation. The present invention concerns pneumonia due to viral infection. Symptoms of pneumonia may include fever, chills, cough with sputum production, chest pain, and shortness of breath. In one embodiment the pneumonia has been confirmed by chest X-ray or computed tomography (CT scan).

“Severe pneumonia” refers to pneumonia in which the heart, kidneys or circulatory system are at risk of failing, or if the lungs can no longer take in sufficient oxygen and develop acute respiratory distress syndrome (ARDS). A patient with severe pneumonia will typically be hospitalized and may be in an intensive care unit (ICU). Typically, the patient has severe dyspnea, respiratory distress, tachypnea (> 30 breaths/min), and hypoxia, optionally with fever. Cyanosis can occur in children. In this definition, the diagnosis is clinical, and radiologic imaging is used for excluding complications. In one embodiment, the patient with severe pneumonia has impaired lung function as determined by peripheral capillary oxygen saturation (SpC>2). In one embodiment, the patient with severe pneumonia has impaired lung function as determined by ratio of arterial oxygen partial pressure to fractional inspired oxygen (Pa02/Fi02). In one embodiment, the patient with severe pneumonia has a SpC>2 < 93%. In one embodiment, the patient with severe pneumonia has a Pa02/Fi02ot < 300 mmHg (optionally adjusted for high altitude areas based on Pa02/FiC>2X [Atmospheric Pressure (mmHg)/760]). In one embodiment, the patient has respiratory distress (RR >30 breaths/minute). In one embodiment, the patient has > 50% lesions in pulmonary imaging.

“Critical pneumonia” refers to a severe pneumonia patient in whom respiratory failure, shock and/or organ dysfunction has occurred. In one embodiment, the patient with critical pneumonia requires mechanical ventilation.

“Mild pneumonia” presents with symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, headache, muscle pain, or malaise. Signs and symptoms of a more serious disease, such as dyspnea, are not present.

In “Moderate Pneumonia,” respiratory symptoms such as cough and shortness of breath (or tachypnea in children) are present without signs of severe pneumonia. The patient with moderate pneumonia may be in a hospital, but not in an ICU or on a ventilator.

“Acute respiratory disease syndrome” or “ARDS” refers to a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into the blood. In one embodiment, the diagnosis of ARDS is made based on the following criteria: acute onset, bilateral lung infiltrates on chest radiography of a non-cardiac origin, and a PaO/FiO ratio of < 300 mmHg. In one embodiment, the ARDS is “mild ARDS” characterized by Pa02/Fi02200 to 300 mmHg. In one embodiment, the ARDS is “moderate ARDS” characterized by Pa02/Fi02 100 to 200mmHg. In one embodiment, the ARDS is “severe ARDS” characterized by Pa02/Fi02 < 100 mmHg. The ARDS may be caused, for example, by a primary pulmonary infection (e.g., a viral infection, e.g., by COVID-19), a systemic infection that spreads to the lungs (e.g., sepsis), or a non-infectious cause (e.g., trauma or hypotensive shock). For a review of ARDS, see, e.g., Thompson et al. New Engl. J. Med. 377:562-572, 2017.

“Viral pneumonia” refers to pneumonia caused by the entrance into a patient of one or more viruses. In one embodiment, the virus is a DNA virus. In one embodiment, the virus is an RNA virus. Examples of viruses causing viral pneumonia contemplated herein include, inter alia, those caused by: human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, influenza virus (including H1 N1 or “swine flu” and H5N1 or “bird flu”), Zika virus, rotavirus, Rabies virus, West Nile virus, herpes virus, adenovirus, respiratory syncytial virus (RSV), norovirus, rotavirus, astrovirus, rhinovirus, human papillomavirus (HPV), polio virus, Dengue fever, Ebola virus, and coronavirus. In one embodiment, the viral pneumonia is caused by a coronavirus.

“Coronavirus” is a virus that infects humans and causes respiratory infection. Coronaviruses that can cause pneumonia in patients include, without limitation, the beta coronavirus that causes Middle East

Respiratory Syndrome (MERS) (also known as MERS-CoV), the beta coronavirus that causes severe acute respiratory syndrome (SARS) (also known as SARS-CoV), and the COVID-19 virus (also known as SARS-CoV-2).

“COVID-19” refers to the virus that causes illness that is typically characterized by fever, cough, and shortness of breath and may progress to pneumonia and respiratory failure. COVID-19 was first identified in Wuhan China in December 2019. In one embodiment, the patient with COVID-19 is confirmed by positive polymerase chain reaction (PCR) test (e.g. real time PCR, RT-PCR test) of a specimen (e.g., respiratory, blood, urine, stool, other bodily fluid specimen) from the patient. In one embodiment, the COVID-19 nucleic acid sequence has been determined to be highly homologous to COVID-19. In one embodiment, the patient has COVID-19 specific antibodies (e.g. IgG and/or IgM antibodies), e.g. as determined by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), etc. Synonyms for COVID-19 include, without limitation, “novel coronavirus,” “2019 Novel Coronavirus,” “SARS-CoV-2” and “2019-nCoV.” The disease caused by COVID-19 may be referred to as “COVID-19” or a “COVID-19 viral infection.”

For the purposes herein, “clinical status” refers to a patient's health condition. Examples Include that the patient is improving or getting worse. In one embodiment, clinical status is based on an ordinal scale of clinical status. In one embodiment, clinica! status Is not based on whether or not the patient has a fever.

An “ordinal scale of clinical status” refers to a scale used to quantify outcomes which are non- dimensional. They include can include an outcome at a single point in time or can examine change which has occurred between two points in time. In one embodiment, the two points of time are “Day 1” (when a dose (e.g., a first dose), e.g. 90 pg/kg, of an IL-22 Fc fusion protein is administered) compared with “Day 28” (when the patient is evaluated) and, optionally, at “Day 60 (when the patient is further evaluated). Ordinal scales include various “categories” which each evaluate patent status or outcome. In one embodiment, the ordinal scale is a “7-category ordinal scale”.

In one embodiment, a “7-category ordinal scale” includes the following categories for evaluating the patient’s status:

1 . Discharged from hospital (or “ready for discharge”, e.g. as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or < 2L supplemental oxygen)

2. Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental oxygen

3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen

4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen

5. ICU, requiring intubation and mechanical ventilation

6. ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy)

7. Death.

For the purposes herein, “standard of care” or “SOC” refers to treatments or drugs commonly used to treat patients with pneumonia (e.g. viral pneumonia, such as COVID-19 pneumonia) including, inter alia, supportive care, administration of one or more anti-viral(s), and/or administration of one or more corticosteroid(s).

“Supportive care” includes, without limitation: respiratory support (e.g. oxygen therapy via face mask or nasal cannula, high-flow nasal oxygen therapy or non-invasive mechanical ventilation, invasive mechanical ventilation, via extracorporeal membrane oxygenation (ECMO), etc.); circulation support (e.g. fluid resuscitation, boost microcirculation, vasoactive drugs); renal replacement therapy; plasma therapy; blood purification therapy; Xuebijing Injection (e.g. 100 mL/day twice a day); microecological preparation (e.g. probiotics, prebiotics, and synbiotics); non-steroidal anti-inflammatory drugs (NSAIDs); herbal medicine; etc.

“Anti-viral” agents include, without limitation: alpha-interferon, lopinavir, ritonavir, lopinavir/ritonavir, remdesivir, ribavirin, hydroxychloroquine, chloroquine, umifenovir, favlplravir, etc.

“Corticosteroid” refers to any one of several synthetic or naturally occurring substances with the general chemical structure of steroids that mimic or augment the effects of the naturally occurring corticosteroids. Examples of synthetic corticosteroids include prednisone, prednisolone (including methylprednisolone, such as methylprednisolone sodium succinate), dexamethasone or dexamethasone triamcinolone, hydrocortisone, and betamethasone. In one embodiment, the corticosteroid is selected from prednisone, methylprednisolone, hydrocortisone, and dexamethasone. In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, the corticosteroid is “low-dose” glucocorticoid (e.g. < 1 -2 mg/kg/day methylprednisolone, e.g. for 3-5 days).

Examples of “non-steroidal anti-inflammatory drugs” or “NSAIDs” include aspirin, acetylsalicylic acid, ibuprofen, flurbiprofen, naproxen, indomethacin, sulindac, tolmetin, phenylbutazone, diclofenac, ketoprofen, benorylate, mefenamic acid, methotrexate, fenbufen, azapropazone; COX-2 inhibitors such as celecoxib (CELEBREX®; 4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl) benzenesulfonamide, valdecoxib (BEXTRA®), meloxicam (MOBIC®), GR 253035 (Glaxo Wellcome); and MK966 (Merck Sharp & Dohme), including salts and derivatives thereof, etc. Specific embodiments include: aspirin, naproxen, ibuprofen, indomethacin, and tolmetin.

The term “cytokine release syndrome (CRS)” refers to a form of systemic inflammatory response syndrome (SIRS) that can be triggered, e.g., by infection (e.g., a viral infection (e.g., a coronavirus infection, e.g., COVID-19)) or by administration of a drug (e.g., a chimeric antigen receptor (CAR) T-cell (CAR-T) therapy). CRS has been identified as a clinically significant, on-target, off-tumor side effect of the CAR T-cell therapies used for treatment of malignancies. Characteristics of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multi-organ dysfunction. The reported incidence of CRS after CAR T-cell therapy ranges from 50% to 100%, with 13% to 48% of patients experiencing the severe or life-threatening form. Serum levels of inflammatory cytokines are elevated, particularly interleukin-6 (IL-6). The severity of symptoms may correlate with the serum cytokine concentrations and the duration of exposure to the inflammatory cytokines. In some embodiments, the CRS patient is an adult or pediatric patient 2 years of age and older with CAR T cell-induced severe or life-threatening cytokine release syndrome.

The term “IL-22 Fc fusion protein” or “IL-22 fusion protein” or “IL-22 Ig fusion protein” as used herein refers to a fusion protein in which IL-22 protein or polypeptide is linked, directly or indirectly, to an IgG Fc region. In some embodiments, the IL-22 protein or polypeptide is glycosylated. In certain preferred embodiments, the IL-22 Fc fusion protein comprises a human IL-22 protein or polypeptide linked to a human IgG Fc region. In certain embodiments, the human IL-22 protein comprises the amino acid sequence of SEQ ID NO:4. However, it is understood that minor sequence variations such as insertions, deletions, substitutions, especially conservative amino acid substitutions of IL-22 or Fc that do not affect the function and/or activity of IL-22 or IL-22 Fc fusion protein are also contemplated by the invention. The IL-22 Fc fusion protein of the invention can bind to IL-22 receptor, which can lead to IL-22 receptor downstream signaling. In certain embodiments, the IL-22 Fc fusion protein is capable of binding to IL-22 receptor, and/or is capable of leading to IL-22 receptor downstream signaling. The functions and/or activities of the IL-22 Fc fusion protein can be assayed by methods known in the art, including without limitation, enzyme-linked immunosorbent assay (ELISA), ligand-receptor binding assay and Stat3 luciferase assay. In certain embodiments, the invention provides an IL-22 Fc fusion protein that binds to IL-22 receptor, in which the binding can lead to IL-22 receptor downstream signaling, the IL-22 Fc fusion protein comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, and SEQ ID NO:16, and wherein the Fc region is not glycosylated. In certain particular embodiments, the Fc region of the IL-22 fusion protein does not possess effector activities (e.g., does not bind to FcylllR) or exhibits substantially lower effector activity than a whole (e.g., wild-type) IgG antibody. In certain other embodiments, the Fc region of the IL-22 Fc fusion protein does not trigger cytotoxicity such as antibody-dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC).

In some embodiments, the IL-22 Fc fusion protein is efmarodocokin alfa. Efmarodocokin alfa is described, e.g., in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3, 2020. In other embodiments, the IL-22 Fc fusion protein is eflepedocokin alfa. Eflepedocokin alfa is described, e.g., in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3, 2020. Unless otherwise specified, “IL-22 fusion protein,” “IL-22 Fc fusion,” “IL-22 Ig fusion protein,” “IL-22 Fc fusion protein,” or “IL-22 Fc” are used interchangeably throughout this application.

The term “IL-22” or “IL-22 polypeptide” or “IL-22 protein” as used herein, broadly refers to any native IL-22 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed IL-22 as well as any forms of IL-22 that result from processing in the cell. For example, both full-length IL-22 containing the N- terminal leader sequence and the mature form IL-22 are encompassed by the current invention. The leader sequence (or signal peptide) can be the endogenous IL-22 leader sequence or an exogenous leader sequence of another mammalian secretary protein. In certain embodiments, the leader sequence can be from a eukaryotic or prokaryotic secretary protein. The term also encompasses naturally occurring variants of IL-22, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human IL-22 is shown in SEQ ID NO:4 (mature form, without a signal peptide). In certain embodiments, the amino acid sequence of full-length IL-22 protein with the endogenous leader sequence is provided in SEQ ID NO:71 ; while in other embodiments, the amino acid sequence of mature IL-22 protein with an exogenous leader sequence is provided in SEQ ID NO:2. Minor sequence variations, especially conservative amino acid substitutions of IL-22 that do not affect the IL-22’s function and/or activity (e.g., binding to IL-22 receptor), are also contemplated by the invention. Fig. 1 shows an amino acid sequence alignment of mature IL-22 from several exemplary mammalian species. The asterisks indicate highly conserved amino acid residues across species that are likely important for the functions and/or activities of IL-22. Accordingly, in certain embodiments, the IL-22 Fc fusion protein comprises an IL-22 polypeptide comprising an amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:4. In certain other embodiments, the IL-22 protein has 95% or more sequence identity to SEQ ID NO:71 ; 96% or more sequence identity to SEQ ID NO:71 ; 97% or more sequence identity to SEQ ID NO:71 ; 98% or more sequence identity to SEQ ID NO:71 ; or 99% or more sequence identity to SEQ ID NO:71 . The IL-22 polypeptides described herein can be isolated from a variety of sources, such as from human tissue or from another source, or prepared by recombinant or synthetic methods.

The term “IL-22 receptor” or “IL-22R” refers to a heterodimer consisting of IL-22R1 and IL-10R2 or naturally occurring allelic variants thereof. See, e.g., Ouyang et al. , 2011 , Annu. Rev. Immunol.

29:159-63. IL-10R2 is ubiquitously expressed by many cell types, and IL-22R1 is expressed only in innate cells such as epithelial cells, hepatocytes and keratinocytes. IL-22R1 is also known as IL-22Ra1 or IL-22Ra1 . IL-22R1 may be paired with other polypeptides to form heterodimeric receptors for other IL- 10 family members, for example IL-20 or IL-24. See, e.g., Ouyang et al., 2011 , supra.

A “native sequence IL-22 polypeptide” or a “native sequence IL-22R polypeptide” refers to a polypeptide comprising the same amino acid sequence as a corresponding IL-22 or IL-22R polypeptide derived from nature. Such native sequence IL-22 or IL-22R polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The terms specifically encompass naturally- occurring truncated or secreted forms of the specific IL-22 or IL-22R polypeptide (e.g., an IL-22 lacking its associated signal peptide), naturally-occurring variant forms (e.g., alternatively spliced forms), and naturally-occurring allelic variants of the polypeptide. In various embodiments of the invention, the native sequence IL-22 or IL-22R polypeptides disclosed herein are mature or full-length native sequence polypeptides. An exemplary full length native human IL-22 is shown in SEQ ID NO:70 (DNA) and SEQ ID NO:71 (protein). While the IL-22 and IL-22R polypeptide sequences are shown to begin with methionine residues designated herein as amino acid position 1 , it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 can be employed as the starting amino acid residue for the IL-22 or IL-22R polypeptides.

An “IL-22 variant,” an “IL-22R variant,” an “IL-22 variant polypeptide,” or an “IL-22R variant polypeptide” means an active IL-22 or IL-22R polypeptide as defined above having at least about 80% amino acid sequence identity with a full-length native sequence IL-22 or IL-22R polypeptide sequence. Ordinarily, an IL-22 or IL-22R polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity, and alternatively at least about 99% amino acid sequence identity to a full-length or mature native sequence IL-22 or IL-22R polypeptide sequence.

The term “Fc region,” “Fc domain,” or “Fc” refers to a C-terminal non-antigen binding region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native Fc regions and variant Fc regions. In certain embodiments, a human IgG heavy chain Fc region extends from Cys226 to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present, without affecting the structure or stability of the Fc region. Unless otherwise specified herein, numbering of amino acid residues in the IgG or Fc region is according to the EU numbering system for antibodies, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

In certain embodiments, Fc region refers to an immunoglobulin IgG heavy chain constant region comprising a hinge region (starting at Cys226), an IgG CH2 domain, and CH3 domain. The term “hinge region” or “hinge sequence” as used herein refers to the amino acid sequence located between the linker and the CH2 domain. In certain embodiments, the hinge region comprises the amino acid sequence CPPCP (SEQ ID NO:31). In certain embodiments, the hinge region for IL-22 lgG4 Fc fusion protein comprises the CPPCP sequence (SEQ ID NO:31), a sequence found in the native IgG 1 hinge region, to facilitate dimerization. In certain other embodiments, the Fc region starts at the hinge region and extends to the C-terminus of the IgG heavy chain. In certain particular embodiments, the Fc region comprises the Fc region of human lgG1 , lgG2, lgG3 or lgG4. In certain particular embodiments, the Fc region comprises the Fc region of human lgG1 or lgG4. In certain particular embodiments, the Fc region comprises the CH2 and CH3 domain of lgG4. In certain other particular embodiments, the Fc region comprises the CH2 and CH3 domain of IgG 1 . In certain other particular embodiments, the Fc region comprises the CH2 and CH3 domain of lgG2.

In certain embodiments, the IgG CH2 domain starts at Ala 231 . In certain other embodiments, the CH3 domain starts at Gly 341 . It is understood that the C-terminus Lys residue of human IgG can be optionally absent. It is also understood that conservative amino acid substitutions of the Fc region without affecting the desired structure and/or stability of Fc is contemplated within the scope of the invention.

In certain embodiments, the IL-22 is linked to the Fc region via a linker. In certain particular embodiments, the linker is a peptide that connects the C-terminus of IL-22 to the Fc region as described herein. In certain embodiments, native IgG sequences are present in the linker and/or hinge region to minimize and/or avoid the risk of immunogenicity. In other embodiments, minor sequence variations can be introduced to the native sequences to facilitate manufacturing. IL-22 Fc fusion constructs comprising exogenous linker or hinge sequences that exhibit high activity (as measured, e.g., by a luciferase assay) are also within the scope of the invention. In certain embodiments, the linker comprises an amino acid sequence that is 8-20 amino acids, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11 , 8-10, 8-9, 10-11 , 10-12, 10-13, 10- 14, 10-15, 10-16, 11 -16, 8, 9, 10, 11 , 12, 13, 14, 15, or 16 amino acids long. In certain other embodiments, the linker comprises the amino acid sequence DKTHT (SEQ ID NO:32). In certain particular embodiments, the linker does not comprise the sequence Gly-Gly-Ser (SEQ ID NO:45), Gly- Gly-Gly-Ser (SEQ ID NO:46), or Gly-Gly-Gly-Gly-Ser (SEQ ID NO:47).

In certain embodiments, the IL-22 Fc fusion protein comprises an IL-22 polypeptide linked to an Fc region by a linker. The term “linked to” or “fused to” refers to a covalent bond, e.g., a peptide bond, formed between two moieties.

The terms “glycosylation” and “glycosylated” as used herein refers to the presence of a carbohydrate (e.g., an oligosaccharide or a polysaccharide, also referred to as a “glycan”) attached to biological molecule (e.g., a protein or a lipid). In particular embodiments, glycosylation refers to the presence of a glycan (e.g., an N-glycan) attached to a protein (e.g., an IL-22 Fc fusion protein) or a portion of a protein of interest (e.g., an IL-22 polypeptide moiety of an IL-22 Fc fusion protein). N-linked glycosylation refers to the attachment of the carbohydrate moiety to the side-chain of an asparagine residue. The tripeptide sequences, asparagine-X-serine and asparagine-X-threonine, wherein X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be involved in O-linked glycosylation. For a review of glycosylation, see, e.g., Varki et al., Essentials of Glycobiology, 3^rd Edition, Cold Spring Harbor Laboratory Press, 2015-2017.

The terms “aglycosylated” and “not glycosylated,” as used interchangeably herein, refer to a protein or a portion of a protein of interest (e.g., the Fc region of an IL-22 Fc fusion protein) that is not glycosylated (e.g., not N-glycosylated). It is to be understood that in some embodiments, a portion of a protein of interest (e.g., an IL-22 Fc fusion protein) is glycosylated (e.g., the IL-22 polypeptide portion of an IL-22 Fc fusion protein), while another portion of the protein of interest is not glycosylated (e.g., the Fc region of the IL-22 Fc fusion protein). In some embodiments, provided herein are IL-22 Fc fusion proteins in which the Fc region or CH2 domain is not glycosylated. In certain embodiments, the N-glycosylation site in the CH2 domain is mutated to prevent glycosylation. For example, an IL-22 Fc fusion protein with an aglycosylated Fc region can be made by mutagenizing the amino acid residue at position 297 as in the EU index in the CH2 domain of the Fc region (e.g., N297). In certain embodiments, the glycosylation in the CH2 domain of the Fc region can be eliminated by altering the glycosylation consensus site, i.e. , Asn at position 297 followed by any amino acid residue (in the case of human IgG, Ser) and Thr. The glycosylation site can be altered by amino acid insertions, deletions, and/or substitutions. For example, one or more amino acid residues can be inserted between Asn and Ser or between Ser and Thr to alter the original glycosylation site, wherein the insertions do not regenerate an N-glycosylation site. In certain particular embodiments, the amino acid residue at position 297 as in the EU index (e.g., the N-glycosylated site in Fc) within the CH2 domain of human IgG Fc is mutated to abolish the glycosylation site. In certain particular embodiments, the amino acid residue at position 297 as in the EU index (e.g., N297) is changed to Gly, Ala, Gin, Asp, or Glu. In some particular embodiments, the amino acid residue at position 297 as in the EU index (e.g., N297) is changed to Gly or Ala. In other particular embodiments, the amino acid residue at position 297 as in the EU index (e.g., N297) is changed to Gly. In certain other embodiments, the amino acid residue at position 299 as in the EU index can be substituted with another amino acid, for example, Ala, Val, or Gly. In certain particular embodiments, the mutations that result in an aglycosylated Fc do not affect the structure and/or stability of the IL-22 Fc fusion protein.

In certain embodiments, the IL-22 Fc fusion protein comprises an Fc region in which the amino acid residue at position 297 as in the EU index in the CH2 domain is mutated. In certain embodiments, the amino acid residue at position 297 as in the EU index is changed to Gly or Ala, preferably to Gly. In certain other embodiments, the amino acid residue at position 297 as in the EU index is deleted. In certain embodiments, the IL-22 Fc fusion protein comprising an Fc having an amino acid substitution at the amino acid residue at position 297 as in the EU index is aglycosylated or not glycosylated.

In other embodiments, the N-glycan attached to the wild-type amino acid residue at position 297 as in the EU index (e.g., N297) can be removed enzymatically, e.g., by deglycosylation. Suitable glycolytic enzymes include without limitation, peptide-N-glycosidase (PNGase).

The term “glycosylation occupancy” as used herein refers to the probability that a protein is glycosylated at a particular glycosylation site (e.g., an Asn residue of a consensus glycosylation site) or the percentage of proteins in a population of proteins that are glycosylated at a particular glycosylation site. For example, an IL-22 polypeptide may be glycosylated on amino acid residues Asn21 , Asn35, Asn64, and/or Asn143 of SEQ ID NO: 4. In a further specific example, (a) the percent N-glycosylation site occupancy at residue Asn21 may be in the range of 70 to 90; (b) the percent N-glycosylation site occupancy at residue Asn35 may be in the range of 90 to 100; (c) the percent N-glycosylation site occupancy at residue Asn64 may be in the range of 90 to 100; and/or (d) the percent N-glycosylation site occupancy at residue Asn 143 may be in the range of 25 to 35.

The terms “sialylation” and “sialylated” refers to the presence of sialic acid on a protein or a portion of a protein of interest, particularly as a component of a glycan (e.g., N-glycan) chain attached to a protein. Sialic acid (also referred to herein as a “sialic acid moiety”) refers generally to N- or O- substituted derivatives of neuraminic acid. N-acetylneuraminic acid (5-acetamido-2-keto-3,5-dideoxy-D- glycero-D-galactonononic acid; also known as NANA or Neu5Ac) is the most common sialic acid in mammals. Other exemplary sialic acids include, without limitation, 2-keto-3-deoxy-D-glycero-D- galactonononic acid (also known as Kdn), N-glycolylneuraminic acid (also known as Neu5Gc or NGNA), neuraminic acid (also known as Neu), and 2-deoxy-2,3-didehydro-Neu5Ac (also known as Neu2en5Ac). Free sialic acid (Sia) can be used for glycan synthesis after activation onto the nucleotide donor CMP-Sia. Transfer of Sia from CMP-Sias onto newly synthesized glycoconjugates (e.g., glycoproteins) in the Golgi system of eukaryotes is catalyzed by a family of linkage-specific sialyl-transferases (STs). Sialic acids are typically the terminating residues of glycan (e.g., N-glycan) branches. In some embodiments, sialic acids can occupy internal positions within glycans, most commonly when one sialic acid residue is attached to another. For a review of sialylation and sialic acid, see, e.g., Chapter 15 of Varki et al., Essentials of Glycobiology, 3^rd Edition, Cold Spring Harbor Laboratory Press, 2015-2017.

The term “sialic acid content” refers to the level or amount of sialylation of a glycosylated protein (e.g., an IL-22 Fc fusion protein) or a portion of a protein of interest. In some embodiments, an IL-22 Fc fusion protein has a sialic acid content of from about 4 to about 16 moles (e.g., about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 , about 12, about 13, about 14, about 15, or about 16 moles) of sialic acid per mole of the IL-22 Fc fusion protein. In some embodiments, an IL-22 Fc fusion protein has a sialic acid content of about 8, 9, 10, 11 , or 12 moles of sialic acid per mole of the IL-22 Fc fusion protein.

The term “average sialic acid content” with respect to a composition containing an IL-22 Fc fusion protein (e.g., a pharmaceutical composition or a batch) according to the invention refers to the total number of moles of sialic acid in the composition per mole of IL-22 Fc fusion protein in the composition. Thus, for example, such a composition may contain a heterogeneous pool of IL-22 Fc fusion proteins with individual IL-22 Fc fusion proteins within the composition having varying levels of sialylation (e.g., in the range of 0-25 moles of sialic acid per mole of IL-22 Fc fusion protein). Unless indicated otherwise, all values for sialic acid content, including average sialic acid content, described herein refer to dimeric IL-22 Fc fusion proteins.

The term “afucosylation,” “afucosylated,” “defucosylation,” or “defucosylated” refers to the absence or removal of core-fucose from an N-glycan, e.g., an N-glycan attached to a protein or a portion of a protein (e.g., the CH2 domain of Fc).

The term “dimeric IL-22 Fc fusion protein” refers to a dimer in which each monomer comprises an IL-22 Fc fusion protein. The term “monomeric IL-22 Fc fusion protein” refers to a dimer in which one monomer comprises an IL-22 Fc fusion protein (the IL-22 Fc arm), while the other monomer comprises an Fc region without the IL-22 polypeptide (the Fc arm). Accordingly, the dimeric IL-22 Fc fusion protein is bivalent with respect to IL-22R binding, whereas the monomeric IL-22 Fc fusion protein is monovalent with respect to IL-22R binding. The heterodimerization of the monomeric IL-22 Fc fusion protein can be facilitated by methods known in the art, including without limitation, heterodimerization by the knob-into- hole technology. The structure and assembly method of the knob-into-hole technology can be found in, e.g., US5.821.333, US7,642,228, US 2011/0287009, and PCT/US2012/059810, hereby incorporated by reference in their entireties. This technology was developed by introducing a “knob” (or a protuberance) by replacing a small amino acid residue with a large one in the CH3 domain of one Fc, and introducing a “hole” (or a cavity) in the CH3 domain of the other Fc by replacing one or more large amino acid residues with smaller ones. In certain embodiments, the IL-22 Fc fusion arm comprises a knob, and the Fc only arm comprises a hole.

The preferred residues for the formation of a knob are generally naturally occurring amino acid residues and are preferably selected from arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W). Most preferred are tryptophan and tyrosine. In one embodiment, the original residue for the formation of the knob has a small side chain volume, such as alanine, asparagine, aspartic acid, glycine, serine, threonine or valine. Exemplary amino acid substitutions in the CH3 domain for forming the knob include without limitation the T366W, T366Y, or F405W substitution.

The preferred residues for the formation of a hole are usually naturally occurring amino acid residues and are preferably selected from alanine (A), serine (S), threonine (T), and valine (V). In one embodiment, the original residue for the formation of the hole has a large side chain volume, such as tyrosine, arginine, phenylalanine, or tryptophan. Exemplary amino acid substitutions in the CH3 domain for generating the hole include without limitation the T366S, L368A, F405A, Y407A, Y407T, and Y407V substitutions. In certain embodiments, the knob comprises T366W substitution, and the hole comprises the T366S/L368A/Y407V substitutions. In certain particular embodiments, the Fc region of the monomeric IL-22 Fc fusion protein comprises an IgG 1 Fc region. In certain particular embodiments, the monomeric IL-22 IgG 1 Fc fusion comprises an IL-22 Fc knob arm and an Fc hole arm. In certain embodiments, the IL-22 Fc knob arm comprises a T366W substitution (SEQ ID NO:61 ), and the Fc hole arm comprises T366S, L368A, and Y407V (SEQ ID NO:62). In certain other embodiments, the Fc region of both arms further comprises an N297G or N297A mutation. In certain embodiments, the monomeric IL-22 Fc fusion protein is expressed in E. coli cells. It is understood that other modifications to the Fc region known in the art that facilitate heterodimerization are also contemplated and encompassed by the instant application.

“Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., a ligand or an antibody) and its binding partner (e.g., a receptor or an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., IL-22 Fc fusion protein and IL-22 receptor). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.

The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SFI, F(ab’)2, diabodies, linear antibodies, single-chain antibody molecules (e.g. scFv), and multispecific antibodies formed from antibody fragments.

The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, lgG3, lgG4, IgAi, and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, d, e, g, and m, respectively.

“Effector functions” or “effector activities” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody- dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation. In certain embodiments, the IL-22 Fc fusion protein does not exhibit any effector function or any detectable effector function. In certain other embodiments, the IL-22 Fc fusion protein exhibits substantially reduced effector function, e.g., about 50%, 60%, 70% 80%, or 90% reduced effector function.

The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. The transformed cell includes transiently or stably transformed cell. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein. In certain embodiments, the host cell is transiently transfected with the exogenous nucleic acid. In certain other embodiments, the host cell is stably transfected with the exogenous nucleic acid.

An “immunoconjugate” is an antibody or a fragment of an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

An “isolated” IL-22 Fc fusion protein is one which has been separated from the environment of a host cell that recombinantly produces the fusion protein. In some embodiments, an IL-22 Fc fusion protein is purified to greater than 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) approaches.

An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. The term “isolated nucleic acid encoding an IL-22 Fc fusion protein” refers to one or more nucleic acid molecules encoding an IL-22 Fc fusion protein, including such nucleic acid molecule(s) in a single vector or separate vectors, such nucleic acid molecule(s) transiently or stably transfected into a host cell, and such nucleic acid molecule(s) present at one or more locations in a host cell.

The term “control sequences” refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

“Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (l), based on the amino acid sequence of its constant domain.

The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6^th ed., W.H. Freeman and Co., page 91 (2007)). A single VFI or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include, without limitation, a native sequence human IgG 1 Fc region (non-A and A allotypes); native sequence human lgG2 Fc region; native sequence human lgG3 Fc region; and native sequence human lgG4 Fc region, as well as naturally occurring variants thereof.

A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith. In certain embodiments, the variant Fc region is not glycosylated.

A “disorder,” a “disease,” or a “condition,” as used interchangeably herein, is any condition that would benefit from treatment by a method described herein (e.g., a method that includes administering an IL-22 Fc fusion protein to the patient) or by a compound described herein (e.g., an IL-22 Fc fusion protein or a composition thereof (e.g., a pharmaceutical composition). This includes chronic and acute disorders or diseases including those pathological conditions which predispose the patient to the disorder in question. Exemplary disorders include, but are not limited to, respiratory diseases (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disorder (COPD), influenza (e.g., influenza A or B), lung diseases, and the like) and CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS). In particular embodiments, the disorder is pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS.

By “reduce or inhibit” is meant the ability to cause an overall decrease preferably of 20% or greater, more preferably of 50% or greater, and most preferably of 75%, 85%, 90%, 95%, or greater. Reduce or inhibit can refer to the symptoms of the disorder being treated (e.g., a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia))), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS)).

The terms “patient,” “subject,” or “individual,” as used interchangeably herein, refers to a human patient.

An “effective amount” or “therapeutically effective amount” of an agent, e.g., an IL-22 Fc fusion protein or a pharmaceutical formulation thereof, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. For example, the expression “effective amount” may refer to an amount of the IL-22 Fc fusion protein that is effective for treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia) and/or for treating or preventing acute respiratory distress syndrome (ARDS). In another example, the “effective amount” may refer to the amount of the IL-22 Fc fusion protein that is effective for treating or preventing CRS (e.g.,

CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS).

As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease (e.g., preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, chronic obstructive pulmonary disorder (COPD), influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS)), alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

The “pathology” of a disease or condition includes all phenomena that compromise the well-being of the patient.

“Amelioration,” “ameliorating,” “alleviation,” “alleviating,” or equivalents thereof, refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to ameliorate, prevent, slow down (lessen), decrease or inhibit a disease or condition, e.g., a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, chronic obstructive pulmonary disorder (COPD), influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell- induced CRS). Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in whom the disease or condition is to be prevented. “Chronic” administration refers to administration of an agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect for an extended period of time.

“Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.

An “intravenous” or “iv” dose, administration, or formulation of a drug is one which is administered via a vein, e.g. by infusion.

A “subcutaneous” or “sc” dose, administration, or formulation of a drug is one which is administered under the skin, e.g. via a pre-filled syringe, auto-injector, or other device.

The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications, and/or warnings concerning the use of such therapeutic products.

“Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

Below are examples of how to calculate the % amino acid sequence identity of the amino acid sequence designated “Comparison Protein” or “Reference Protein” to the amino acid sequence designated “IL-22,” wherein “IL-22” represents the amino acid sequence of an IL-22 polypeptide of interest, “Comparison Protein” represents the amino acid sequence of a polypeptide against which the “IL-22 “ polypeptide of interest is being compared, and “X,” “Y,” and “Z” each represent different amino acid residues.

IL-22 XXXXXXXXXXXXXXX (Length = 15 amino acids)

Reference Protein XXXXXYYYYYYY (Length = 12 amino acids)

% amino acid sequence identity =

(the number of identically matching amino acid residues between the two polypeptide sequences) divided by (the total number of amino acid residues of the IL-22 polypeptide) =

5 divided by 15 = 33.3%

IL-22 XXXXXXXXXX (Length = 10 amino acids)

Reference Protein XXXXXYYYYYYZZYZ (Length = 15 amino acids)

% amino acid sequence identity =

5 divided by 10 = 50%

The term “agonist” is used in the broadest sense and includes any molecule that partially or fully mimics a biological activity of an IL-22 polypeptide. Also encompassed by “agonist” are molecules that stimulate the transcription or translation of mRNA encoding the polypeptide.

Suitable agonist molecules include, e.g., agonist antibodies or antibody fragments; a native polypeptide; fragments or amino acid sequence variants of a native polypeptide; peptides; antisense oligonucleotides; small organic molecules; and nucleic acids that encode polypeptides agonists or antibodies. Reference to “an” agonist encompasses a single agonist or a combination of two or more different agonists.

The term “IL-22 agonist” is used in the broadest sense, and includes any molecule that mimics a qualitative biological activity (as hereinabove defined) of a native sequence IL-22 polypeptide. IL-22 agonists specifically include IL-22-Fc or IL-22 Ig polypeptides (immunoadhesins), but also small molecules mimicking at least one IL-22 biological activity. Preferably, the biological activity is binding of the IL-22 receptor, interacting with IL-22BP, or facilitating an innate immune response pathway.

IL-22R1 pairs with other proteins to form heterodimers as the receptors for certain IL-10 family members. See Ouyang et al., 2011 , supra. Thus, in certain embodiments, IL-22 agonists may include an

IL-22 receptor agonist, including a cytokine (or a fusion protein or agonist thereof) that binds to and triggers downstream signaling of the IL-22R1 . In certain embodiments, the IL-22 agonists include an IL- 22R1 agonist, including without limitation an anti-IL-22R1 agonist antibody; an IL-20 agonist, including without limitation IL-20 polypeptide or IL-20 Fc fusion protein; and an IL-24 agonist, including without limitation IL-24 polypeptide or IL-24 fusion protein. In certain other embodiments, the IL-22R1 agonists include an IL-19 agonist, including without limitation IL-19 polypeptide or IL-19 Fc fusion protein; and an IL-26 agonist, including without limitation IL-26 polypeptide or IL-26 Fc fusion protein. Exemplary sequences for IL-19 (GenBank Accession No. AAG16755.1 , SEQ ID NO:77), IL-20 (GenBank Accession No. AAH69311 .1 , SEQ ID NO:78), IL-24 (GenBank Accession No. AAH09681 .1 , SEQ ID NO:79) and IL- 26 (GenBank Accession No. NP_060872.1 , SEQ ID NO:80) are provided herein. In certain embodiments, an IL-19 polypeptide comprises the amino acid sequence of SEQ ID NO:77 or the mature protein without the signal peptide. In certain other embodiments, an IL-20 polypeptide comprises the amino acid sequence of SEQ ID NO:78 or the mature protein without the signal peptide. In yet other embodiments, an IL-24 polypeptide comprises the amino acid sequence of SEQ ID NO:79 or the mature protein without the signal peptide. In certain other embodiments, an IL-26 polypeptide comprises the amino acid sequence of SEQ ID NO:80 or the mature protein without the signal peptide.

A “small molecule” is defined herein to have a molecular weight below about 600, preferably below about 1000 daltons.

An “agonist antibody,” as used herein, is an antibody which partially or fully mimics a biological activity of an IL-22 polypeptide.

The terms “pharmaceutical formulation” or “pharmaceutical composition” are used interchangeably herein and refer to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. In one embodiment, the formulation is for intravenous (iv) administration.

A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, diluent, stabilizer, or preservative.

A "sterile" formulation is aseptic or free from all living microorganisms and their spores.

As used herein, “biological activity” of protein (e.g., an IL-22 Fc fusion protein) refers to the ability of the protein (e.g., an IL-22 Fc fusion protein) to bind its target, for example, the ability of an IL-22 Fc fusion protein to bind an IL-22 receptor. It can further include a biological response which can be measured in vitro or in vivo. Such activity may be antagonistic or agonistic. In particular embodiments, the activity is agonistic (e.g., receptor activation).

Within this application, unless otherwise stated, the techniques utilized may be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al. , 1989, Cold Spring Harbor Laboratory Press), PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, CA), and Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted. Before the present methods and uses therefore are described, it is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, animal species or genera, constructs, and reagents described as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

II. METHODS OF TREATMENT OR PREVENTION

Interleukin-22 (IL-22) belongs to the IL-10 cytokine family and binds specifically to the IL-22 receptor (IL-22R) heterodimer. IL-22R is expressed on a variety of epithelial and stromal tissues, including lung ciliated epithelial and endothelial cells, gastrointestinal (Gl) tract epithelium, epidermal keratinocytes, liver hepatocytes, pancreatic acinar epithelium, and renal tubular epithelium. IL-22 binding results in activation of the transcription factor STAT3. IL-22 signaling has been shown to increase lung epithelial cell proliferation and wound healing (Nguyen et al. Mediators Inflamm. 2020:6705428; Barthelemy et al. 2017) and to decrease apoptosis of epithelial and endothelial cells in acute lung injury models (Wu et al. Sci Rep. 2017 May 19;7(1 ):2210; Ren et al. Dis Markers. 2017;2017:1917804). IL-22 signaling also increases expression of tight junction proteins and antimicrobial proteins such as Reg3 (the murine homolog of the human Reg3a gene) (Ito et al. J Exp Med. 2017 Oct 2;214(10):3037-3050; Pichavant et al. EBioMedicine. 2015 Sep 26;2(11 ):1686-96). As a result, IL-22 modulates innate immunity through multiple different regenerative and protective mechanisms in epithelial tissues, including the Gl tract mucosal epithelium, epidermal keratinocytes, and lung epithelial cells.

IL-22 levels were shown to be reduced in the bronchoalveolar lavage of ARDS patients compared with healthy controls (Whittington et al. 2004). Furthermore, nonclinical studies have demonstrated that IL22 promotes endothelial and epithelial proliferation, barrier function and antimicrobial host defense (Ouyang and Valdez, Annu Rev Immunol 2011 ;29:71 —109). Specifically, IL-22 has been shown to increase lung epithelial cell proliferation and wound healing (Barthelemy et al. 2017, supra ; Nguyen et al. 2020, supra), increase expression of tight junction proteins (Barthelemy et al. 2017, supra ; Abood et al. Mucosal Immunol. 2019 Sep;12(5):1231 -1243., Hebert et al. 2020 Jan;13(1 ):64-74), and decrease apoptosis of epithelial and endothelial cells in acute lung injury models (Ren et al. 2017, supra ; Wu et al. 2017, supra). IL-22 directly increases endothelial barrier function by stabilizing intracellular junction proteins, reducing endothelial permeability following LPS, reducing apoptosis, and increasing proliferation. IL-22 also plays a role in protecting and repairing damage to lung epithelial tissue caused by high-pressure ventilation-induced damage and angiotensin ll-induced acute lung injury and edema. IL-22 decreases levels of cytokines (IL-6, IFN-g, IL-17A) and chemokines (MCP-1 , Ml P-1 a/b) in bronchoalveolar lavage, which correlates with decreased numbers of lung neutrophils and lymphocytes and reduced alveolitis in viral infection models (Abood et al. 2019, supra ; Hebert et al. 2020, supra). Moreover, treatment with post-viral murine IL-22 immunoglobulin fusion protein (IL-22Fc), a fusion protein with prolonged half-life in vivo, promotes repair of the lung epithelial barrier, reduces inflammation, and mitigates the pathological consequences of bacterial superinfections (Barthelemy et al. Infection and Immunity, 2018 Volume 86 Issue 7). In acute lung injury murine models, IL-22 was shown to be protective against multiple viral and bacterial respiratory pathogens and enhanced recovery (Abood et al. 2019, supra ; Barthelemy et al.

2018, supra, Pociask et al. Front Cell Dev Biol. 2016 Jan 13;3:85; Ivanov et al. J Virol. 2013 Jun;87(12):6911-24; Trevejo-Nunez et al. J Immunol. 2016 Sep 1 ;197(5):1877-83; Hebert et al. 2020, supra). In a murine model of bacterial superinfection post-influenza, treatment with murine IL-22Fc following viral infection increased pulmonary barrier function and decreased inflammation and systemic dissemination of bacteria (Barthelemy et al. 2018, supra). Pretreatment of small intestinal epithelial cells with porcine IL-22 prior to infection with swine enteric alpha CoVs showed dose-dependent inhibition of viral infection (Xue et al. Antiviral Res. 2017 Jun;142:68-75). IL-22 treatment of lung epithelial cells induces antimicrobial protein production such as Reg3y (REG3A is human equivalent) (Pichavant et al. 2015, supra ; Ito et al. 2017, supra), and protects against influenza virus-bacterial co-infection (Ivanov et al. 2013, supra ; Abood et al. 2019, supra) and coronavirus infection (Xue et al. 2017, supra).

Furthermore, IL-22 induces the expression of other anti-bacterial factors such as Lipocalin, Defal ,

Defb14, and Crp in lung epithelial cells.

In the gastrointestinal tract, IL-22 can increase mucin gene expression through STAT3- dependent signaling (Sugimoto et al. J Clin Invest. 2008 Feb;118(2):534-44) and promotes goblet cell hyperplasia activation (Turner PLoS Pathog. 2013;9(10):e1003698). However, different types of mucins are expressed in gastrointestinal and respiratory mucosa where lung secretory cells secrete MUC5B and MUC5AC, which are important for mucociliary clearance of pathogens. Excessive secretion of mucins or changes in MUC5AC:MUC5B mucin ratio that affects fluidity can contribute to mucus plugging and airway obstruction in chronic diseases such as COPD and cystic fibrosis. Studies conducted by the Sponsor showed that IL-22Fc treatment of primary human bronchial epithelial cells grown at air-liquid interface for 24 hours did not significantly increase expression of mucin or secretory cell genes, nor alter the ratio of the MUC5AC:MUC5B gene expression, generally considered a measure of pathogenic mucus. These genes were also unchanged in the lungs of mice administered murine IL-22Fc intranasally or intravenously after 24 hours. In addition, goblet cell hyperplasia was not observed following intravenous administration of IL-22Fc to mice exposed to cigarette smoke for 8 weeks followed by lung injury by influenza virus infection for 1 week, by PAS/AB histology staining. Neither increased mucus nor goblet cell hyperplasia have been reported following IL-22 treatment in respiratory infection studies (Barthelemy et al. 2018, supra).

Thus, provided herein are methods of treating or preventing respiratory diseases or CRS in a patient that include administering to the patient an IL-22 agonist such as an IL-22 Fc fusion protein or a pharmaceutical composition thereof. Also provided are related uses, compositions, articles of manufacture, and kits.

A. Methods, Compositions, and Uses for Treating or Preventing Pneumonia, ARDS, other Respiratory Diseases, and CRS

The majority of patients with COVID-19 present with symptoms ranging from asymptomatic transmission via respiratory droplets to mild disease with fever, cough, and shortness of breath that resolve with supportive care. However, approximately 20% of patients develop severe disease requiring hospitalization, and up to 10% of the total infected population require ICU admission. The dominant finding in critically ill COVID-19 patients is interstitial pneumonia, which progresses to acute respiratory distress syndrome (ARDS) and hypoxemic respiratory failure. Complications of COVID-19 include acute kidney injury, elevated liver enzymes, pericarditis, multiple organ failure (MOF) and death (WHO 2020), with in-hospital mortality rates of approximately 25%. Risk factors for progression to severe COVID-19 include advanced age, cardiovascular disease, diabetes mellitus, chronic lung disease, and chronic kidney disease (Liang et al. 2020; Wu et al. 2020; Zhou et al. 2020).

ARDS, which is characterized by increased epithelial and endothelial permeability leading to alveolar edema, has been observed in 16%-42% of patients with severe COVID-19. Typical imaging findings are consistent with viral pneumonia, showing rapidly worsening bilateral pulmonary opacities and ground glass opacification with or without consolidation. Early-phase ARDS with epithelial desquamation, hyaline membrane formation, and edema was seen in lung pathology in a patient who died of COVID-19. Hyperinflammatory responses, including increased pro-inflammatory cytokines (interleukin-6) and other inflammatory markers (ferritin and D dimer) are associated with increased mortality in patients with COVID-19. Approximately 10% of COVID-19 patients develop secondary bacterial infections, and 50% of those patients have died.

In general, the methods, compositions, and uses of the invention described herein include administering an IL-22 Fc fusion protein (e.g., any IL-22 Fc fusion protein described herein, e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to a patient having or at risk for a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS).

In one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

For example, provided herein is a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In yet another example, provided herein is a method of treating or preventing ARDS in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In another aspect, provided herein is a method of reducing disease progression to ARDS in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In yet another aspect, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In another aspect, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In another aspect, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In another aspect, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving interferon (IFN)-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In another aspect, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID

NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient. For example, in any of the methods, compositions, and uses disclosed herein, the anti-bacterial epithelial factor may be any anti-bacterial factor that is induced by IL-22. Exemplary anti-bacterial epithelial factors are described, e.g., in Barthelemy et al. Infect. Immun. 86:e00706-17, 2018; Abood et al. Mucusal Immunology 12:1231-1243, 2019; and Ito et al. J. Exp. Med. 214(10):3037-3050, 2017, which are incorporated herein by reference in their entirety. In some examples, the anti-bacterial epithelial factors include a regenerating (REG) protein family member (e.g., REG3A). In some examples, the anti bacterial epithelial factors include one or more defensins (e.g., DEFA1 or DEFB14). In some examples, the anti-bacterial epithelial factors include one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or all 10) of REG3A, Lipocalin 2, INFAR1 , INFA11 , CXCL10, DEFA1 , DEFB14, midkine (MDK), pleiotrophin (PTN), and C- reactive protein (CRP).

In some examples, the anti-bacterial epithelial factors include REG3A.

In some examples, the anti-bacterial epithelial factors include Lipocalin 2.

In some examples, the anti-bacterial epithelial factors include INFAR1 .

In some examples, the anti-bacterial epithelial factors include INFA11 .

In some examples, the anti-bacterial epithelial factors include CXCL10.

In some examples, the anti-bacterial epithelial factors include DEFA1 .

In some examples, the anti-bacterial epithelial factors include DEFB14.

In some examples, the anti-bacterial epithelial factors include MDK.

In some examples, the anti-bacterial epithelial factors include PTN.

In some examples, the anti-bacterial epithelial factors include CRP.

In another aspect, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient.

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient.

In yet another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing ARDS in a patient. In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing disease progression to ARDS in a patient.

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like).

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS.

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing lung inflammation in a patient without compromising antiviral host defense.

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance.

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient.

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like).

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS. In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing ARDS in a patient.

In another aspect provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing disease progression to ARDS in a patient.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma,

COPD, influenza (e.g., influenza A or B), lung diseases, and the like).

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing lung inflammation in a patient without compromising antiviral host defense.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like).

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection.

In another aspect, provided herein is a method of treating or preventing cytokine release syndrome (CRS) (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient.

In yet another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient.

In yet another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient. Any suitable form of CRS can be treated or prevented in accordance with the methods, compositions, and uses disclosed herein. For example, the CRS may be caused by a viral infection (e.g., a coronavirus infection such as COVID-19). For example, another non-limiting form of CRS is CAR T- cell-induced CRS.

The IL-22 Fc fusion protein may be administered at any suitable dose, e.g., any dose described herein. For example, in some instances, the IL-22 Fc fusion protein is administered at a dose of between about 30 pg/kg and about 120 pg/kg. For example, in some instances, the IL-22 Fc fusion protein is administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg. In particular instances, the IL-22 Fc fusion protein is administered at a dose of 90 pg/kg. In other particular instances, the IL-22 Fc fusion protein is administered at a dose of 60 pg/kg. Additional non-limiting doses are described below.

In one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is a method of treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In yet another example, provided herein is a method of treating or preventing ARDS in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is a method of reducing disease progression to ARDS in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In yet another aspect, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously. In another aspect, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In yet another example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg. In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL- 22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered at a dose between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In another aspect, provided herein is a method of treating or preventing CRS (e.g., CAR T-cell- induced CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 to the patient at a dose of between about 30 pg/kg to about 120 pg/kg.

In yet another aspect, provided herein is an IL-22 Fc fusion comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 for use in treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID- 19) or CAR-T-cell-induced CRS) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In yet another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 in the manufacture of a medicament for treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

In one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

For example, provided herein is a method of treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In yet another example, provided herein is a method of treating or preventing ARDS in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is a method of reducing disease progression to ARDS in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In yet another aspect, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously. In another aspect, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In yet another example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL- 22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously. In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously. For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In another aspect, provided herein is a method of treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 to the patient at a dose of 90 pg/kg intravenously. In yet another aspect, provided herein is an IL-22 Fc fusion comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 for use in treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID- 19) or CAR-T-cell-induced CRS) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.

In yet another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 in the manufacture of a medicament for treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 90 pg/kg intravenously.ln one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma,

COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

For example, provided herein is a method of treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In yet another example, provided herein is a method of treating or preventing ARDS in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of reducing disease progression to ARDS in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In yet another aspect, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In yet another example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL- 22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

For example, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously. For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

For example, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 in the manufacture of a medicament for prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In another aspect, provided herein is a method of treating or preventing CRS (e.g., CAR T-cell- induced CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 to the patient at a dose of 60 pg/kg intravenously.

In yet another aspect, provided herein is an IL-22 Fc fusion comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 for use in treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID- 19) or CAR-T-cell-induced CRS) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

In yet another aspect, provided herein is the use of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20 in the manufacture of a medicament for treating or preventing CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS) in a patient, wherein the IL-22 Fc fusion protein is to be administered at a dose of 60 pg/kg intravenously.

Any suitable number of doses may be administered to the patient. For example, in some instances, a single dose is administered to the patient. In other instances, more than one dose (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or more doses) of the IL-22 Fc fusion protein is administered to the patient. Any number of doses described herein may be administered to the patient, e.g., about one to about twenty doses, about one to about nineteen doses, about one to about eighteen doses, about one to about seventeen doses, about one to about sixteen doses, about one to about fifteen doses, about one to about fourteen doses, about one to about thirteen doses, about one to about twelve doses, about one to about eleven doses, about one to about ten doses, about one to about nine doses, about one to about eight doses, about one to about seven doses, about one to about six doses, about one to about five doses, about one to about four doses, about one to about three doses, about one to about two doses, about two to about twenty doses, about two to about nineteen doses, about two to about eighteen doses, about two to about seventeen doses, about two to about sixteen doses, about two to about fifteen doses, about two to about fourteen doses, about two to about thirteen doses, about two to about twelve doses, about two to about eleven doses, about two to about ten doses, about two to about nine doses, about two to about eight doses, about two to about seven doses, about two to about six doses, about two to about five doses, about two to about four doses, about two to about three doses, about three to about twenty doses, about three to about nineteen doses, about three to about eighteen doses, about three to about seventeen doses, about three to about sixteen doses, about three to about fifteen doses, about three to about fourteen doses, about three to about thirteen doses, about three to about twelve doses, about three to about eleven doses, about three to about ten doses, about three to about nine doses, about three to about eight doses, about three to about seven doses, about three to about six doses, about three to about five doses, about three to about four doses, about four to about twenty doses, about four to about nineteen doses, about four to about eighteen doses, about four to about seventeen doses, about four to about sixteen doses, about four to about fifteen doses, about four to about fourteen doses, about four to about thirteen doses, about four to about twelve doses, about four to about eleven doses, about four to about ten doses, about four to about nine doses, about four to about eight doses, about four to about seven doses, about four to about six doses, about four to about five doses, about five to about twenty doses, about five to about nineteen doses, about five to about eighteen doses, about five to about seventeen doses, about five to about sixteen doses, about five to about fifteen doses, about five to about fourteen doses, about five to about thirteen doses, about five to about twelve doses, about five to about eleven doses, about five to about ten doses, about five to about nine doses, about five to about eight doses, about five to about seven doses, about five to about six doses, about six to about twenty doses, about six to about nineteen doses, about six to about eighteen doses, about six to about seventeen doses, about six to about sixteen doses, about six to about fifteen doses, about six to about fourteen doses, about six to about thirteen doses, about six to about twelve doses, about six to about eleven doses, about six to about ten doses, about six to about nine doses, about six to about eight doses, about six to about seven doses, about seven to about twenty doses, about seven to about nineteen doses, about seven to about eighteen doses, about seven to about seventeen doses, about seven to about sixteen doses, about seven to about fifteen doses, about seven to about fourteen doses, about seven to about thirteen doses, about seven to about twelve doses, about seven to about eleven doses, about seven to about ten doses, about seven to about nine doses, about seven to about eight doses, about eight to about twenty doses, about eight to about nineteen doses, about eight to about eighteen doses, about eight to about seventeen doses, about eight to about sixteen doses, about eight to about fifteen doses, about eight to about fourteen doses, about eight to about thirteen doses, about eight to about twelve doses, about eight to about eleven doses, about eight to about ten doses, about eight to about nine doses, about nine to about twenty doses, about nine to about nineteen doses, about nine to about eighteen doses, about nine to about seventeen doses, about nine to about sixteen doses, about nine to about fifteen doses, about nine to about fourteen doses, about nine to about thirteen doses, about nine to about twelve doses, about nine to about eleven doses, about nine to about ten doses, about ten to about twenty doses, about ten to about nineteen doses, about ten to about eighteen doses, about ten to about seventeen doses, about ten to about sixteen doses, about ten to about fifteen doses, about ten to about fourteen doses, about ten to about thirteen doses, about ten to about twelve doses, about ten to about eleven doses, about eleven to about twenty doses, about eleven to about nineteen doses, about eleven to about eighteen doses, about eleven to about seventeen doses, about eleven to about sixteen doses, about eleven to about fifteen doses, about eleven to about fourteen doses, about eleven to about thirteen doses, about eleven to about twelve doses, about twelve to about twenty doses, about twelve to about nineteen doses, about twelve to about eighteen doses, about twelve to about seventeen doses, about twelve to about sixteen doses, about twelve to about fifteen doses, about twelve to about fourteen doses, about twelve to about thirteen doses, about thirteen to about twenty doses, about thirteen to about nineteen doses, about thirteen to about eighteen doses, about thirteen to about seventeen doses, about thirteen to about sixteen doses, about thirteen to about fifteen doses, about thirteen to about fourteen doses, about fourteen to about twenty doses, about fourteen to about nineteen doses, about fourteen to about eighteen doses, about fourteen to about seventeen doses, about fourteen to about sixteen doses, about fourteen to about fifteen doses, about fifteen to about twenty doses, about fifteen to about nineteen doses, about fifteen to about eighteen doses, about fifteen to about seventeen doses, about fifteen to about sixteen doses, about sixteen to about twenty doses, about sixteen to about nineteen doses, about sixteen to about eighteen doses, about sixteen to about seventeen doses, about seventeen to about twenty doses, about seventeen to about nineteen doses, about seventeen to about eighteen doses, about eighteen to about twenty doses, about eighteen to about nineteen doses, or about nineteen to about twenty doses.

For example, in some instances, the method comprises administering at least a first dose and a second dose of the IL-22 Fc fusion protein to the patient. The second dose may be administered to the patient about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, or longer, after the first dose. In some instances, the second dose is administered about 7 to about 21 days after the first dose. In some instances, the second dose is administered 14 days after the first dose.

In some embodiments, the dose(s) (e.g., the first dose, the second dose, and any additional dose(s)) are administered to the patient every week (q1 w), every two weeks (q2w), every three weeks (q3w), every four weeks, (q4w), every five weeks (q5w), every six weeks (q6w), every seven weeks (q7w), every eight weeks (q8w), every nine weeks (q9w), every ten weeks (q1 Ow), every 12 weeks (q12w), every fourteen weeks (q14w), every sixteen weeks (q16w), every eighteen weeks (q18w), or every twenty weeks (q20w). For example, in some embodiments, the doses are administered to the patient every week (q1 w), every two weeks (q2w), every four weeks (q4w), or every six weeks (q6w). For example, in particular instances, the IL-22 Fc fusion protein is administered to the patient every two weeks (q2w).

In one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

For example, provided herein is a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In yet another example, provided herein is a method of treating or preventing ARDS in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of reducing disease progression to ARDS in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In yet another aspect, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient every two weeks (q2w).

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient every two weeks (q2w).

In yet another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing ARDS in a patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing disease progression to ARDS in a patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) every two weeks (q2w).

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient every two weeks (q2w).

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient every two weeks (q2w).

In yet another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing ARDS in a patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing disease progression to ARDS in a patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma,

COPD, influenza (e.g., influenza A or B), lung diseases, and the like) every two weeks (q2w). For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient every two weeks (q2w).

In another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In another aspect, provided herein is a method of treating or preventing CRS (e.g., CAR T-cell- induced CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient every two weeks (q2w).

In yet another aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing CRS (e.g., CAR T-cell-induced CRS) in a patient every two weeks (q2w).

In yet another aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing CRS (e.g., CAR T-cell-induced CRS) in a patient every two weeks (q2w).

In some embodiments, the patient experiences improvement of clinical status after the first dose. In some instances, a second dose or additional dose is administered to a patient who experiences improvement of clinical status after the first dose.

In other embodiments, the patient experiences no improvement or worsening of clinical status after the first dose. In some instances, a second or additional dose is administered to the patient who experiences no improvement or worsening of clinical status after the first dose. In some instances, the patient experiences > one-category worsening on an ordinal scale of clinical status following the first dose.

In some embodiments, the patient remains in a hospital and/or is receiving oxygen after the first dose. In some instances, the second or additional dose is administered to a patient who remains in a hospital and/or is receiving oxygen. In some instances, the second or additional dose is administered to a patient who remains in a hospital. In some instances, the second or additional dose is administered to a patient who is receiving oxygen.

For example, in one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is a method of treating or preventing ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example still, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL- 22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is an IL-22 Fc fusion protein for use in a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or

B), lung diseases, and the like) in a patient, the method comprising: (a) administering a first dose of an IL- 22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is an IL-22 Fc fusion protein for use in a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is an IL-22 Fc fusion protein for use in a method of treating or preventing acute respiratory distress syndrome (ARDS) in a patient, the method comprising:

(a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is an IL-22 Fc fusion protein for use in a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is an IL-22 Fc fusion protein for use in a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is an IL-22 Fc fusion protein for use in a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID

NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is an IL-22 Fc fusion protein for use in a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is an IL-22 Fc fusion protein for use in a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is an IL-22 Fc fusion protein for use in a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is an IL-22 Fc fusion protein for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose if the patient remains in a hospital and is receiving oxygen.

For example, provided herein is an IL-22 Fc fusion protein for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NQ:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose if the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is an IL-22 Fc fusion protein for use in a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of treating or preventing ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen. In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen. In a further example still, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose if the patient remains in a hospital and is receiving oxygen.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose if the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein to the patient; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In any of the preceding examples, the second dose may be administered to the patient 14 days after the first dose.

Any suitable first dose of the IL-22 Fc fusion protein may be administered to the patient, e.g., any dose described herein. For example, in some instances, the first dose is between about 30 pg/kg to about 120 pg/kg. For example, in some instances, the first dose is about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg. In particular instances, the first dose is about 90 pg/kg. In other particular instances, the first dose is about 60 pg/kg. Additional non-limiting doses are described below.

Any suitable second dose of the IL-22 Fc fusion protein may be administered to the patient, e.g., any dose described herein. For example, in some instances, the first dose is between about 30 pg/kg to about 120 pg/kg. For example, in some instances, the second dose is about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg. In particular instances, the second dose is about 90 pg/kg. In other particular instances, the second dose is about 60 pg/kg. Additional non-limiting doses are described below.

For example, in one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is a method of treating or preventing ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen. In another example, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example still, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: ((a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is an IL-22 Fc fusion protein for use in a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, the method comprising: (a) administering a first dose of an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is an IL-22 Fc fusion protein for use in a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

(a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is an IL-22 Fc fusion protein for use in a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is an IL-22 Fc fusion protein for use in a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is an IL-22 Fc fusion protein for use in a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia

(e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is an IL-22 Fc fusion protein for use in a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is an IL-22 Fc fusion protein for use in a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is an IL-22 Fc fusion protein for use in a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is an IL-22 Fc fusion protein for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is an IL-22 Fc fusion protein for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is an IL-22 Fc fusion protein for use in a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of treating or preventing acute respiratory distress syndrome (ARDS) in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22

Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10,

SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of reducing disease progression to ARDS in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In yet a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In a further example still, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for use in a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising: (a) administering a first dose of an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8 to the patient at a dose of 90 pg/kg intravenously; and (b) administering a second dose of the IL-22 Fc fusion protein to the patient at a dose of 90 pg/kg intravenously 14 days following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

The patient may have a respiratory disease. Any suitable respiratory disease may be treated or prevented by administration of an IL-22 Fc fusion protein, e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like.

The patient may have a viral infection. In some instances, the viral infection is a coronavirus infection, e.g., an infection with SARS-CoV-2, MERS-CoV, or SARS-CoV.

In particular instances, the coronavirus infection is COVID-19. In one embodiment, the patient with COVID-19 is confirmed by positive polymerase chain reaction (PCR) test (e.g. real time PCT, RT- PCT test) of a specimen (e.g., respiratory, blood, urine, stool, other bodily fluid specimen) from the patient. In one embodiment, the COVID-19 nucleic acid sequence has been determined to be highly homologous to COVID-19. In one embodiment, the patient has COVID-19 specific antibodies (e.g. IgG and/or IgM antibodies), e.g. as determined by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), etc.

In some embodiments, the patient may have pneumonia or ARDS or is at risk of developing pneumonia or ARDS. In some embodiments, the ARDS has progressed from pneumonia.

The methods, compositions, and uses can be used to treat or prevent ARDS of any cause. In some non-limiting examples, the ARDS may be caused, for example, by a primary pulmonary infection (e.g., a viral infection, e.g., by COVID-19), a systemic infection that spreads to the lungs (e.g., sepsis), or a non-infectious cause (e.g., trauma or hypotensive shock).

In one embodiment, the pneumonia is severe pneumonia.

In one embodiment, the pneumonia is critical pneumonia.

In one embodiment, the pneumonia is moderate pneumonia.

In one embodiment, the pneumonia is moderate-severe pneumonia.

In one embodiment, the pneumonia is viral pneumonia.

In one embodiment, the viral pneumonia is coronavirus pneumonia.

In one embodiment, the pneumonia is COVID-19 pneumonia, Middle East respiratory syndrome (MERS-CoV) pneumonia, or severe acute respiratory syndrome (SARS-CoV) pneumonia.

In one embodiment, the viral pneumonia is COVID-19 pneumonia.

In one embodiment, the viral pneumonia is severe COVID-19 pneumonia.

In one embodiment, the viral pneumonia is critical COVID-19 pneumonia.

In one embodiment, the viral pneumonia is moderate COVID-19 pneumonia.

In one embodiment, the viral pneumonia is moderate-severe COVID-19 pneumonia.

In one embodiment, the pneumonia is interstitial pneumonia.

The invention provides methods of treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) with an IL-22 Fc fusion protein, which achieves a greater improvement in clinical outcome than standard of care (SOC). In one aspect, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is a method of treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is a method of treating or preventing ARDS in a patient comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In yet another example, provided herein is a method of reducing disease progression to ARDS in a patient comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example, provided herein is a method of promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is a method of promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is a method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID

NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In yet another example, provided herein is a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example, provided herein is a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example still, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In one aspect, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing a respiratory disease

(e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In yet another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting convalescence of a patient having pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In yet another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in reducing maladaptive hyper- inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example still, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in inducing expression of anti bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma,

COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In one aspect, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID

NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma,

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting convalescence of a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status. In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In yet another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In a further example still, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like), wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for inducing expression of anti-bacterial epithelial factors in a patient having pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

In another example, provided herein is the use of an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) in the manufacture of a medicament for prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

For example, the invention provides methods of treating pneumonia (e.g. viral pneumonia, coronavirus pneumonia, or COVID-19 pneumonia) with an IL-22 Fc fusion protein, which achieves a greater improvement in clinical outcome than standard of care (SOC).

Methods for confirming the improvement in clinical outcome compared with SOC, include, without limitation, any one or more of the following:

1 . clinical outcome measured on an ordinal scale of clinical status (e.g. at Day 28 and/or Day 60);

2. clinical outcome measured on a 7-category ordinal scale of clinical status (e.g. at Day 28 and/or

Day 60);

3. clinical outcome comprising time to improvement of at least 2 categories relative to baseline on a

7-category ordinal scale of clinical status (e.g. at Day 28 and/or Day 60);

4. clinical outcome comprising time to clinical improvement (TTCI) defined as a National Early

Warning Score 2 (NEWS2) of < 2 maintained for 24 hours;

5. incidence of mechanical ventilation (e.g. at Day 28 and/or Day 60);

6. ventilator-free days (e.g. to Day 28);

7. organ failure-free days (e.g. to Day 28 and/or Day 60);

8. incidence of intensive care unit (ICU) stay (e.g. to Day 28 and/or Day 60);

9. duration of ICU stay (e.g. to Day 28 and/or Day 60);

10. time to clinical failure, e.g. defined as the time to death, mechanical ventilation, ICU admission, or withdrawal, whichever occurs first;

11 . mortality rate (e.g. at Days 7, 14, 21 , 28, and 60 following treatment on Day 1 ).

12. time to hospital discharge;

13. time to ready for discharge (e.g. as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or < 2L supplemental oxygen);

14. duration of supplemental oxygen;

15. incidence of vasopressor use;

16. duration of vasopressor use;

17. incidence of extracorporeal membrane oxygenation (ECMO); and

18. duration of ECMO

19. incidence of starting hemodialysis

20. SARS-CoV-22 viral load (e.g., on Day 15 or on day of hospital discharge (whichever occurs first)

21 . The proportion of patients with secondary bacterial infections.

In one embodiment, the method of treatment with the IL-22 Fc fusion protein is associated with acceptable safety outcome compared with standard of care (SOC). Exemplary safety outcomes include any one or more of:

1 . incidence and severity of adverse events;

2. severity of adverse events determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0; 3. COVID-19 (SARS-CoV-2) viral load over time;

4. time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity;

5. post-treatment infection; and

6. change from baseline in targeted clinical laboratory test results.

Any suitable SOC may be used. For example, SOC for pneumonia, in particular viral pneumonia (such as COVID-19 pneumonia) includes any one or more of (e.g. one, two, or three of):

1. supportive care;

2. one or more anti-viral agent(s);

3. one or more corticosteroid(s), e.g. low dose corticosteroid(s).

In one embodiment, the SOC comprises supportive care. Example of supportive care, include, without limitation:

1 . oxygen therapy (e.g. via face mask or nasal cannula; high-flow nasal oxygen therapy or non- invasive mechanical ventilation; invasive mechanical ventilation; lung expansion via extracorporeal membrane oxygenation (ECMO), etc.);

2. circulation support (e.g. fluid resuscitation, boost microcirculation, and/or vasoactive drugs);

3. renal replacement therapy;

4. plasma therapy;

5. blood purification therapy;

6. Xuebijing Injection (e.g. 100 mL/day twice a day); and

7. microecological agents (e.g. probiotics, prebiotics, and synbiotics), etc.

In one embodiment, the SOC includes treatment with one or more anti-viral agents (preferably only one or two) anti-viral agent(s). Exemplary anti-viral treatments include, without limitation:

1 . alpha-interferon (e.g. via nebulization; e.g. about 5 million units or equivalent per time for adult, add 2 ml_ of sterile water for injection; e.g. via aerosol inhalation twice per day);

2. lopinavir/ritonavir (e.g. 200 mg/50 mg per capsule, 2 capsules each time, twice per day for adults, e.g. <10 days);

3. ribavirin (e.g. combined with alpha-interferon or lopinavir/ritonavir, e.g. 500 mg for adults per time, 2-3 times per day intravenously, e.g. <10 days);

4. Chloroquine phosphate or hydroxychloroquine (e.g. for adults from 18 to 65 years of age; e.g. if the body weight is greater than 50 kg, 500 mg per time, twice per day for 7 days; if the body weight is less than 50 kg, 500 mg per time, twice per day for day 1 and day 2; 500 mg per time, once per day for day 3 to 7); and

5. Umifenovir (e.g. 200 mg for adults, e.g. three times per day, e.g. <10 days).

In one embodiment, the SOC includes treatment with corticosteroid(s), e.g.

1 . wherein the patient has progressive deterioration of oxygenation, rapid X-ray progression, and/or excessive inflammatory response;

2. prednisone, prednisolone, methylprednisolone, methylprednisolone sodium succinate, dexamethasone, dexamethasone triamcinolone, hydrocortisone, and/or betamethasone; 3. prednisone, methylprednisolone, hydrocortisone, or dexamethasone.

4. methylprednisolone;

5. “low dose” corticosteroid;

6. corticosteroid administered < 1-2 mg/kg/day;

7. methylprednisolone < 1-2 mg/kg/day;

8. methylprednisolone < 1 -2 mg/kg/day for 3-5 days.

In one aspect, the invention provides a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR T-cell-induced CRS) that includes administering to the patient an IL-22 Fc fusion protein in a dosing regimen comprising a dosing cycle, wherein the dosing cycle comprises at least one or at least two doses of the IL-22 Fc fusion protein. In some embodiments, a total of about 1 pg/kg to about 900 pg/kg of the IL-22 Fc fusion protein is administered to the patient in the dosing cycle. In some embodiments, each dose of the IL-22 Fc fusion protein is a dose in the range of 30 to 120 pg/kg. In some embodiments, each dose of the IL-22 Fc fusion protein is a dose selected from 30, 45, 60, 90, and 120 pg/kg.

In some embodiments, provided herein is a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR T-cell-induced CRS) that includes administering to the patient an IL-22 Fc fusion protein in a dosing regimen comprising a dosing cycle, wherein the dosing cycle comprises between one and ten doses, and wherein a total of about 30 pg/kg to about 900 pg/kg of the IL-22 Fc fusion protein is administered to the patient in the dosing cycle. In some embodiments, the doses are administered to the patient every week (q1 w), every two weeks (q2w), every three weeks (q3w), or every four weeks (q4w). Preferably, the doses are administered every two weeks. In some embodiments, the doses are administered until symptoms of the disease being treated are resolved. In some embodiments, a total dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, about 180 pg/kg, about 270 pg/kg, about 360 pg/kg, or about 540 pg/kg of the IL-22 Fc fusion protein is administered to the patient over the course of the dosing cycle.

In another aspect, the invention features a method of treating or preventing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) or CRS that includes administering to the patient an IL-22 Fc fusion protein every two weeks (q2w).

In another aspect, the invention features a method of treating or preventing pneumonia in a patient that includes administering to the patient an IL-22 Fc fusion protein every one week, every two weeks (q2w), or every three weeks. In some aspects, the pneumonia is viral pneumonia. In some aspects the pneumonia is coronavirus-associated pneumonia. In another aspect, the invention features a method of treating or preventing ARDS in a patient that includes administering to the patient an IL-22 Fc fusion protein every one week, every two weeks (q2w), or every three weeks. In some embodiments, the total dose of IL-22 Fc fusion protein in the dosing regimen is between about 1 pg/kg to about 500 pg/kg, between about 1 pg/kg to about 450 pg/kg, between about 1 pg/kg to about 400 pg/kg, between about 1 pg/kg to about 350 pg/kg, between about 1 pg/kg to about 300 pg/kg, between about 1 pg/kg to about 250 pg/kg, between about 1 pg/kg to about 200 pg/kg, between about 1 pg/kg to about 150 pg/kg, between about 1 pg/kg to about 135 pg/kg, between about 1 pg/kg to about 100 pg/kg, between about 1 pg/kg to about 90 pg/kg, between about 1 pg/kg to about 75 pg/kg, between about 1 pg/kg to about 50 pg/kg, between about 1 pg/kg to about 25 pg/kg, between about 25 pg/kg to about 500 pg/kg, between about 25 pg/kg to about 450 pg/kg, between about 25 pg/kg to about 400 pg/kg, between about 25 pg/kg to about 350 pg/kg, between about 25 pg/kg to about 300 pg/kg, between about 25 pg/kg to about 250 pg/kg, between about 25 pg/kg to about 200 pg/kg, between about 25 pg/kg to about 150 pg/kg, between about 25 pg/kg to about 135 pg/kg, between about 25 pg/kg to about 100 pg/kg, between about 25 pg/kg to about 75 pg/kg, between about 25 pg/kg to about 50 pg/kg, between about 50 pg/kg to about 500 pg/kg, between about 50 pg/kg to about 450 pg/kg, between about 50 pg/kg to about 400 pg/kg, between about 50 pg/kg to about 350 pg/kg, between about 50 pg/kg to about 300 pg/kg, between about 50 pg/kg to about 250 pg/kg, between about 50 pg/kg to about 200 pg/kg, between about 50 pg/kg to about 150 pg/kg, between about 50 pg/kg to about 135 pg/kg, between about 50 pg/kg to about 100 pg/kg, between about 50 pg/kg to about 75 pg/kg, between about 75 pg/kg to about 500 pg/kg, between about 75 pg/kg to about 450 pg/kg, between about 75 pg/kg to about 400 pg/kg, between about 75 pg/kg to about 350 pg/kg, between about 75 pg/kg to about 300 pg/kg, between about 75 pg/kg to about 250 pg/kg, between about 75 pg/kg to about 200 pg/kg, between about 75 pg/kg to about 150 pg/kg, between about 75 pg/kg to about 135 pg/kg, between about 75 pg/kg to about 100 pg/kg, between about 80 pg/kg to about 500 pg/kg, between about 80 pg/kg to about 450 pg/kg, between about 80 pg/kg to about 400 pg/kg, between about 80 pg/kg to about 350 pg/kg, between about 80 pg/kg to about 300 pg/kg, between about 80 pg/kg to about 250 pg/kg, between about 80 pg/kg to about 200 pg/kg, between about 80 pg/kg to about 150 pg/kg, between about 80 pg/kg to about 135 pg/kg, between about 80 pg/kg to about 100 pg/kg, between about 90 pg/kg to about 500 pg/kg, between about 90 pg/kg to about 450 pg/kg, between about 90 pg/kg to about 400 pg/kg, between about 90 pg/kg to about 350 pg/kg, between about 90 pg/kg to about 300 pg/kg, between about 90 pg/kg to about 250 pg/kg, between about 90 pg/kg to about 200 pg/kg, between about 90 pg/kg to about 150 pg/kg, between about 90 pg/kg to about 135 pg/kg, between about 90 pg/kg to about 100 pg/kg, between about 100 pg/kg to about 500 pg/kg, between about 100 pg/kg to about 450 pg/kg, between about 100 pg/kg to about 400 pg/kg, between about 100 pg/kg to about 350 pg/kg, between about 100 pg/kg to about 300 pg/kg, between about 100 pg/kg to about 250 pg/kg, between about 100 pg/kg to about 200 pg/kg, between about 100 pg/kg to about 150 pg/kg, between about 100 pg/kg to about 135 pg/kg, between about 125 pg/kg to about 500 pg/kg, between about 125 pg/kg to about 450 pg/kg, between about 125 pg/kg to about 400 pg/kg, between about 125 pg/kg to about 350 pg/kg, between about 125 pg/kg to about 300 pg/kg, between about 125 pg/kg to about 250 pg/kg, between about 125 pg/kg to about 200 pg/kg, between about 125 pg/kg to about 150 pg/kg, between about 125 pg/kg to about 135 pg/kg, between about 135 pg/kg to about 500 pg/kg, between about 135 pg/kg to about 450 pg/kg, between about 135 pg/kg to about 400 pg/kg, between about 135 pg/kg to about 350 pg/kg, between about 135 pg/kg to about 300 pg/kg, between about 135 g/kg to about 250 gg/kg, between about 135 gg/kg to about 200 gg/kg, between about 135 gg/kg to about 150 gg/kg, between about 150 gg/kg to about 500 gg/kg, between about 150 gg/kg to about 450 gg/kg, between about 150 gg/kg to about 400 gg/kg, between about 150 gg/kg to about 350 gg/kg, between about 150 gg/kg to about 300 gg/kg, between about 150 gg/kg to about 250 gg/kg, between about 150 gg/kg to about 200 gg/kg, between about 200 gg/kg to about 500 gg/kg, between about 200 gg/kg to about 450 gg/kg, between about 200 gg/kg to about 400 gg/kg, between about 200 gg/kg to about 350 gg/kg, between about 200 gg/kg to about 300 gg/kg, between about 200 gg/kg to about 250 gg/kg, between about 250 gg/kg to about 500 gg/kg, between about 250 gg/kg to about 450 gg/kg, between about 250 gg/kg to about 400 gg/kg, between about 250 gg/kg to about 350 gg/kg, between about 250 gg/kg to about 300 gg/kg, between about 300 gg/kg to about 500 gg/kg, between about 300 gg/kg to about 450 gg/kg, between about 300 gg/kg to about 400 gg/kg, between about 300 gg/kg to about 350 gg/kg, between about 350 gg/kg to about 500 gg/kg, between about 350 gg/kg to about 450 gg/kg, between about 350 gg/kg to about 400 gg/kg, between about 400 gg/kg to about 500 gg/kg, between about 400 gg/kg to about 450 gg/kg, or between about 450 gg/kg to about 500 gg/kg. In some embodiments, each dose of the dosing regimen is between about 15 gg/kg to about 90 gg/kg. In some embodiments, each dose of the dosing regimen is about 30 gg/kg, about 60 gg/kg, or about 90 gg/kg. In some embodiments, each dose of the dosing regimen is about 30 gg/kg. In some embodiments, each dose of the dosing regimen is about 60 gg/kg. In some embodiments, each dose of the dosing regimen is about 90 gg/kg.

In any of the preceding methods, the IL-22 Fc fusion protein may be included in a pharmaceutical composition, e.g., a pharmaceutical composition comprising an IL-22 Fc fusion protein and a pharmaceutically acceptable carrier.

The pharmaceutical composition may have any suitable average sialic acid content. For example, in some embodiments, the pharmaceutical composition may have an average sialic acid content in the range of 8 to 12 moles of sialic acid per mole of the IL-22 Fc fusion protein. In one example, the pharmaceutical composition has an average sialic acid content in the range of 8 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein. In another example, the pharmaceutical composition has an average sialic acid content in the range of 8 to 9 moles of sialic acid per mole of the IL-22 Fc fusion protein. In yet another example, the pharmaceutical composition has an average sialic acid content in the range of 9 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein. In some embodiments, the pharmaceutical composition may have an average sialic acid content of 8 moles of sialic acid per mole of the IL-22 Fc fusion protein. In other embodiments, the pharmaceutical composition may have an average sialic acid content of 9 moles of sialic acid per mole of the IL-22 Fc fusion protein.

In some embodiments, the sialic acid comprises N-acetylneuraminic acid (NANA). In some embodiments, the pharmaceutical composition has an average NGNA content of less than 1 mole of NGNA per mole of the IL-22 Fc fusion protein.

In any of the preceding methods, the IL-22 polypeptide may be N-glycosylated. In some embodiments, the IL-22 polypeptide is glycosylated at one or more locations corresponding to amino acid residues Asn21 , Asn35, Asn64, and/or Asn143 of SEQ ID NO: 4. In some embodiments, the IL-22 Fc fusion protein comprises a glycosylated IL-22 polypeptide linked to an Fc region by a linker, wherein the IL-22 polypeptide is glycosylated at one or more locations corresponding to amino acid residues Asn21 , Asn35, Asn64, and/or Asn143 of SEQ ID NO: 4, and wherein: (a) the percent N-glycosylation site occupancy at residue Asn21 is in the range of 70 to 90; (b) the percent N-glycosylation site occupancy at residue Asn35 is in the range of 90 to 100; (c) the percent N-glycosylation site occupancy at residue Asn64 is in the range of 90 to 100; and/or (d) the percent N-glycosylation site occupancy at residue Asn143 is in the range of 25 to 35.

In any of the preceding methods, the pharmaceutical composition may be a liquid composition.

In any of the preceding methods, (i) the IL-22 Fc fusion protein may have a maximum observed concentration (Cmax) of about 8,000 ng/mL to about 19,000 ng; (ii) the IL-22 Fc fusion protein may have an area under the serum concentration-time curve from time 0 to the last measurable time point (AUCiast) of about 7,000 day-ng/mL to about 25,000 day-ng/mL; and/or (iii) the IL-22 Fc fusion protein may have a clearance (CL) of about 40 mL/kg/day to about 140 mL/kg/day. In some embodiments, the Cmax, AUCiast, and/or CL is assessed following intravenous administration of about 1 ,000 pg/kg of the IL-22 Fc fusion protein to a CD1 mouse.

In any of the preceding methods, the IL-22 polypeptide may comprise N-glycans having monoantennary, biantennary, triantennary, and/or tetraantennary structure. In some embodiments: (i) about 0.1% to about 2% of the N-glycans have monoantennary structure; (ii) about 10% to about 25% of the N-glycans have biantennary structure; (iii) about 25% to about 40% of the N-glycans have triantennary structure; and/or (iv) about 30% to about 51% of the N-glycans have tetraantennary structure. In some embodiments: (i) 0.1% to 2% of the N-glycans have monoantennary structure; (ii) 10% to 25% of the N-glycans have biantennary structure; (iii) 25% to 40% of the N-glycans have triantennary structure; and/or (iv) 30% to 51% of the N-glycans have tetraantennary structure.

In any of the preceding methods, the IL-22 Fc fusion protein may comprise N-glycans comprising zero, one, two, three, or four galactose moieties. In some embodiments: (i) about 9% to about 32% of the N-glycans comprise zero galactose moieties; (ii) about 10% to about 20% of the N-glycans comprise one galactose moiety; (iii) about 8% to about 25% of the N-glycans comprise two galactose moieties; (iv) about 12% to about 25% of the N-glycans comprise three galactose moieties; and/or (v) about 12% to about 30% of the N-glycans comprise four galactose moieties. In some embodiments: (i) 9% to 32% of the N-glycans comprise zero galactose moieties; (ii) 10% to 20% of the N-glycans comprise one galactose moiety; (iii) 8% to 25% of the N-glycans comprise two galactose moieties; (iv) 12% to 25% of the N-glycans comprise three galactose moieties; and/or (v) 12% to 30% of the N-glycans comprise four galactose moieties.

In any of the preceding methods, the IL-22 Fc fusion protein may comprise N-glycans comprising zero, one, two, three, or four sialic acid moieties. In some embodiments: (i) about 12% to about 35% of the N-glycans comprise zero sialic acid moieties; (ii) about 10% to about 30% of the N-glycans comprise one sialic acid moiety; (iii) about 10% to about 30% of the N-glycans comprise two sialic acid moieties;

(iv) about 10% to about 30% of the N-glycans comprise three sialic acid moieties; and/or (v) about 1% to about 20% of the N-glycans comprise four sialic acid moieties. In some embodiments: (i) 12% to 35% of the N-glycans comprise zero sialic acid moieties; (ii) 10% to 30% of the N-glycans comprise one sialic acid moiety; (iii) 10% to 30% of the N-glycans comprise two sialic acid moieties; (iv) 10% to 30% of the N- glycans comprise three sialic acid moieties; and/or (v) 1% to 20% of the N-glycans comprise four sialic acid moieties.

In any of the preceding methods, (i) the IL-22 polypeptide may comprise about 0% to about 10% N-glycans comprising a terminal mannose moiety; and/or (ii) the IL-22 polypeptide may comprise about 30% to about 55% N-glycans comprising a terminal N-acetylglucosamine (GlcNAc) moiety. In some embodiments, (i) the IL-22 polypeptide comprises 0% to 10% N-glycans comprising a terminal mannose moiety; and/or (ii) the IL-22 polypeptide comprises 30% to 55% N-glycans comprising a terminal GlcNAc moiety. In some embodiments, the IL-22 polypeptide comprises 0% to 10% N-glycans comprising a terminal mannose moiety. In some embodiments, the IL-22 polypeptide comprises 30% to 55% N- glycans comprising a terminal GlcNAc moiety.

In any of the preceding methods, the N-glycans may comprise one, two, three, or four terminal GlcNAc moieties. In some embodiments: (i) about 1% to about 20% of the N-glycans comprise one terminal GlcNAc moiety; (ii) about 1% to about 20% of the N-glycans comprise two terminal GlcNAc moieties; (iii) about 5% to about 25% of the N-glycans comprise three terminal GlcNAc moieties; and/or (iv) about 0% to about 15% of the N-glycans comprise four terminal GlcNAc moieties. In some embodiments: (i) 1% to 20% of the N-glycans comprise one terminal GlcNAc moiety; (ii) 1% to 20% of the N-glycans comprise two terminal GlcNAc moieties; (iii) 5% to 25% of the N-glycans comprise three terminal GlcNAc moieties; and/or (iv) 0% to 15% of the N-glycans comprise four terminal GlcNAc moieties.

In any of the preceding methods, (i) the IL-22 polypeptide may comprise about 20% to about 45% N-glycans comprising a terminal galactose (Gal) moiety; and/or (ii) the N-glycans comprise one, two, or three terminal Gal moieties. In some embodiments, (i) the IL-22 polypeptide comprises 20% to 45% N- glycans comprising a terminal Gal moiety; and/or (ii) the N-glycans comprise one, two, or three terminal Gal moieties.

In any of the preceding methods, (i) about 15% to about 30% of the N-glycans may comprise one terminal Gal moiety; (ii) about 1% to about 15% of the N-glycans may comprise two terminal Gal moieties; and/or (iii) about 0.1% to about 6% of the N-glycans may comprise three terminal Gal moieties. In some embodiments: (i) 15% to 30% of the N-glycans comprise one terminal Gal moiety; (ii) 1% to 15% of the N- glycans comprise two terminal Gal moieties; and/or (iii) 0.1% to 6% of the N-glycans comprise three terminal Gal moieties.

In any of the preceding methods, (i) the IL-22 polypeptide may comprise N-glycans comprises galactose N-acetylglucosamine (LacNAc) repeats; (ii) the IL-22 polypeptide may comprise N-glycans comprising fucosylated N-glycans; and/or (iii) the IL-22 polypeptide may comprise N-glycans comprising afucosylated N-glycans.

Any suitable concentration of the IL-22 Fc fusion protein may be used. For example, in some embodiments, the concentration of the IL-22 Fc fusion protein is about 0.5 mg/mL to about 20 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 0.5 mg/mL to about 5 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 1 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 8 mg/mL to about 12 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 10 mg/mL. In any of the preceding methods, the IL-22 Fc fusion may be produced from a production culture having a volume of at least about 500 L. In some embodiments of any of the preceding aspects, the IL- 22 Fc fusion protein has been produced from a production culture having a volume of about 500 L to about 5,000 L. In some embodiments, the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 1 ,000 L to about 3,000 L. In some embodiments the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 1 ,500 L to about 2,500 L.

In some embodiments, the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 2000 L.

In any of the preceding methods, the IL-22 Fc fusion protein can be any IL-22 Fc fusion protein described in Subsection 1 below.

For example, the IL-22 Fc fusion protein may include an amino acid sequence having at least 95% sequence identity (e.g., at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, at least 99% sequence identity, or higher) to the amino acid sequence of SEQ ID NO:8.

For example, the IL-22 Fc fusion protein may comprise the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16.

In some embodiments, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein is a dimer, wherein each arm of the dimer comprises the amino acid sequence of SEQ ID NO:8.

In some embodiments, the IL-22 Fc fusion protein consists of the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein is a dimer, wherein each arm of the dimer consists of the amino acid sequence of SEQ ID NO:8.

In some embodiments, the IL-22 Fc fusion protein is efmarodocokin alfa.

In other examples, the IL-22 Fc fusion protein may include an amino acid sequence having at least 95% sequence identity (e.g., at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, at least 99% sequence identity, or higher) to the amino acid sequence of SEQ ID NO:12.

For example, the IL-22 Fc fusion protein may comprise the amino acid sequence of SEQ ID NO:12, SEQ ID NO:14, or SEQ ID NO:20.

In other examples, the IL-22 Fc fusion protein may be any IL-22 Fc fusion protein disclosed in U.S. Patent Application Publication Nos. 2013/0121959 or 2013/0171100. For example, the IL-22 Fc fusion protein may include an amino acid sequence of SEQ ID NO: 81 , SEQ ID NO:82, or SEQ ID NO:83, or an amino acid sequence having at least 95% sequence identity (e.g., at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, at least 99% sequence identity, or higher) to SEQ ID NO: 81 , SEQ ID NO:82, or SEQ ID NO:83. The IL-22 Fc fusion proteins of SEQ ID NO:81 and SEQ ID NO:82 are human IL-22 Fc fusion proteins having lgG1 Fc regions. The IL-22 Fc fusion protein of SEQ ID NO:83 is a human IL-22 Fc fusion protein having an lgG2 Fc region. The exemplified IL-22 Fc fusion proteins have IgG 1 , lgG2 and lgG4 Fc regions; however, Fc regions from lgG3, IgA IgD, IgE and IgM can also be used in the IL-22 Fc fusion proteins of the invention.

In some aspects, the IL-22 Fc fusion protein is eflepedocokin alfa. In some embodiments, the IL-22 Fc fusion protein is administered to the patient as a monotherapy.

In other embodiments, the IL-22 Fc fusion protein is administered to the patient as a combination therapy. In some embodiments, the IL-22 Fc fusion protein is administered to the patient concurrently with an additional therapeutic agent. In other embodiments, the IL-22 Fc fusion protein is administered to the patient prior to the administration of an additional therapeutic agent. In other embodiments, the IL-22 Fc fusion protein is administered to the patient following the administration of an additional therapeutic agent.

The IL-22 Fc fusion protein may be administered in combination with any suitable therapeutic agents. For example, the combination therapy may include the administration of tocilizumab (ACTEMRA®), hydroxychloroquine, azithromycin, or a combination thereof.

In one particular example, in any of the methods, compositions, and uses disclosed herein, an IL-22 Fc fusion protein can be administered in combination with tocilizumab (ACTEMRA®).

For example, in some embodiments, the IL-22 Fc fusion protein is administered to the patient in combination with SOC. Any suitable SOC known in the art or disclosed herein can be used. For example, the SOC may include supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s).

In some embodiments, the SOC includes supportive care.

In some embodiments, the supportive care includes oxygen therapy.

In any of the preceding methods, the IL-22 Fc fusion protein of the invention (and any additional therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary, topical and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein. In some embodiments, the administering is intravenous, e.g., by intravenous infusion or injection. In other embodiments, the administering is by subcutaneous administration, e.g., injection.

In another aspect, a composition (e.g., an IL-22 Fc fusion protein or a pharmaceutical composition thereof) for use as a medicament is provided.

In a further aspect, the invention provides for the use of a composition (e.g., an IL-22 Fc fusion protein or a pharmaceutical composition thereof) in the manufacture or preparation of a medicament.

In any of the preceding methods, uses, and compositions, the patient may be a human.

1. Exemplary IL-22 Fc Fusion Proteins for Use in the Methods

Any suitable IL-22 Fc fusion protein can be used in the methods, uses, articles of manufacture, and kits described herein. In general, the IL-22 Fc fusion proteins include an IL-22 polypeptide linked to an Fc region by a linker. Any of the IL-22 Fc fusion proteins described in U.S. Patent No. 9,815,880, U.S.

Patent Application Publication No. 2013/0121959 (e.g., the IL-22 Fc fusion proteins having the amino acid sequence of SEQ ID NO: 4 or 5, corresponding to SEQ ID NO:81 or 82 herein), or U.S. Patent Application Publication No. 2013/0171100 (e.g., the IL-22 Fc fusion protein having the amino acid sequence of SEQ ID NO:2, corresponding to SEQ ID NO:83 herein), which are incorporated by reference herein in their entirety, may be used in the methods and uses described herein. In some embodiments of any of the preceding IL-22 Fc fusion proteins, the Fc region is not glycosylated. In some embodiments, the amino acid residue at position 297 as in the EU index of the Fc region is Gly. In some embodiments, the amino acid residue at position 297 as in the EU index of the Fc region is Ala. In some embodiments, the amino acid residue at position 299 as in the EU index of the Fc region is Ala, Gly, or Val. In some embodiments, the Fc region comprises the CH2 and CH3 domain of lgG1 or lgG4. In some embodiments, the Fc region comprises the CH2 and CH3 domain of lgG4. In other embodiments, the Fc region comprises the CH2 and CH3 domain of lgG2.

In some embodiments of any of the preceding methods, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20. In some embodiments, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL- 22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16. In some embodiments, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein consists of the amino acid sequence of SEQ ID NO:8. In some embodiments, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:10. In some embodiments, the IL-22 Fc fusion protein consists of the amino acid sequence of SEQ ID NO:10.

In some embodiments, the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:16. In some embodiments, the IL-22 Fc fusion protein consists of the amino acid sequence of SEQ ID NO:16. In some embodiments, the Fc region is not N-glycosylated.

In some examples, the IL-22 Fc fusion protein is efmarodocokin alfa.

In other examples, the IL-22 Fc fusion protein may be any IL-22 Fc fusion protein disclosed in U.S. Patent Application Publication Nos. 2013/0121959 or 2013/0171100. For example, the IL-22 Fc fusion protein may include an amino acid sequence of SEQ ID NO: 81 , SEQ ID NO:82, or SEQ ID NO:83, or an amino acid sequence having at least 95% sequence identity (e.g., at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, at least 99% sequence identity, or higher) to SEQ ID NO: 81 , SEQ ID NO:82, or SEQ ID NO:83. The IL-22 Fc fusion proteins of SEQ ID NO:81 and SEQ ID NO:82 are human IL-22 Fc fusion proteins having lgG1 Fc regions disclosed in U.S. Patent Application Publication No. 2013/0121959. The IL-22 Fc fusion protein of SEQ ID NO:83 is a human IL-22 Fc fusion protein having an lgG2 Fc region disclosed in U.S. Patent Application Publication No. 2013/0171100.

In some examples, the IL-22 Fc fusion protein is eflepedocokin alfa.

Any of the preceding IL-22 Fc fusion proteins can be a dimeric IL-22 Fc fusion protein. In other embodiments, any of the preceding IL-22 Fc fusion proteins can be a monomeric IL-22 Fc fusion protein.

Any of the preceding IL-22 Fc fusion proteins can include a human IL-22 polypeptide. In some embodiments, the amino acid sequence of SEQ ID NO:4.

Any suitable linker can be used in the IL-22 Fc fusion proteins described herein. In some embodiments, the linker comprises the amino acid sequence RVESKYGPP (SEQ ID NO: 44). In some embodiments, the linker consists of the amino acid sequence RVESKYGPP (SEQ ID NO: 44).

In some embodiments, any of the IL-22 Fc fusion proteins described herein binds to IL-22 receptor. In some embodiments, the IL-22 receptor is human IL-22 receptor. In some embodiments, the IL-22 Fc fusion protein binds to IL-22RA1 and/or IL-10R2. In some embodiments, the IL-22 Fc fusion protein binds to IL-22RA1 .

In some embodiments, any of the preceding IL-22 Fc fusion proteins is produced by the method comprising the step of culturing a host cell capable of expressing the IL-22 Fc fusion protein under conditions suitable for expression of the IL-22 Fc fusion protein. In some embodiments, the method further comprises the step of obtaining the IL-22 Fc fusion protein from the cell culture or culture medium. In some embodiments, the host cell is a CHO cell.

In certain embodiments, any of the IL-22 Fc fusion proteins described herein binds to and induces IL-22 receptor activity or signaling and/or is an agonist of IL-22 receptor activity.

In another aspect, an IL-22 Fc fusion protein provided herein comprises a polypeptide having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:4. In other embodiments, the IL-22 Fc fusion protein comprises a polypeptide having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an IL-22 Fc fusion protein comprising that sequence retains the ability to bind to IL-22 receptor. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NOs:8, 10, 12, 14, 16, 24, or 26. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the IL-22 (i.e., in the Fc). In some embodiments, the substitutions, insertions, or deletions can be in the linker, the hinge, the CH2 domain, the CH3 domain of the IL-22 Fc fusion protein. In certain particular embodiments, the C-terminus Lys residue of Fc is deleted. In certain other embodiments, the C-terminus Gly and Lys residues of Fc are both deleted.

In some embodiments, the IL-22 Fc fusion proteins or compositions thereof (e.g., pharmaceutical compositions) described in International Patent Application Publication No. WO 2019/148026, which is incorporated herein by reference in its entirety, may be used in the methods, dosing regimens, and dosing cycles described herein. Without intending to be bound by any one particular theory or mechanism of action, in some embodiments, it is preferred for the IL-22 Fc fusion protein to have an average sialic content in the range of 8 to 12 moles (e.g., about 8, about 9, about 10, about 11 , or about

12 moles) of sialic acid per mole of the IL-22 Fc fusion protein such that both the potency and pharmacokinetic properties of the IL-22 Fc fusion proteins are within the desired range (e.g., as described in detail in International Patent Application Publication No. WO 2019/148026). This discovery was made in part in connection with identifying certain properties of the molecule that are affected by the manufacturing process and that impact the activity and PK/PD properties of the molecule. For example, such IL-22 Fc-containing compositions having overall low glycosylation (including, but not limited to, e.g., IL-22 Fc fusion proteins and compositions thereof with an average sialic acid content of less than about 8 moles of sialic acid per mole of IL-22 Fc fusion protein), as described in International Patent Application Publication No. WO 2019/148026, have undesirably fast clearance in vivo. Further, high glycosylation of those compositions (including, but not limited to, e.g., IL-22 Fc fusion proteins and compositions thereof having greater than about 12 moles of sialic acid per mole of IL-22 Fc fusion protein) can have undesirable binding properties to the IL-22 receptor. Thus, in certain aspects, a solution to the identified problems was to identify a range of average sialic acid content for the IL-22 Fc fusion proteins and compositions thereof which have both suitable clearance rates as well as suitable binding activity. In a specific embodiment, a particularly preferred range of average sialic acid content for the IL-22 Fc fusion proteins and compositions thereof for use in the methods described herein (e.g. methods treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, chronic obstructive pulmonary disorder (COPD), influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR T-cell-induced CRS)) is 8 to 9 moles of sialic acid per mole of IL-22 Fc fusion protein. In a another specific embodiment, a particularly preferred range of average sialic acid content for the IL-22 Fc fusion proteins and compositions thereof for use in the methods described herein (e.g. methods treating or preventing a respiratory disease (e.g., pneumonia (e.g. viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) or CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR T-cell-induced CRS)) is 9 to 10 moles of sialic acid per mole of IL-22 Fc fusion protein.

For example, in some embodiments, the composition has an average sialic acid content in the range of 8 to 12 moles (e.g., about 8, about 9, about 10, about 11 , or about 12 moles) of sialic acid per mole of the IL-22 Fc fusion protein. In some embodiments, the IL-22 polypeptide is N-glycosylated. In some embodiments, the IL-22 polypeptide is glycosylated at one or more locations corresponding to amino acid residues Asn21 , Asn35, Asn64, and/or Asn143 of SEQ ID NO: 4. In some embodiments, the IL-22 Fc fusion protein comprises a glycosylated IL-22 polypeptide linked to an Fc region by a linker, wherein the IL-22 polypeptide is glycosylated at one or more locations corresponding to amino acid residues Asn21 , Asn35, Asn64, and/or Asn143 of SEQ ID NO: 4, and wherein: (a) the percent N- glycosylation site occupancy at residue Asn21 is in the range of 70 to 90; (b) the percent N-glycosylation site occupancy at residue Asn35 is in the range of 90 to 100; (c) the percent N-glycosylation site occupancy at residue Asn64 is in the range of 90 to 100; and/or (d) the percent N-glycosylation site occupancy at residue Asn143 is in the range of 25 to 35.

In some embodiments of any of the preceding aspects, the composition has an average sialic acid content in the range of 8 to 9 moles of sialic acid per mole of the IL-22 Fc fusion protein. In some embodiments, the composition has an average sialic acid content of 8 or 9 moles of sialic acid per mole of the IL-22 Fc fusion protein. In some embodiments, the composition has an average sialic acid content of 8 moles of sialic acid per mole of the IL-22 Fc fusion protein. In other embodiments, the composition has an average sialic acid content of 9 moles of sialic acid per mole of the IL-22 Fc fusion protein.

In any of the compositions described herein, the sialic acid may be N-acetylneuraminic acid

(NANA).

Any of the compositions may have an average NGNA content of less than 1 mole of NGNA per mole of the IL-22 Fc fusion protein.

In some embodiments of any of the preceding aspects, the composition has an average N- glycolylneuraminic acid (NGNA) content of less than 1 mole of NGNA per mole of the IL-22 Fc fusion protein.

In some embodiments of any of the preceding aspects, the composition is a liquid composition.

In some embodiments of any of the preceding aspects: (i) the IL-22 Fc fusion protein has a maximum observed concentration (Cmax) of about 8,000 ng/mL to about 19,000 ng; (ii) the IL-22 Fc fusion protein has an area under the serum concentration-time curve from time 0 to the last measurable time point (AUCiast) of about 7,000 day-ng/mL to about 25,000 day-ng/mL; and/or (iii) the IL-22 Fc fusion protein has a clearance (CL) of about 40 mL/kg/day to about 140 mL/kg/day. In some embodiments, the Cmax, AUCiast, and/or CL is assessed following intravenous administration of about 1 ,000 pg/kg of the IL- 22 Fc fusion protein to a CD1 mouse.

In any of the compositions, the IL-22 polypeptide may include N-glycans having monoantennary, biantennary, triantennary, and/or tetraantennary structure. In some embodiments: (i) about 0.1% to about 2% of the N-glycans have monoantennary structure; (ii) about 10% to about 25% of the N-glycans have biantennary structure; (iii) about 25% to about 40% of the N-glycans have triantennary structure; and/or (iv) about 30% to about 51 % of the N-glycans have tetraantennary structure. In some embodiments: (i) 0.1% to 2% of the N-glycans have monoantennary structure; (ii) 10% to 25% of the N-glycans have biantennary structure; (iii) 25% to 40% of the N-glycans have triantennary structure; and/or (iv) 30% to 51% of the N-glycans have tetraantennary structure.

In any of the compositions, the IL-22 Fc fusion protein may include N-glycans including zero, one, two, three, or four galactose moieties. In some embodiments: (i) about 9% to about 32% of the N-glycans include zero galactose moieties; (ii) about 10% to about 20% of the N-glycans include one galactose moiety; (iii) about 8% to about 25% of the N-glycans include two galactose moieties; (iv) about 12% to about 25% of the N-glycans include three galactose moieties; and/or (v) about 12% to about 30% of the N-glycans include four galactose moieties. In some embodiments: (i) 9% to 32% of the N-glycans include zero galactose moieties; (ii) 10% to 20% of the N-glycans include one galactose moiety; (iii) 8% to 25% of the N-glycans include two galactose moieties; (iv) 12% to 25% of the N-glycans include three galactose moieties; and/or (v) 12% to 30% of the N-glycans include four galactose moieties.

In any of the compositions, the IL-22 Fc fusion protein may include N-glycans including zero, one, two, three, or four sialic acid moieties. In some embodiments: (i) about 12% to about 35% of the N- glycans include zero sialic acid moieties; (ii) about 10% to about 30% of the N-glycans include one sialic acid moiety; (iii) about 10% to about 30% of the N-glycans include two sialic acid moieties; (iv) about 10% to about 30% of the N-glycans include three sialic acid moieties; and/or (v) about 1% to about 20% of the N-glycans include four sialic acid moieties. In some embodiments: (i) 12% to 35% of the N-glycans include zero sialic acid moieties; (ii) 10% to 30% of the N-glycans include one sialic acid moiety; (iii) 10% to 30% of the N-glycans include two sialic acid moieties; (iv) 10% to 30% of the N-glycans include three sialic acid moieties; and/or (v) 1% to 20% of the N-glycans include four sialic acid moieties.

In any of the compositions, (i) the IL-22 polypeptide may include about 0% to about 10% N- glycans including a terminal mannose moiety; and/or (ii) the IL-22 polypeptide includes about 30% to about 55% N-glycans including a terminal N-acetylglucosamine (GlcNAc) moiety. In some embodiments, (i) the IL-22 polypeptide includes 0% to 10% N-glycans including a terminal mannose moiety; and/or (ii) the IL-22 polypeptide includes 30% to 55% N-glycans including a terminal GlcNAc moiety. In some embodiments, the IL-22 polypeptide includes 0% to 10% N-glycans including a terminal mannose moiety. In some embodiments, the IL-22 polypeptide includes 30% to 55% N-glycans including a terminal GlcNAc moiety.

In any of the compositions, the N-glycans may include one, two, three, or four terminal GlcNAc moieties. In some embodiments: (i) about 1% to about 20% of the N-glycans include one terminal GlcNAc moiety; (ii) about 1% to about 20% of the N-glycans include two terminal GlcNAc moieties; (iii) about 5% to about 25% of the N-glycans include three terminal GlcNAc moieties; and/or (iv) about 0% to about 15% of the N-glycans include four terminal GlcNAc moieties. In some embodiments: (i) 1% to 20% of the N-glycans include one terminal GlcNAc moiety; (ii) 1% to 20% of the N-glycans include two terminal GlcNAc moieties; (iii) 5% to 25% of the N-glycans include three terminal GlcNAc moieties; and/or (iv) 0% to 15% of the N-glycans include four terminal GlcNAc moieties.

In any of the compositions, (i) the IL-22 polypeptide may include about 20% to about 45% N- glycans including a terminal galactose (Gal) moiety; and/or (ii) the N-glycans include one, two, or three terminal Gal moieties. In some embodiments, (i) the IL-22 polypeptide includes 20% to 45% N-glycans including a terminal Gal moiety; and/or (ii) the N-glycans include one, two, or three terminal Gal moieties.

In any of the compositions: (i) about 15% to about 30% of the N-glycans may include one terminal Gal moiety; (ii) about 1% to about 15% of the N-glycans may include two terminal Gal moieties; and/or (iii) about 0.1% to about 6% of the N-glycans may include three terminal Gal moieties. In some embodiments: (i) 15% to 30% of the N-glycans include one terminal Gal moiety; (ii) 1% to 15% of the N- glycans include two terminal Gal moieties; and/or (iii) 0.1% to 6% of the N-glycans include three terminal Gal moieties.

In any of the compositions: (i) the IL-22 polypeptide may include N-glycans including galactose N- acetylglucosamine (LacNAc) repeats; (ii) the IL-22 polypeptide may include N-glycans including fucosylated N-glycans; and/or (iii) the IL-22 polypeptide may include N-glycans including afucosylated N- glycans.

Any suitable concentration of the IL-22 Fc fusion protein may be used. For example, in some embodiments, the concentration of the IL-22 Fc fusion protein may be about 0.5 mg/mL to about 20 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 0.5 mg/mL to about 5 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 1 mg/mL. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 8 mg/mL to about 12 mg/ml_. In some embodiments, the concentration of the IL-22 Fc fusion protein is about 10 mg/mL.

The IL-22 Fc fusion proteins described herein may be produced from a production culture having a volume of at least about 500 L. In some embodiments of any of the preceding aspects, the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 500 L to about 5,000 L. In some embodiments, the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 1 ,000 L to about 3,000 L. In some embodiments the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 1 ,500 L to about 2,500 L. In some embodiments, the IL-22 Fc fusion protein has been produced from a production culture having a volume of about 2000 L.

In certain embodiments, IL-22 Fc fusion proteins variants having one or more amino acid substitutions are provided. Conservative substitutions are shown in Table A under the heading of “preferred substitutions.” More substantial changes are provided in Table A under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into the IL-22 Fc fusion protein and the products screened for a desired activity, e.g., retained/improved IL-22 receptor binding, decreased immunogenicity, or improved IL-22 receptor signaling.

Table A

Amino acids may be grouped according to common side-chain properties:

(1) hydrophobic: Norleucine, Met, Ala, Val, Leu, lie;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;

(3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

A useful method for identification of residues or regions of a protein that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081 -1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the protein with its binding partner is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of a protein complex (e.g., a cytokine-receptor complex) can be used to identify contact points between a protein and its binding partner. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.

Provided herein are nucleic acids encoding IL-22 Fc fusion proteins. In some embodiments, the nucleic acid encodes the IL-22 Fc fusion protein comprising the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:24, or SEQ ID NO:26, preferably SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16, more preferably SEQ ID NO:8. In certain other embodiments, the nucleic acid comprises the polynucleotide sequence of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 , SEQ ID NO:13, SEQ ID NO:23 or SEQ ID NO:25. In certain particular embodiments, the nucleic acid comprises the polynucleotide sequence of SEQ ID NO:7 or SEQ ID NO:11 , preferably SEQ ID NO:7. In certain embodiments, the isolated nucleic acid comprises a polynucleotide sequence that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the polynucleotide sequence of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 , SEQ ID NO:13; SEQ ID NO:23 or SEQ ID NO:25. In certain embodiments, the isolated nucleic acid comprises a polynucleotide sequence that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the polynucleotide sequence of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 , SEQ ID NO:13; SEQ ID NO:23 or SEQ ID NO:25, wherein the isolated nucleic acid is capable of encoding an IL-22 Fc fusion protein that is capable of binding to IL-22R and/or triggering IL-22R activity and wherein the Fc region of the IL-22 Fc fusion protein is not glycosylated. In certain embodiments, the isolated nucleic acid comprises a polynucleotide sequence that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the polynucleotide sequence of SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11 , SEQ ID NO:13; SEQ ID NO:23, or SEQ ID NO:25, wherein the isolated nucleic acid is capable of encoding an IL-22 Fc fusion protein comprising the amino acid sequence of SEQ ID NO:8, 10, 12, or 14. In related aspects, the invention provides vectors comprising the nucleic acid described above, and a host cell comprising the vector. In certain embodiments, the host cell is a prokaryotic cell or eukaryotic cell. In certain particular embodiments, the host cell is a prokaryotic cell, including without limitation, an E. coli cell. In certain other embodiments, the host cell is a eukaryotic cell, including without limitation, a CHO cell. In certain embodiments, the host cell comprises a vector comprising a nucleic acid encoding the IL-22 Fc fusion protein comprising the amino acid sequence of SEQ ID NO:8. a) Glycosylation variants

In certain embodiments, an IL-22 Fc fusion protein described herein is altered to increase or decrease the extent to which the fusion protein or a portion thereof (e.g., the Fc portion of the fusion protein) is glycosylated. Addition or deletion of glycosylation sites to a protein may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

Where the fusion protein comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody or the Fc region of an antibody may be made in order to create Fc variants with certain improved properties.

The amount of fucose attached to the CH2 domain of the Fc region can be determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 or N297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108; US 2004/0093621 . Examples of publications related to “defucosylated” or “fucose- deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621 ; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742; W02002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Pat. Appl. No. US 2003/0157108 A1 ; and WO 2004/056312 A1 , especially at Example 11 ), and knockout cell lines, such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003/085107).

Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878; US Patent No. 6,602,684; and US 2005/0123546. Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087; WO 1998/58964; and WO 1999/22764. b) Fc region variants

In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an Fc fusion protein provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG 1 , lgG2, lgG3, or lgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions. For example, the hinge may include a Ser to Pro substitution, for example, as shown in the bolded and underlined Pro residue in the amino acid sequence of CPPCP (SEQ ID NO:31 ). Such a Ser to Pro substitution may increase the stability of the molecule.

In certain embodiments, the invention contemplates an Fc variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody or a fusion protein comprising an Fc region in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody or Fc lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch et al., Annu. Rev. Immunol. 9:457-492 (1991 ). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Hellstrom et al., Proc. Nat’l Acad.

Sci. USA 83:7059-7063 (1986) and Hellstrom et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); U.S. Patent No. 5,821 ,337 (see Bruggemann et al., J. Exp. Med. 166:1351 -1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. N at 7 Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody or Fc is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg et al., Blood 101 : 1045-1052 (2003); and Cragg et al., Stood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova et al., Int’l. Immunol. 18(12):1759-1769 (2006)).

Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 ).

Certain antibody or Fc variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591 -6604 (2001 ).)

In certain embodiments, an IL-22 Fc fusion protein comprises an Fc variant with one or more amino acid substitutions which reduce ADCC, e.g., substitution at position 297 of the Fc region to remove the N-glycosylation site and yet retain FcRn binding activity (EU numbering of residues).

In some embodiments, alterations are made in the Fc region that result in diminished C1 q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 ,

WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311 , 312, 317, 340, 356, 360, 362, 376, 378,

380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821 ; and WO 94/29351 concerning other examples of Fc region variants. c) Cysteine engineered variants

In certain embodiments, it may be desirable to create cysteine engineered Fc fusion protein, in which one or more residues of the Fc region of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the Fc. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the Fc and may be used to conjugate the Fc to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. For example, S400 (EU numbering) of the heavy chain Fc region can be substituted with Cys. See, e.g., U.S. Patent No. 7,521 ,541 .

2. Exemplary IL-22 Polypeptides

Any suitable IL-22 polypeptide can be included in the IL-22 Fc fusion proteins used in the methods, uses, articles of manufacture, and kits described herein. For example, in any of the IL-22 Fc fusion proteins described herein, the IL-22 polypeptide can include a polypeptide comprising an amino acid sequence comprising SEQ ID NO:71 (human IL-22 with the endogenous IL-22 leader sequence), or a polypeptide comprising an amino acid sequence that has at least 80% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) with SEQ ID NO:71 . In certain embodiments, the IL-22 polypeptide comprises an amino acid sequence comprising SEQ ID NO:4 (human IL-22 without a leader sequence) or a polypeptide comprising an amino acid sequence that has at least 80% sequence identity (e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) with SEQ ID NO:4. In certain embodiments, the IL-22 polypeptide comprises an amino acid sequence comprising SEQ ID NO:4.

The preparation of native IL-22 molecules, along with their nucleic acid and polypeptide sequences, can be achieved through methods known to those of ordinary skill in the art. For example, IL- 22 polypeptides can be produced by culturing cells transformed or transfected with a vector containing IL- 22 nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, can be employed to prepare IL-22. For instance, the IL-22 sequence, or portions thereof, can be produced by direct peptide synthesis using solid-phase techniques (see, e.g., Stewart et al. , 1969, Solid- Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, Calif. (1969); Merrifield, J. Am. Chem.

Soc., 1963, 85:2149-2154). In vitro protein synthesis can be performed using manual techniques or by automation. Automated synthesis can be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, Calif.) using manufacturer's instructions. Various portions of IL-22 can be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length IL-22.

IL-22 variants can be prepared by introducing appropriate nucleotide changes into the DNA encoding a native sequence IL-22 polypeptide, or by synthesis of the desired IL-22 polypeptide. Those skilled in the art will appreciate that amino acid changes can alter post-translational processes of IL-22, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics. Variations in the native sequence IL-22 polypeptides described herein can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934. Variations can be a substitution, deletion, or insertion of one or more codons encoding a native sequence or variant IL-22 that results in a change in its amino acid sequence as compared with a corresponding native sequence or variant IL-22. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of a native sequence IL-22 polypeptide. Guidance in determining which amino acid residue can be inserted, substituted or deleted without adversely affecting the desired activity can be found by comparing the sequence of the IL-22 with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e. , conservative amino acid replacements. Insertions or deletions can optionally be in the range of 1 to 5 amino acids. The variation allowed can be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity, for example, in the in vitro assay described in the Examples below.

In particular embodiments, conservative substitutions of interest are shown in Table 2 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 2, or as further described below in reference to amino acid classes, are introduced and the products screened.

Another type of covalent modification of the IL-22 polypeptides included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptides. “Altering the native glycosylation pattern” is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence IL-22, and/or adding one or more glycosylation sites that are not present in the native sequence IL-22, and/or alteration of the ratio and/or composition of the sugar residues attached to the glycosylation site(s).

Glycosylation of polypeptides is typically either /V-linked or O-linked. Addition of glycosylation sites to the IL-22 polypeptide can be accomplished by altering the amino acid sequence. The alteration can be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence IL-22 (for /V-linked glycosylation sites), or the addition of a recognition sequence for O-linked glycosylation. The IL-22 amino acid sequence can optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the IL-22 polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on the IL-22 polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 and in Aplin et al ., CRC Crit. Rev. Biochem., pp. 259-306 (1981).

Removal of carbohydrate moieties present on an IL-22 polypeptide can be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin et al., Arch. Biochem. Biophys. 259:52 (1987) and by Edge et al., Anal. Biochem. 118:131 (1981 ). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al. , Meth. Enzymol. 138:350 (1987).

The variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis (Carter et al., 1986, Nucl. Acids Res. 13:4331 ; Zoller et al., 1987, Nucl. Acids Res. 10:6487), cassette mutagenesis (Wells et al., 1985, Gene 34:315), restriction selection mutagenesis (Wells et al., 1986, Philos. Trans. R. Soc. London A 317:415), or other known techniques can be performed on the cloned DNA to produce the IL-22 variant DNA.

Fragments of an IL-22 polypeptide are also provided herein. Such fragments can be truncated at the N-terminus or C-terminus, or can lack internal residues, for example, when compared with a full- length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of an IL-22 polypeptide of the present invention. Accordingly, in certain embodiments, a fragment of an IL-22 polypeptide is biologically active. In certain embodiments, a fragment of full-length IL-22 lacks the N-terminal signal peptide sequence.

Covalent modifications of native sequence and variant IL-22 polypeptides are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of IL-22 with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues of the IL-22 polypeptide. Derivatization with bifunctional agents is useful, for instance, for crosslinking IL-22 to a water-insoluble support matrix or surface, for example, for use in the method for purifying anti-IL-22 antibodies. Commonly used crosslinking agents include, e.g., 1 ,1- bis(diazo-acetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'- dithiobis(succinimidyl-propionate), bifunctional maleimides such as bis-N-maleimido-1 ,8-octane, and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.

Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, 1983, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco, pp. 79-86i), acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.

Another type of covalent modification of IL-22 comprises linking the IL-22 polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, for example in the manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301 ,144; 4,670,417; 4,791 ,192; or 4,179,337. The native sequence and variant IL-22 can also be modified in a way to form a chimeric molecule comprising IL-22, including fragments of IL-22, fused to another, heterologous polypeptide or amino acid sequence.

In one embodiment, such a chimeric molecule comprises a fusion of IL-22 with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl-terminus of the IL-22 polypeptide. The presence of such epitope-tagged forms of the IL-22 polypeptide can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the IL-22 polypeptide to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptide and its antibody 12CA5 (Field et al., 1988, Mol. Cell. Biol., 8:2159-2165); the c-myc tag and the 8F9, 3C7, 6E10, G4, and 9E10 antibodies thereto (Evan et al., 1985, Mol. Cell. Biol. 5:3610-3616); and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody (Paborsky et al., 1990, Protein Engineering 3(6) :547-553). Other tag polypeptides include the Flag-peptide (Hopp et al., 1988, BioTechnology 6:1204-1210); the KT3 epitope peptide (Martin et al., 1992, Science 255:192-194); a tubulin epitope peptide (Skinner et al., 1991 , J. Biol. Chem. 266:15163-15166); and the T7 gene 10 protein peptide tag (Lutz-Freyermuth et al., 1990, Proc. Natl. Acad. Sci. USA, 87:6393-6397).

In another embodiment, the chimeric molecule can comprise a fusion of the IL-22 polypeptide or a fragment thereof with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule, such a fusion can be to the Fc region of an IgG molecule. These fusion polypeptides are antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains, and are often referred to as immunoadhesins. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence of IL-22, or a variant thereof, and an immunoglobulin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin can be obtained from any immunoglobulin, such as IgG 1 , lgG2, lgG3, or lgG4 subtypes, IgA (including lgA1 and lgA2), IgE, IgD, or IgM. In certain embodiments, the IL-22 Fc fusion protein exhibits modified effector activities.

The IL-22 polypeptide, or a fragment thereof, can be fused, for example, to an immunoglobulin heavy chain constant region sequence to produce an IL-22-lg fusion protein (e.g., IL-22 Fc fusion protein). The IL-22 polypeptide can be human or murine IL-22. The immunoglobulin heavy chain constant region sequence can be human or murine immunoglobulin heavy chain constant region

B. Methods of Making IL-22 Fc Fusion Proteins for Use in the Methods

The IL-22 Fc fusion proteins used in the methods, uses, articles of manufacture, and kits described herein can be prepared by any suitable method, e.g., culturing cells transformed or transfected with a vector containing a nucleic acid encoding an IL-22 Fc fusion protein, a fragment, or a variant thereof. In some embodiments, the IL-22 Fc fusion proteins are produced by a method described in International Patent Application Publication No. WO 2019/148026. Host cells comprising any such vector are also provided. Any suitable host cell can be used, e.g., mammalian cells (e.g., CHO cells), E. coli, or yeast. Processes for producing any of the herein described IL-22 Fc fusion proteins are further provided and, in general, involve culturing host cells under conditions suitable for expression of the desired IL-22 Fc fusion protein and recovering, and optionally purifying, the desired IL-22 Fc fusion protein from the cell culture. Host cells are transfected or transformed with expression or cloning vectors described herein for IL-22 polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: A Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra.

Methods of transfection are known to the ordinarily skilled artisan, for example, by CaPC and electroporation. Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes or other cells that contain substantial cell-wall barriers. Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published 29 June 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology, 52:456-457 (1978) can be employed. General aspects of mammalian cell host system transformations have been described in U.S. Pat. No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et al., J. Bact, 130:946 (1977) and Hsiao et al., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, can also be used. For various techniques for transforming mammalian cells, see Keown et al., Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).

Recombinantly expressed polypeptides disclosed herein can be recovered from culture medium or from host cell lysates. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of a polypeptide of the present invention. Various methods of protein purification can be employed, and such methods are known in the art and described for example in Deutscher, Methods in Enzymology, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step(s) selected will depend, for example, on the nature of the production process used and the particular polypeptide produced.

Alternative methods, which are well known in the art, can be employed to prepare a polypeptide disclosed herein. For example, a sequence encoding a polypeptide or portion thereof, can be produced by direct peptide synthesis using solid-phase techniques (see, e.g., Stewart et al., 1969, Solid-Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, CA; Merrifield, J. 1963, Am. Chem. Soc., 85:2149- 2154. In vitro protein synthesis can be performed using manual techniques or by automation. Automated synthesis can be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster

City, CA) using manufacturer's instructions. Various portions of a polypeptide disclosed herein, or portion thereof can be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length polypeptide or portion thereof.

In other embodiments, provided herein are chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence. Examples of such chimeric molecules include, but are not limited to, any of the herein described polypeptides fused to an epitope tag sequence or an Fc region of an immunoglobulin.

Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae, such as E. coli. Various E. coli strains are publicly available, such as E. coli K12 strain MM294 (ATCC 31 ,446); E. coli 1776 (ATCC 31 ,537); E. coli strain W3110 (ATCC 27,325) and K5772 (ATCC 53,635).

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for IL-22-encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism.

Suitable host cells for the expression of glycosylated IL-22 are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CV1 cells transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney cells (293 or 293 cells subcloned for growth in suspension culture, Graham et al. , J. Gen Virol., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor cells (MMT 060562, ATCC CCL51 ). The selection of the appropriate host cell is deemed to be within the skill in the art.

The nucleic acid (e.g., cDNA or genomic DNA) encoding IL-22 can be inserted into a replicable vector for cloning (amplification of the DNA) or for expression. Various vectors are publicly available. The vector can, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence can be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan.

The IL-22 polypeptides can be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which can be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide, as well as an IL-22 Fc fusion protein. In general, the signal sequence can be a component of the vector, or it can be a part of the IL-22 DNA that is inserted into the vector. The signal sequence can be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, 1 pp, or heat-stable enterotoxin II leaders. For yeast secretion the signal sequence can be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces alpha-factor leaders, the latter described in U.S. Pat. No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published 4 Apr. 1990), or the signal described in WO 90/13646 published 15 Nov. 1990. In mammalian cell expression, mammalian signal sequences can be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.

Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2: plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.

Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.

An example of suitable selectable markers for mammalian cells is one that enables the identification of cells competent to take up the IL-22 nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitable selection gene for use in yeast is the trp1 gene present in the yeast plasmid YRp7 (see, e.g., Stinchcomb et al., Nature, 282:39(1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene,

10:157 (1980)). The trp1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 (Jones, Genetics, 85:12 (1977)).

Expression and cloning vectors usually contain a promoter operably linked to the IL-22 nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the quadrature-lactamase and lactose promoter systems (see, e.g., Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature,

281 :544 (1979)), alkaline phosphatase, a tryptophan (trp) promoter system (see, e.g., Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776), and hybrid promoters such as the tac promoter (see, e.g., deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21 -25 (1983)). Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding IL-22.

Examples of suitable promoter sequences for use with yeast hosts include the promoters for 3- phosphoglycerate kinase (see, e.g., Hitzeman et al., J. Biol. Chem, 255:2073 (1980)) or other glycolytic enzymes (see, e.g., Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900 (1978)), such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.

Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.

IL-22 transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211 ,504 published 5 Jul. 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.

Transcription of a DNA encoding the IL-22 polypeptides by higher eukaryotes can be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, which act on a promoter to increase its transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, a-fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.

The enhancer can be spliced into the vector at a position 5' or 3' to the IL-22 coding sequence, but is preferably located at a site 5' from the promoter.

Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding IL-22.

Still other methods, vectors, and host cells suitable for adaptation to the synthesis of IL-22 in recombinant vertebrate cell culture are described in Gething et al. , Nature, 293:620-625 (1981); Mantei et al„ Nature, 281 :4046 (1979); EP 117,060; and EP 117,058.

Gene amplification and/or expression can be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA (see, e.g., Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)), dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies can be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn can be labeled and the assay can be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.

Gene expression, alternatively, can be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids can be either monoclonal or polyclonal, and can be prepared in any mammal. Conveniently, the antibodies can be prepared against a native sequence IL-22 polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to IL-22 DNA and encoding a specific antibody epitope.

IL-22 Fc fusion proteins can be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. TRITON® X-100) or by enzymatic cleavage. Cells employed in expression of IL-22 can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.

It may be desired to purify IL-22 Fc fusion proteins from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the IL-22 polypeptide. Various methods of protein purification may be employed, and such methods are known in the art and described for example in Deutscher, Methods in Enzymology, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step(s) selected will depend, for example, on the nature of the production process used and the particular IL-22 produced. The above-described general methods can be applied to the preparation of IL-2 Fc fusion protein as well.

Similarly, IL-22 Fc fusion proteins may be produced using recombinant methods and compositions, as described in, e.g., Molecular Cloning: A Laboratory Manual (Sambrook, et al. , 1989,

Cold Spring Harbor Laboratory Press) and PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, CA). In one embodiment, isolated nucleic acid encoding IL-22 Fc fusion proteins described herein is provided. In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In a further embodiment, a host cell comprising such nucleic acid is provided. In one such embodiment, a host cell comprises (e.g., has been transformed with) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the IL-22 Fc fusion protein. In certain embodiment, the vector is an expression vector. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell). In one embodiment, a method of making an IL-22 Fc fusion protein is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the IL-22 Fc fusion protein, as provided above, under conditions suitable for expression of the Fc fusion protein, and optionally recovering the Fc fusion protein from the host cell (or host cell culture medium).

For recombinant production of an IL-22 Fc fusion protein, nucleic acid encoding an Fc fusion protein, e.g., as described herein, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the fusion protein). In certain embodiments, when preparing the IL-22 Fc fusion proteins, nucleic acid encoding the IL-22 polypeptide or a fragment thereof can be ligated to nucleic acid encoding an immunoglobulin constant domain sequence at specified location on the constant domain to result in an Fc fusion at the C-terminus of IL-22; however N-terminal fusions are also possible.

As an example of constructing an IL-22 Fc fusion protein, the DNA encoding IL-22 is cleaved by a restriction enzyme at or proximal to the 3' end of the DNA encoding IL-22 and at a point at or near the DNA encoding the N-terminal end of the mature polypeptide (where use of a different leader is contemplated) or at or proximal to the N-terminal coding region for IL-22 full-length protein (where a native signal is employed). This DNA fragment then is readily inserted into DNA encoding an immunoglobulin light or heavy chain constant region and, if necessary, tailored by deletional mutagenesis. Preferably, this is a human immunoglobulin when the fusion protein is intended for in vivo therapy for humans.

In some embodiments, the IL-22-immunoglobulin chimeras are assembled as monomers, hetero- or homo-multimer, or as dimers or tetramers. Generally, these assembled immunoglobulins will have known unit structures as represented by the following diagrams. A basic four chain structural unit is the form in which IgG, IgD, and IgE exist. A four chain unit is repeated in the higher molecular weight immunoglobulins; IgM generally exists as a pentamer of, basic four-chain units held together by disulfide bonds. IgA globulin, and occasionally IgG globulin, may also exist in a multimeric form in serum. In the case of multimers, each four chain unit may be the same or different. See also Capon et al. U.S. Patent No. 5,116,964, incorporated herein by reference in its entirety.

DNA encoding immunoglobulin light or heavy chain constant regions is known or readily available from cDNA libraries or is synthesized. See for example, Adams et al., Biochemistry 19:2711 -2719 (1980); Gough et al., Biochemistry 19:2702-2710 (1980); Dolby et al; P.N.A.S. USA, 77:6027-6031 (1980); Rice et al P.N.A.S USA 79:7862-7865 (1982); Falkner et al; Nature 298:286-288 (1982); and Morrison et al; Ann. Rev. Immunol. 2:239-256 (1984). DNA sequence encoding human IL-22 with the endogenous leader sequence is provided herein (SEQ ID NO:70). DNA sequences encoding other desired binding partners which are known or readily available from cDNA libraries are suitable in the practice of this invention.

DNA encoding an IL-22 Fc fusion protein of this invention is transfected into a host cell for expression. If multimers are desired then the host cell is transformed with DNA encoding each chain that will make up the multimer, with the host cell optimally being selected to be capable of assembling the chains of the multimers in the desired fashion. If the host cell is producing an immunoglobulin prior to transfection then one needs only transfect with the binding partner fused to light or to heavy chain to produce a heteroantibody. The aforementioned immunoglobulins having one or more arms bearing the binding partner domain and one or more arms bearing companion variable regions result in dual specificity for the binding partner ligand and for an antigen or therapeutic moiety. Multiply cotransformed cells are used with the above-described recombinant methods to produce polypeptides having multiple specificities such as the heterotetrameric immunoglobulins discussed above.

Although the presence of an immunoglobulin light chain is not required in the immunoadhesins of the present invention, an immunoglobulin light chain might be present either covalently associated to an IL-22-immunoglobulin heavy chain fusion polypeptide. In this case, DNA encoding an immunoglobulin light chain is typically co-expressed with the DNA encoding the IL-22-immunoglobulin heavy chain fusion protein. Upon secretion, the hybrid heavy chain and the light chain will be covalently associated to provide an immunoglobulin-like structure comprising two disulfide-linked immunoglobulin heavy chain- light chain pairs. Methods suitable for the preparation of such structures are, for example, disclosed in U.S. Pat. No. 4,816,567. Suitable host cells for cloning or expression of target protein-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, IL-22 Fc fusion protein may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed or are detrimental. For expression of polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Flumana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli. After expression, the Fc fusion protein may be isolated from the bacterial cell paste in a soluble fraction and can be further purified. As exemplified in the example section, further purification methods include without limitation purification using a Protein A column.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al. , Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated proteins are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177; 6,040,498; 6,420,548; 7,125,978; and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 ( B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003). C. Assays

The compositions (e.g., IL-22 Fc fusion proteins, or pharmaceutical compositions thereof) for use in the methods, uses, articles of manufacture, and kits described herein may be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art.

1. Binding assays and other assays

In one aspect, an IL-22 Fc fusion protein is tested for its receptor binding activity, e.g., by known methods such as ELISA, western blotting analysis, cell surface binding by Scatchard, surface plasmon resonance. In another aspect, competition assays may be used to identify an antibody that competes with the IL-22 Fc fusion protein for binding to the IL-22 receptor. In a further aspect, an IL-22 Fc fusion protein of the invention can be used for detecting the presence or amount of IL-22 receptor or IL22- Binding Protein (soluble receptor) present in a biological sample. In a further aspect, an IL-22 Fc fusion protein of the invention can be used for detecting the presence or amount of IL-22 receptor present in a biological sample. In certain embodiments, the biological sample is first blocked with a non-specific isotype control antibody to saturate any Fc receptors in the sample. Exemplary assays are described in Example 1 of International Patent Application Publication No. WO 2019/148020, which is incorporated herein by reference in its entirety.

2. Activity assays

In one aspect, assays are provided for identifying biological activity of a composition (e.g., an IL- 22 Fc fusion protein or a pharmaceutical composition thereof). Biological activity of an IL-22 polypeptide or IL-22 Fc fusion protein in a composition (e.g., a pharmaceutical composition) may include, e.g., binding to IL-22 receptor, stimulating IL-22 signaling, and inducing STAT3, or REG3 (also known as PAP or HIP/PAP (hepatocarcinoma-intestine-pancrease/pancreatic associated protein) expression.

3. Stability assays

In one aspect, assays are provided for determining the stability of a composition (e.g., an IL-22 Fc fusion protein or a pharmaceutical composition thereof). For example, a composition (e.g., a pharmaceutical composition) can be evaluated qualitatively and/or quantitatively in a variety of different ways, including evaluation of aggregate formation (for example, using size exclusion chromatography, by measuring turbidity, and/or by visual inspection); evaluation of ROS formation (for example, by using a light stress assay or an 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) stress assay); oxidation of specific amino acid residues of the protein (for example, a Met residue of an IL-22 Fc fusion protein); by assessing charge heterogeneity using cation exchange chromatography, image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis; amino-terminal or carboxy-terminal sequence analysis; mass spectrometric analysis; SDS-PAGE analysis to compare reduced and intact polypeptides (e.g., IL- 22 Fc fusion proteins); peptide map (for example, tryptic or LYS-C) analysis; evaluating biological activity or target binding function of the protein (e.g., binding of an IL-22 Fc fusion protein to an IL-22 receptor); and the like. Instability may involve any one or more of: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation and/or Trp oxidation), isomerization (e.g., Asp isomerization), clipping/hydrolysis/fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine(s), N-terminal extension, C-terminal processing, glycosylation differences, and the like. Exemplary assays are described in Example 1 and Example 3 of International Patent Application Publication No. WO 2019/148020.

D. Conjugates for Use in the Methods

In any of the methods, uses, articles of manufacture, and kits described herein, the IL-22 Fc fusion protein may be a conjugate comprising an IL-22 Fc fusion protein described herein conjugated to one or more agents for detection, formulation, half-life extension, mitigating immunogenicity, or tissue penetration. Exemplary types of conjugation include, without limitation, PEGylation and conjugation to radioactive isotopes.

In another embodiment, a conjugate comprises an IL-22 Fc fusion protein as described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹², and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123 again, iodine-131 , indium-111 , fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

E. Pharmaceutical Formulations

The invention also provides compositions (e.g., pharmaceutical compositions) that include IL-22 Fc fusion proteins for use in the methods, uses, articles of manufacture, and kits described herein. Any of the IL-22 Fc fusion proteins described herein can be used in the compositions. In some embodiments, any of the pharmaceutical compositions described in International Patent Application Publication No.

WO 2019/148020 may be used in the methods, uses, articles of manufacture, and kits described herein.

Pharmaceutical formulations can be prepared using standard methods known in the art by mixing the active ingredient having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (see, e.g., Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) and Remington's Pharmaceutical Sciences 20^th edition, ed. A. Gennaro, 2000, Lippincott, Williams & Wilkins, Philadelphia, Pa), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes ( e.g . Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH- 20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Optionally, the formulation contains a pharmaceutically acceptable salt, preferably sodium chloride, and preferably at about physiological concentrations.

Optionally, the formulations of the invention can contain a pharmaceutically acceptable preservative. In some embodiments the preservative concentration ranges from 0.1 to 2.0%, typically v/v. Suitable preservatives include those known in the pharmaceutical arts. Benzyl alcohol, phenol, m-cresol, methylparaben, benzalkonium chloride and propylparaben are preferred preservatives. Optionally, the formulations of the invention can include a pharmaceutically acceptable surfactant, e.g., at a concentration of 0.005 to 0.02%.

The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

Exemplary lyophilized formulations are described in US Patent No. 6,267,958. Aqueous formulations include those described in US Patent No. 6,171 ,586 and W02006/044908, the latter formulations including a histidine-acetate buffer.

The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide a steroid, TNF antagonist or other anti-inflammatory therapeutics. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the IL-22 Fc fusion protein, which matrices are in the form of shaped articles, e.g., films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and .gamma. ethyl-L-glutamate, non-degradable ethylene -vinyl acetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 °C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

The compositions (e.g., IL-22 Fc fusion proteins or pharmaceutical compositions thereof) are typically administered intravenously, e.g., by intravenous injection. In other embodiments, the compositions (e.g., IL-22 Fc fusion proteins or pharmaceutical compositions thereof) may be administered subcutaneously, e.g., by subcutaneous injection.

Other methods of administration can also be used, which includes but is not limited to, topical, parenteral, intraperitoneal, intrapulmonary, intranasal, ocular, intraocular, intravitreal, intralesional, intracerobrospinal, intra-articular, intrasynovial, intrathecal, oral, or inhalation administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In addition, the compounds described herein are administered to a human subject, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time.

F. Articles of Manufacture and Kits

In another aspect of the invention, an article of manufacture or kit containing materials useful for the methods and uses described herein is provided. The article of manufacture may include any of the compositions (e.g., IL-22 Fc fusion proteins or compositions thereof (e.g., pharmaceutical compositions)) provided herein. The articles of manufacture and kits may include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In some embodiments, at least one active agent in the composition is an IL-22 Fc fusion protein. The label or package insert indicates that the composition is used for treating the condition of choice. In some embodiments, the article of manufacture or the containers are protected from light. The articles of manufacture can include any of the compositions (e.g., pharmaceutical compositions) described herein. In another embodiment of the invention, articles of manufacture containing materials useful for the treatment or prevention of pneumonia (including viral pneumonia, e.g. coronavirus pneumonia, such as COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) and/or acute respiratory distress syndrome (ARDS) described above are provided.

The article of manufacture optionally further comprises a package insert with instructions for treating or preventing pneumonia (including viral pneumonia, e.g. coronavirus pneumonia, such as COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)) and/or acute respiratory distress syndrome (ARDS) in a subject, wherein the instructions indicate that treatment with the composition (e.g., an IL-22 Fc fusion protein or a pharmaceutical composition thereof) as disclosed herein treats or prevents the pneumonia (e.g. including viral pneumonia, e.g. coronavirus pneumonia, such as COVID-19 pneumonia) and/or the acute respiratory distress syndrome (ARDS).

In another embodiment of the invention, provided herein are articles of manufacture containing materials useful for the treatment or prevention of CRS (e.g., CRS caused by a viral infection (e.g., COVID- 19) or CAR T-cell-induced CRS), e.g., in accordance with any of methods disclosed herein.

In one aspect, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient having or at risk of developing a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in accordance with any one of the methods disclosed herein.

For example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient having or at risk of developing pneumonia in accordance with any one of the methods disclosed herein.

In another example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL- 22 Fc fusion protein to a patient having or at risk of developing ARDS in accordance with any one of the methods disclosed herein.

In yet another example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient to reduce disease progression to ARDS in accordance with any one of the methods disclosed herein.

In a further example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-

22 Fc fusion protein to a patient to promote convalescence of a patient having a respiratory disease (e.g., pneumonia (e.g., viral pneumonia, including COVID-19 pneumonia (e.g., severe COVID-19 pneumonia)), ARDS, asthma, COPD, influenza (e.g., influenza A or B), lung diseases, and the like) in accordance with any one of the methods disclosed herein.

For example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient to promote convalescence of a patient having pneumonia or ARDS in accordance with any one of the methods disclosed herein.

In another example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL- 22 Fc fusion protein to a patient to reduce lung inflammation in the patient without compromising antiviral host defense in accordance with any one of the methods disclosed herein.

In yet another example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient to reduce maladaptive hyper-inflammatory responses in the patient without inhibiting development of protective adaptive immunity and viral clearance in accordance with any one of the methods disclosed herein.

In another example still, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient to promote epithelial lung repair, improve lung epithelial barrier integrity, improve lung endothelial barrier integrity, and/or reduce pulmonary edema in accordance with any one of the methods disclosed herein.

In another example, provided herein is a kit comprising an IL-22 Fc fusion protein (e.g., an IL-22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL- 22 Fc fusion protein to a patient having a viral infection to provide prophylaxis against secondary bacterial and/or fungal infection of the lung in accordance with any one of the methods disclosed herein.

In another example, provided herein is a a kit comprising an IL-22 Fc fusion protein (e.g., an IL- 22 Fc fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, and SEQ ID NO:20) and instructions to administer the IL-22 Fc fusion protein to a patient to treat or prevent CRS (e.g., CRS caused by a viral infection (e.g., COVID-19) or CAR-T-cell-induced CRS). In some instances, the CRS is caused by a viral infection, including a coronavirus infection (e.g., COVID-19). In some instances, the CRS is CAR T -cell- induced CRS.

It is understood that any of the above articles of manufacture may include a conjugate of the invention in place of or in addition to an IL-22 Fc fusion protein. EXAMPLES

The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, given the general description provided above, and the examples are not intended to limit the scope of the claims.

Example 1 : A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study to Evaluate the Safety and Efficacy of UTTR1147A (R07021610) plus Standard of Care versus Placebo for the Treatment of Patients with Severe COVID-19 Pneumonia

1. General Investigational Plan

This is a phase II study to evaluate the efficacy and safety of UTTR1147A in the treatment of hospitalized patients with severe COVID-19 pneumonia (Table 1).

The route of administration is IV infusion.

Table 1 : Overview of Planned Study

SOC=standard of care.

2. Background

UTTR1147A (RO7021610) is an IL-22 fusion protein that links the cytokine interleukin 22 (IL-22) with the Fc portion of human immunoglobulin G4 (lgG4) to improve the cytokine’s pharmacokinetic (PK) characteristics and has the amino acid sequence set forth in SEQ ID NO: 8. The Fc portion of the fusion protein incorporates a mutation (N227G (numbering from the N-terminus of the entire fusion polypeptide of the cytokine and Fc, which corresponds to an N297G mutation with respect to the numbering of the Fc region according to the EU index)) that minimizes the potential for Fc effector function.

Human interleukin-22 (IL-22) belongs to the IL-10 cytokine family and binds specifically to the IL-22 receptor (IL-22R) heterodimer. IL-22R is expressed on a variety of epithelial tissues, including the gastrointestinal (Gl) tract epithelium, epidermal keratinocytes, liver hepatocytes, pancreatic acinar epithelium, renal tubular epithelium, as well as alveolar epithelial cells. IL-22 binding results in modulation of innate immunity through multiple different regenerative and protective mechanisms in epithelial tissues, including the Gl tract mucosal epithelium, epidermal keratinocytes, and inflamed pulmonary tissue. This is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of RO7021610 plus standard of care versus placebo for the treatment of patients with severe COVID-19 pneumonia.

3. Primary Efficacy Objective

The primary efficacy objective for this study is to evaluate the efficacy of UTTR1147A compared with placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the basis of the following endpoint:

• Clinical status assessed using a 7-category ordinal scale at Day 28

The “7-category ordinal scale” includes the following categories for evaluating the patient’s status:

5. ICU, requiring intubation and mechanical ventilation

7. Death.

4. Secondary Efficacy Objectives

The secondary efficacy objective for this study is to evaluate the efficacy of UTTR1147 A compared with placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the basis of the following endpoints:

• Time to clinical improvement (TTCI) defined as a National Early Warning Score 2 (NEWS2) of > 2 maintained for 24 hours

• Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal scale of clinical status

• Incidence of mechanical ventilation

• Ventilator-free days to Day 28

• Organ failure-free day to Day 28

• Incidence of intensive care unit (ICU) stay

• Duration of ICU stay

• Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission, or withdrawal (whichever occurs first) • Mortality rate at Days 7, 14, 21 , 28, and 60

• Time to hospital discharge or “ready for discharge” (as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or < 2L supplemental oxygen)

• Duration of supplemental oxygen

National Early Warning Score (NEWS) 2

The NEWS2 score is disclosed in Royal College of Physicians. National early warning score (NEWS) 2. Standardizing the assessment of acute-illness severity in the NFIS. London: RCP (2017).

It involves evaluating the following parameters (SpC>2 = oxygen saturation).

The oxygen saturation should be scored according to either the SpC>2 Scale 1 or 2 presented in the table above. The SpC>2 Scale 2 is for patients with a target oxygen saturation requirement of 88%-92% (e.g., in patients with hypercapnic respiratory failure related to advanced lung diseases, such as chronic obstructive pulmonary disease (COPD)). This should only be used in patients confirmed to have hypercapnic respiratory failure by blood gas analysis on either a prior or their current hospital admission.

The decision to use the SpC>2 Scale 2 should be made by the treating physician and should be recorded in the eCRF. In all other circumstances, the SpC>2 Scale 1 should be used. For physiological parameter “Air or Oxygen?”: Any patients requiring the use of oxygen or other forms of ventilation to maintain oxygen saturations and support respiration should be assigned a score of

The consciousness level should be recorded according to the best clinical condition of the patient during the assessment. Patients who are assessed as “Alert” (A) should be assigned a score of 0. Patients assessed as “New Confusion” (C), “Responsive to Voice” (V), “Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3.

Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and temperature according to the table above.

NEWS2 values will be calculated electronically throughout the study by the Sponsor based upon entry of vital sign parameters by the investigator in the appropriate eCRF.

Example Case Calculation:

An 82-year-old woman was admitted, tested positive to COVID-19 and admitted to the high dependency unit for non-invasive ventilation. Her taken observations and corresponding NEWS2 score are as follows:

5. Exploratory Efficacy Objectives

The exploratory efficacy objective for this study is to evaluate the efficacy of UTTR1147 A compared with placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the basis of the following endpoints:

Incidence of vasopressor use Duration of vasopressor use

Incidence of extracorporeal membrane oxygenation (ECMO)

Incidence of starting hemodialysis

SARS-CoV-2 viral load on Day 15 or day of hospital discharge (whichever occurs first)

The proportion of patients with secondary bacterial infections

6. Safety Objectives

The safety objective for this study is to evaluate the safety of UTTR1147A compared with placebo in combination with SOC for the treatment of severe COVID-19 pneumonia on the basis of the following endpoints:

• Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0

• Change from baseline in targeted vital signs

• Change from baseline in targeted clinical laboratory test results 7. Clinical Pharmacology of R07021610

The PK of RO7021610 has been evaluated in a single ascending-dose (SAD) escalation study (Study GA29468) in healthy volunteers (HVs), and multiple ascending-dose (MAD) study (Study GA29469) in HVs and patients with inflammatory bowel disease (IBD). The doses tested ranged from 1 to 120 pg/kg IV and from 3 to 120 pg/kg SC single dose in Study GA29468, and from 30 pg/kg IV every 4 weeks (Q4W) for 3 doses to 90 pg/kg IV every 2 weeks (Q2W) for 6 doses in Study GA29469.

In Study GA29468, following IV administration, the observed maximum concentration (Cmax) and area under the serum concentration-time curve from time 0 to infinity (AUCint) were both dose-proportional across the 10- to 120-pg/kg IV dose levels. Following SC administration, the systemic exposure, including Cmax and AUCint, increased with increasing dose levels. The SC bioavailability ranged from 53% to 79% at dose levels of 10 to 60 pg/kg.

In Study GA29469, based on non-compartmental analysis (NCA), the mean elimination half-life ranged from 14.3 to 16.7 days (averaged 15.6 days) in HVs and 11 .7 to 12.7 days (averaged 12.2 days) in patients with ulcerative colitis (UC). The observed group mean of Cmax and area under the serum concentration-time curve from Days 56 to 70 [last dosing day for the Q2W regimen] (AUC56-70) for protocol-defined maximum tolerated dose (MTD) in HVs at the dose of 60 pg/kg Q2W, were 1070 ng/mL and 7460 ng day/mL, respectively. MTD in patients with UC has not yet been defined as the 90 pg/kg Q2W regimen is currently ongoing.

Dose-dependent increases in serum levels of PD biomarkers serum amyloid A (SAA), REG3A, and C-reactive protein (CRP) demonstrated IL-22 dependent target engagement and activation of signaling pathways downstream of IL-22R following treatment with R07021610 compared with placebo. The transient increases in CRP and SAA returned to baseline at Week 4 and Week 2 post dose, respectively, whereas for REG3A at higher R07021610 doses (doses > 60 pg/kg), levels returned to near baseline level by the end of study at Week 8. Increases in CRP were consistent with data from nonclinical studies and importantly, occurred in the absence of symptoms of inflammation (fever, leukocytosis, vital sign changes). These PD biomarker results provide evidence of IL-22R engagement and dose-dependent pharmacological activity of R07021610 in HVs.

8. Dose Regimen

For the UTTR1147A arm, 90 pg/kg IV was selected for the first dose. For patients who remain in hospital and on oxygen after two weeks of the first dose (Day 15), a second dose at 90 pg/kg IV will be offered.

The selected dose is based on clinical experience (safety, PK, and PD) observed in the single ascending dose study in healthy volunteers (Study GA29468), and in the multiple ascending dose study in healthy volunteers and patients with inflammatory bowel disease (Study GA29469). In GA29469, at least 4 participants per cohort received six doses of UTTR1147A up to 90 pg/kg IV Q2W. Approximately 70 participants in total were exposed to UTTR1147A. In Phase la, 90 pg/kg was well tolerated in healthy volunteers. In Phase lb, although 60 pg/kg q2w was the MTD in healthy volunteers due to skin tolerability, in patients with ulcerative colitis (UC), the highest dose tested, 90 pg/kg q2w x 6, was tolerated and a MTD was not reached. PK exposure in UC patients were observed relatively lower than that in healthy volunteers, suggesting faster clearance (CL) in patients with UC. Based on non-compartmental analysis, the elimination half-life of UTTR1147A ranged from 14.3 to 16.7 days in healthy volunteers and 11 .7 to 12.7 days in patients with UC.

The observation of different PK profile in UC patients versus healthy volunteers is consistent with literature reporting patients with Gl damage may have faster drug clearance than in healthy volunteers, a phenomenon observed in studies with infliximab and other biologies.

In SARS-CoV-2 (COVID-19) infected patients with pneumonia, there is vascular leakage and pulmonary tissue damage in the lung, a situation similar to Gl damage, and without wishing to be bound by any particular theory, the PK could be altered by disease status. Based on experience with a Phase 2 trial of MHAA4549A, a monoclonal antibody in combination with oseltamivir versus oseltamivir for treatment of severe influenza A infection, PK in severe influenza patients showed faster CL compared with in healthy volunteers. For another molecule, DSTA4637S, an antibody conjugate, faster CL was observed in hospitalized patients with Staphylococcus (staph) infection compared with in healthy volunteers. The first dose of 90 pg/kg is targeted to maximize the drug exposure in COVID-19 pneumonia patients. The second dose is targeted to help the patients still in hospital and on oxygen to maintain the drug level and reinforce the epithelial repair and protective mechanism.

The serum biomarker Reg3A was used in Phase la and Phase lb studies to demonstrate target engagement. A preliminary PK/PD model suggests that pharmacological effect at 90 pg/kg was not plateaued.

Taking these evidence together, 90 pg/kg q2w was selected as the clinical study dose.

9. Description of Study

Patients must meet the following criteria for study entry:

• Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X- ray or CT scan

• Sp02 < 93% (on room air or supplemental oxygen) or Pa02/Fi02 < 300 mmHg

This study includes two treatment arms: IL-22Fc + SOC (approximately 100 patients) and placebo + SOC (approximately 100 patients). Screening for the study occurs on Days -3 to Day 1 of the Study. On the Study Baseline (Day 1), the subject is administered IL-22 Fc at a dose of 90 pg/kg IV or placebo IV. The Study Baseline (Day 1 ) is not the day of COVID-19 diagnosis. After two weeks, if the patient is still on oxygen, on Day 15, the patient is administered IL-22 Fc at a dose of 90 pg/kg IV or placebo IV.

Patients will be randomized as soon as possible after screening at a 2:2:1 :1 ratio to receive blinded treatment of UTTR1147A, or its matching placebo. Study treatment will be given in combination with SOC as defined by the site, including anti-virals and supportive care. Randomization will be stratified by need for mechanical ventilation (yes vs. no) and region. Enrollment of patients with need for mechanical ventilation will be capped at 25%.

Patients assigned to the UTTR1147A arm will receive one infusion of UTTR1147A 90 pg/kg on Day 1 , respectively, and patients assigned to the placebo arm will receive one infusion of matched placebo. A second dose of UTTR1147A 90 pg/kg, or matching placebo will be given on Day 15 if the patient still remains hospitalized with a requirement for supplemental oxygen therapy at that time. Following discharge, patients will be followed up remotely and may return to the clinic for a study completion visit (Day 60), if feasible.

The primary endpoint is assessed at Day 28. Secondary endpoints and a safety follow-up are assessed at Day 60.

The specification is considered to be sufficient to enable one skilled in the art to practice the invention. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1 . A method of treating or preventing pneumonia in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

2. A method of treating or preventing acute respiratory distress syndrome (ARDS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

3. A method of reducing disease progression to ARDS in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

4. A method of promoting convalescence of a patient having pneumonia or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

5. A method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

6. A method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

7. A method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving interferon (IFN)-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

8. A method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

9. A method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

10. The method of any one of claims 1 -8, wherein the patient has a viral infection.

11 . The method of claim 9 or 10, wherein the viral infection is a coronavirus infection.

12. The method of claim 11 , wherein the coronavirus infection is with SARS-CoV-2, MERS-CoV, or SARS-CoV.

13. The method of claim 12, wherein the coronavirus infection is with SARS-CoV-2.

14. The method of claim 13, wherein the patient has a positive polymerase chain reaction (PCR) test for SARS-CoV-2 from a biological sample obtained from the patient.

15. The method of any one of claims 1 -14, wherein the patient has been admitted to a hospital.

16. The method of any one of claims 5-7 and 9-15, wherein the patient has pneumonia or ARDS or is at risk of developing pneumonia or ARDS.

17. The method of any one of claims 2-4, 8, and 16, wherein the ARDS is caused by a primary pulmonary infection, a systemic infection that spreads to the lungs, or a non-infectious cause.

18. The method of claim 17, wherein the non-infectious cause is trauma or hypotensive shock.

19. The method of any one of claims 2-4, 8, and 16-18, wherein the ARDS has progressed from pneumonia.

20. The method of any one of claims 1 , 4, 8, 16, and 19, wherein the pneumonia is viral pneumonia.

21 . The method of any one of claims 1 , 4, 8, 16, 19, and 20, wherein the pneumonia is moderate, severe, or critical pneumonia.

22. The method of claim 21 , wherein the pneumonia is severe pneumonia.

23. The method of any one of claims 1 , 4, 8, 16, and 19-22, wherein the pneumonia is coronavirus pneumonia.

24. The method of claim 23, wherein the coronavirus pneumonia is COVID-19 pneumonia, Middle East respiratory syndrome pneumonia, or severe acute respiratory syndrome pneumonia.

25. The method of claim 24, wherein the coronavirus pneumonia is COVID-19 pneumonia.

26. The method of claim 25, wherein the COVID-19 pneumonia is severe COVID-19 pneumonia.

27. The method of any one of claims 1 -26, wherein the IL-22 Fc fusion protein is administered at a dose of between about 30 pg/kg to about 120 pg/kg.

28. The method of any one of claims 1 -27, wherein the IL-22 Fc fusion protein is administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

29. The method of any one of claims 1 -28, wherein the IL-22 Fc fusion protein is administered at a dose of about 90 pg/kg.

30. The method of any one of claims 1 -28, wherein the IL-22 Fc fusion protein is administered at a dose of about 60 pg/kg.

31 . The method of any one of claims 1 -30, wherein the method comprises administering at least a first dose and a second dose of the IL-22 Fc fusion protein to the patient.

32. The method of claim 31 , wherein the second dose is administered to the patient about 7 to about 21 days after the first dose.

33. The method of claim 31 or 32, wherein the patient experiences improvement of clinical status after the first dose.

34. The method of claim 31 or 32, wherein the patient experiences no improvement or worsening of clinical status after the first dose.

35. The method of any one of claims 31 -34, wherein the patient remains in a hospital and is receiving oxygen.

36. A method of treating or preventing pneumonia in a patient, the method comprising:

(a) administering a first dose of an IL-22 Fc fusion protein to the patient; and

(b) administering a second dose of the IL-22 Fc fusion protein to the patient about two weeks following the first dose, wherein the patient remains in a hospital and is receiving oxygen.

37. A method of treating or preventing ARDS in a patient, the method comprising:

38. A method of reducing disease progression to ARDS in a patient, the method comprising:

39. A method of promoting convalescence of a patient having pneumonia or ARDS, the method comprising:

40. A method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising:

41 . A method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising:

42. A method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising:

43. A method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS, the method comprising:

44. A method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising:

45. The method of any one of claims 31 -44, wherein the second dose is administered to the patient 14 days after the first dose.

46. The method of any one of claims 31 -45, wherein the first dose is between about 30 pg/kg to about 120 pg/kg.

47. The method of any one of claims 31 -46, wherein the first dose is about 30 g/kg, about 60 pg/kg, about 90 pg/kg, or about 120 gg/kg.

48. The method of any one of claims 31 -46, wherein the first dose is about 90 gg/kg.

49. The method of any one of claims 31 -46, wherein the first dose is about 60 gg/kg.

50. The method of any one of claims 31 -49, wherein the second dose is between about 30 gg/kg to about 120 gg/kg.

51 . The method of any one of claims 31 -50, wherein the second dose is about 30 gg/kg, about 60 gg/kg, about 90 gg/kg, or about 120 gg/kg.

52. The method of any one of claims 31 -51 , wherein the second dose is about 90 gg/kg.

53. The method of any one of claims 31 -51 , wherein the second dose is about 60 gg/kg.

54. The method of any one of claims 1 -53, which achieves a greater improvement in clinical outcome compared to standard of care (SOC).

55. A method of treating or preventing pneumonia in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

56. A method of treating or preventing ARDS in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

57. A method of reducing disease progression to ARDS in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

58. A method of promoting convalescence of a patient having pneumonia or ARDS comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

59. A method of reducing lung inflammation in a patient without compromising antiviral host defense comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

60. A method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

61 . A method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

62. A method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

63. A method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection comprising administering an IL-22 Fc fusion protein to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

64. The method of any one of claims 54-63, wherein the clinical outcome is measured on an ordinal scale of clinical status.

65. The method of claim 64, wherein the ordinal scale is a 7-category ordinal scale.

66. The method of claim 64 or 65, wherein the clinical outcome is measured on the ordinal scale of clinical status at Day 28 following treatment on Day 1 .

67. The method of any one of claims 54-66, wherein the clinical outcome is time to clinical improvement (TTCI) defined as a National Early Warning Score 2 (NEWS2) of < 2 maintained for 24 hours.

68. The method of any one of claims 54-67, wherein the clinical outcome is time to improvement of at least 2 categories relative to baseline on the ordinal scale of clinical status.

69. The method of any one of claims 54-68, wherein the clinical outcome is incidence of mechanical ventilation.

70. The method of any one of claims 54-69, wherein the clinical outcome is ventilator-free days to Day 28 following treatment on Day 1 .

71 . The method of any one of claims 54-70, wherein the clinical outcome is organ failure-free days to Day 28 following treatment on Day 1 .

72. The method of any one of claims 54-71 , wherein the clinical outcome is incidence of intensive care unit (ICU) stay.

73. The method of any one of claims 54-72, wherein the clinical outcome is duration of ICU stay.

74. The method of any one of claims 54-73, wherein the clinical outcome is time to clinical failure defined as the time to death, mechanical ventilation, ICU admission, or withdrawal, whichever occurs first.

75. The method of any one of claims 54-74, wherein the clinical outcome is mortality rate at Days 7, 14, 21 , 28, and 60 following treatment on Day 1 .

76. The method of any one of claims 54-75, wherein the clinical outcome is time to hospital discharge; or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or < 2L supplemental oxygen.

77. The method of any one of claims 54-76, wherein the clinical outcome is duration of supplemental oxygen.

78. The method of any one of claims 54-77, wherein the clinical outcome is selected from the group consisting of incidence of vasopressor use, duration of vasopressor use, incidence of extracorporeal membrane oxygenation (ECMO), incidence of starting dialysis, SARS-CoV-2 viral load on Day 15 or day of hospital discharge (whichever occurs first), and proportion of patients with secondary bacterial infections.

79. The method of any one of claims 1-78, which is associated with an acceptable safety outcome compared with standard of care (SOC).

80. The method of claim 79, wherein the safety outcome is selected from the group consisting of: incidence and severity of adverse events; incidence and severity of adverse events with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0; change from baseline in targeted vital signs; and change from baseline in targeted clinical laboratory test results.

81 . The method of any one of claims 54-80, wherein the SOC comprises supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s).

82. The method of any one of claims 8, 10-35, 43, 45-54, 62, and 64-81 , wherein the anti bacterial epithelial factors comprise one or more of REG3A, Lipocalin 2, INFAR1 , INFA11 , CXCL10, DEFA1 , DEFB14, MDK, PTN, and CRP.

83. A method of treating or preventing cytokine release syndrome (CRS) in a patient comprising administering an effective amount of an IL-22 Fc fusion protein to the patient.

84. The method of claim 83, wherein the IL-22 Fc fusion protein is administered at a dose of between about 30 pg/kg to about 120 pg/kg.

85. The method of claim 83 or 84, wherein the IL-22 Fc fusion protein is administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

86. The method any one of claims 83-85, wherein the IL-22 Fc fusion protein is administered at a dose of about 90 pg/kg.

87. The method of any one of claims 83-85, wherein the IL-22 Fc fusion protein is administered at a dose of about 60 pg/kg.

88. The method of any one of claims 83-87, wherein the CRS is caused by a viral infection (e.g., COVID-19) or is chimeric antigen receptor (CAR) T cell-induced CRS.

89. The method of any one of claims 1 -88, wherein the IL-22 Fc fusion protein comprises an IL-22 polypeptide linked to an Fc region by a linker.

90. The method of claim 89, wherein the IL-22 polypeptide is glycosylated and/or the Fc region is not glycosylated.

91 . The method of claim 90, wherein: (i) the amino acid residue at position 297 as in the EU index of the Fc region is Gly or Ala; and/or (ii) the amino acid residue at position 299 as in the EU index of the Fc region is Ala, Gly, or Val.

92. The method of any one of claims 89-91 , wherein the Fc region is an IgG 1 Fc region, an lgG2 Fc region, or an lgG4 Fc region.

93. The method of claim 92, wherein the Fc region comprises the CH2 and CH3 domain of lgG4.

94. The method of any one of claims 1 -93, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8.

95. The method of claim 94, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:8.

96. The method of claim 95, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:8.

97. The method of claim 96, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:8.

98. The method of claim 97, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8.

99. The method of any one of claims 1 -98, wherein the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16.

100. The method of claim 99, wherein the IL-22 Fc fusion protein comprises or consists of the amino acid sequence of SEQ ID NO:8.

101 . The method of any one of claims 1 -93, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:12.

102. The method of claim 101 , wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:12.

103. The method of claim 102, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:12.

104. The method of claim 103, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:12.

105. The method of claim 104, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:12.

106. The method of any one of claims 1 -93 and 101 -105, wherein the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:12, SEQ ID NO:14, or SEQ ID NQ:20.

107. The method of any one of claims 1 -93, wherein the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:81 , SEQ ID NO:82, or SEQ ID NO:83.

108. The method of any one of claims 1 -107, wherein the IL-22 Fc fusion protein is a dimeric IL- 22 Fc fusion protein.

109. The method of any one of claims 1 -107, wherein the IL-22 Fc fusion protein is a monomeric IL-22 Fc fusion protein.

110. The method of any one of claims 89-109, wherein the IL-22 polypeptide is a human IL-22 polypeptide.

111. The method of claim 110, wherein the IL-22 polypeptide comprises the amino acid sequence of SEQ ID NO:4.

112. The method of any one of claims 89-111 , wherein the linker comprises or consists of the amino acid sequence RVESKYGPP (SEQ ID NO: 44).

113. The method of any one of claims 1-112, wherein the IL-22 Fc fusion protein binds to IL-22 receptor.

114. The method of claim 113, wherein the IL-22 receptor is human IL-22 receptor.

115. The method of any one of claims 1-114, wherein the IL-22 Fc fusion protein is administered to the patient in a pharmaceutical composition.

116. The method of claim 115, wherein the pharmaceutical composition has an average sialic acid content in the range of 8 to 12 moles of sialic acid per mole of the IL-22 Fc fusion protein.

117. The method of claim 116, wherein the pharmaceutical composition has an average sialic acid content in the range of 8 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein.

118. The method of claim 117, wherein the pharmaceutical composition has an average sialic acid content in the range of 8 to 9 moles of sialic acid per mole of the IL-22 Fc fusion protein.

119. The method of claim 118, wherein the pharmaceutical composition has an average sialic acid content in the range of 9 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein.

120. The method of any one of claims 1 -119, wherein the IL-22 Fc fusion protein is administered to the patient as a monotherapy.

121 . The method of any one of claims 1 -119, wherein the IL-22 Fc fusion protein is administered to the patient as a combination therapy.

122. The method of claim 121 , wherein the combination therapy comprises administering tocilizumab, hydroxychloroquine, azithromycin, or a combination thereof.

123. The method of claim 122, wherein the combination therapy comprises administering tocilizumab.

124. The method of any one of claims 121 -123, wherein the IL-22 Fc fusion protein is administered to the patient in combination with SOC.

125. The method of claim 124, wherein the IL-22 Fc fusion protein is administered to the patient prior to, concurrently with, or after the SOC.

126. The method of claim 124 or 125, wherein the SOC comprises supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s).

127. The method of claim 126, wherein the supportive care comprises oxygen therapy.

128. The method of any one of claims 1 -127, wherein the administering is by intravenous infusion.

129. The method of any one of claims 1 -127, wherein the patient is a human.

130. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient having or at risk of developing pneumonia in accordance with the method of any one of claims 1 , 10-36, 45-55, 64-82, and 89-129.

131 . A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient having or at risk of developing ARDS in accordance with the method of any one of claims 2, 10-35, 37, 45-54, 56, 64-82, and 89-129.

132. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to reduce disease progression to ARDS in accordance with the method of any one of claims 3, 10-35, 38, 45-54, 57, 64-82, and 89-129.

133. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to promote convalescence of a patient having pneumonia or ARDS in accordance with the method of any one of claims 4, 10-35, 39, 45-54, 58, 64-82, and 89-129.

134. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to reduce lung inflammation in the patient without compromising antiviral host defense in accordance with the method of any one of claims 5, 10-35, 40, 45-54, 59, 64-82, and 89-129.

135. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to reduce maladaptive hyper-inflammatory responses in the patient without inhibiting development of protective adaptive immunity and viral clearance in accordance with the method of any one of claims 6, 10-35, 41 , 45-54, 60, 64-82, and 89-129.

136. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to promote epithelial lung repair, improve lung epithelial barrier integrity, improve lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reduce pulmonary edema in accordance with the method of any one of claims 7, 10-35, 42, 45-54, 61 , 64-82, and 89-129.

137. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient to induce expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS in accordance with the method of any one of claims 8, 10-35, 43, 45-54, 62, 64-82, and 89-129.

138. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to a patient having a viral infection to provide prophylaxis against secondary bacterial and/or fungal infection of the lung in accordance with the method of any one of claims 9-35, 44-54, 63-82, and 89-129.

139. A kit comprising an IL-22 Fc fusion protein and instructions to administer the IL-22 Fc fusion protein to treat or prevent CRS in a patient in accordance with the method of any one of claims 83-129.

140. An IL-22 Fc fusion protein for use in treating or preventing pneumonia in a patient.

141 . An IL-22 Fc fusion protein for use in treating or preventing ARDS in a patient.

142. An IL-22 Fc fusion protein for use in reducing disease progression to ARDS in a patient.

143. An IL-22 Fc fusion protein for use in promoting convalescence of a patient having pneumonia or ARDS.

144. An IL-22 Fc fusion protein for use in reducing lung inflammation in a patient without compromising antiviral host defense.

145. An IL-22 Fc fusion protein for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance.

146. An IL-22 Fc fusion protein for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient.

147. An IL-22 Fc fusion protein for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS.

148. An IL-22 Fc fusion protein for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection.

149. The IL-22 Fc fusion protein for use of any one of claims 140-148, wherein the patient has a viral infection.

150. The IL-22 Fc fusion protein for use of claim 148 or 149, wherein the viral infection is a coronavirus infection.

151 . The IL-22 Fc fusion protein for use of claim 150, wherein the coronavirus infection is with SARS-CoV-2, MERS-CoV, or SARS-CoV.

152. The IL-22 Fc fusion protein for use of claim 151 , wherein the coronavirus infection is with SARS-CoV-2.

153. The IL-22 Fc fusion protein for use of claim 152, wherein the patient has a positive PCR test for SARS-CoV-2 from a biological sample obtained from the patient.

154. The IL-22 Fc fusion protein for use of any one of claims 140-153, wherein the patient has been admitted to a hospital.

155. The IL-22 Fc fusion protein for use of any one of claims 144-146 and 148-154, wherein the patient has pneumonia or ARDS or is at risk of developing pneumonia or ARDS.

156. The IL-22 Fc fusion protein for use of any one of claims 141 -143, 147, and 155, wherein the ARDS is caused by a primary pulmonary infection, a systemic infection that spreads to the lungs, or a non-infectious cause.

157. The IL-22 Fc fusion protein for use of claim 156, wherein the non-infectious cause is trauma or hypotensive shock.

158. The IL-22 Fc fusion protein for use of any one of claims 141 -143, 147, and 155-157, wherein the ARDS has progressed from pneumonia.

159. The IL-22 Fc fusion protein for use of any one of claims 140, 143, 147, 155, and 158, wherein the pneumonia is viral pneumonia.

160. The IL-22 Fc fusion protein for use of any one of claims 140, 143, 147, 155, 158, and 159, wherein the pneumonia is moderate, severe, or critical pneumonia.

161 . The IL-22 Fc fusion protein for use of claim 160, wherein the pneumonia is severe pneumonia.

162. The IL-22 Fc fusion protein for use of any one of claims 140, 143, 147, 155, and 158-161 , wherein the pneumonia is coronavirus pneumonia.

163. The IL-22 Fc fusion protein for use of claim 162, wherein the coronavirus pneumonia is COVID-19 pneumonia, Middle East respiratory syndrome pneumonia, or severe acute respiratory syndrome pneumonia.

164. The IL-22 Fc fusion protein for use of claim 163, wherein the coronavirus pneumonia is COVID-19 pneumonia.

165. The IL-22 Fc fusion protein for use of claim 164, wherein the COVID-19 pneumonia is severe COVID-19 pneumonia.

166. The IL-22 Fc fusion protein for use of any one of claims 140-165, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

167. The IL-22 Fc fusion protein for use of any one of claims 140-166, wherein the IL-22 Fc fusion protein is to be administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

168. The IL-22 Fc fusion protein for use of any one of claims 140-167, wherein the IL-22 Fc fusion protein is to be administered at a dose of about 90 pg/kg.

169. The IL-22 Fc fusion protein for use of any one of claims 140-167, wherein the IL-22 Fc fusion protein is to be administered at a dose of about 60 pg/kg.

170. The IL-22 Fc fusion protein for use of any one of claims 140-169, wherein the IL-22 Fc fusion potein is to be administered to the patient in at least a first dose and a second dose.

171 . The IL-22 Fc fusion protein for use of claim 170, wherein the second dose is to be administered to the patient about 7 to about 21 days after the first dose.

172. The IL-22 Fc fusion protein for use of claim 170 or 171 , wherein the patient experiences improvement of clinical status after the first dose.

173. The IL-22 Fc fusion protein for use of claim 170 or 171 , wherein the patient experiences no improvement or worsening of clinical status after the first dose.

174. The IL-22 Fc fusion protein for use of any one of claims 170-173, wherein the patient remains in a hospital and is receiving oxygen.

175. An IL-22 Fc fusion protein for use in a method of treating or preventing pneumonia in a patient, the method comprising:

176. An IL-22 Fc fusion protein for use in a method of treating or preventing ARDS in a patient, the method comprising:

177. An IL-22 Fc fusion protein for use in a method of reducing disease progression to ARDS in a patient, the method comprising:

178. An IL-22 Fc fusion protein for use in a method of promoting convalescence of a patient having pneumonia or ARDS, the method comprising:

179. An IL-22 Fc fusion protein for use in a method of reducing lung inflammation in a patient without compromising antiviral host defense, the method comprising:

180. An IL-22 Fc fusion protein for use in a method of reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, the method comprising:

181 . An IL-22 Fc fusion protein for use in a method of promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, the method comprising:

182. An IL-22 Fc fusion protein for use in a method of inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS, the method comprising:

183. An IL-22 Fc fusion protein for use in a method of prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, the method comprising:

184. The IL-22 Fc fusion protein for use of any one of claims 170-183, wherein the second dose is to be administered to the patient 14 days after the first dose.

185. The IL-22 Fc fusion protein for use of any one of claims 170-184, wherein the first dose is between about 30 pg/kg to about 120 pg/kg.

186. The IL-22 Fc fusion protein for use of any one of claims 170-185, wherein the first dose is about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

187. The IL-22 Fc fusion protein for use of any one of claims 170-186, wherein the first dose is about 90 pg/kg.

188. The IL-22 Fc fusion protein for use of any one of claims 170-186, wherein the first dose is about 60 pg/kg.

189. The IL-22 Fc fusion protein for use of any one of claims 170-188, wherein the second dose is between about 30 pg/kg to about 120 pg/kg.

190. The IL-22 Fc fusion protein for use of any one of claims 170-189, wherein the second dose is about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

191 . The IL-22 Fc fusion protein for use of any one of claims 170-190, wherein the second dose is about 90 pg/kg.

192. The IL-22 Fc fusion protein for use of any one of claims 170-190, wherein the second dose is about 60 pg/kg.

193. The IL-22 Fc fusion protein for use of any one of claims 140-192, which achieves a greater improvement in clinical outcome compared to SOC.

194. An IL-22 Fc fusion protein for use in treating or preventing pneumonia in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

195. An IL-22 Fc fusion protein for use in treating or preventing ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

196. An IL-22 Fc fusion protein for use in reducing disease progression to ARDS in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

197. An IL-22 Fc fusion protein for use in promoting convalescence of a patient having pneumonia or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

198. An IL-22 Fc fusion protein for use in reducing lung inflammation in a patient without compromising antiviral host defense, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

199. An IL-22 Fc fusion protein for use in reducing maladaptive hyper-inflammatory responses in a patient without inhibiting development of protective adaptive immunity and viral clearance, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

200. An IL-22 Fc fusion protein for use in promoting epithelial lung repair, improving lung epithelial barrier integrity, improving lung endothelial barrier integrity, improving IFN-mediated antiviral responses, and/or reducing pulmonary edema in a patient, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

201 . An IL-22 Fc fusion protein for use in inducing expression of anti-bacterial epithelial factors in a patient having pneumonia or ARDS, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

202. An IL-22 Fc fusion protein for use in prophylaxis against secondary bacterial and/or fungal infection of the lung in a patient having a viral infection, wherein the IL-22 Fc fusion protein is to be administered to the patient in an amount effective to achieve a greater improvement in clinical outcome than SOC as measured on an ordinal scale of clinical status.

203. The IL-22 Fc fusion protein for use of any one of claims 193-202, wherein the clinical outcome is measured on an ordinal scale of clinical status.

204. The IL-22 Fc fusion protein for use of claim 203, wherein the ordinal scale is a 7-category ordinal scale.

205. The IL-22 Fc fusion protein for use of claim 203 or 204, wherein the clinical outcome is measured on the ordinal scale of clinical status at Day 28 following treatment on Day 1 .

206. The IL-22 Fc fusion protein for use of any one of claims 193-205, wherein the clinical outcome is TTCI defined as a NEWS2 of < 2 maintained for 24 hours.

207. The IL-22 Fc fusion protein for use of any one of claims 193-206, wherein the clinical outcome is time to improvement of at least 2 categories relative to baseline on the ordinal scale of clinical status.

208. The IL-22 Fc fusion protein for use of any one of claims 193-207, wherein the clinical outcome is incidence of mechanical ventilation.

209. The IL-22 Fc fusion protein for use of any one of claims 193-208, wherein the clinical outcome is ventilator-free days to Day 28 following treatment on Day 1 .

210. The IL-22 Fc fusion protein for use of any one of claims 193-209, wherein the clinical outcome is organ failure-free days to Day 28 following treatment on Day 1 .

211 . The IL-22 Fc fusion protein for use of any one of claims 193-210, wherein the clinical outcome is incidence of ICU stay.

212. The IL-22 Fc fusion protein for use of any one of claims 193-211 , wherein the clinical outcome is duration of ICU stay.

213. The IL-22 Fc fusion protein for use of any one of claims 193-212, wherein the clinical outcome is time to clinical failure defined as the time to death, mechanical ventilation, ICU admission, or withdrawal, whichever occurs first.

214. The IL-22 Fc fusion protein for use of any one of claims 193-213, wherein the clinical outcome is mortality rate at Days 7, 14, 21 , 28, and 60 following treatment on Day 1 .

215. The IL-22 Fc fusion protein for use of any one of claims 193-214, wherein the clinical outcome is time to hospital discharge; or ready for discharge as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or < 2L supplemental oxygen.

216. The IL-22 Fc fusion protein for use of any one of claims 193-215, wherein the clinical outcome is duration of supplemental oxygen.

217. The IL-22 Fc fusion protein for use of any one of claims 193-216, wherein the clinical outcome is selected from the group consisting of incidence of vasopressor use, duration of vasopressor use, incidence of ECMO, incidence of starting dialysis, SARS-CoV-2 viral load on Day 15 or day of hospital discharge (whichever occurs first), and proportion of patients with secondary bacterial infections.

218. The IL-22 Fc fusion protein for use of any one of claims 140-217, which is associated with an acceptable safety outcome compared with SOC.

219. The IL-22 Fc fusion protein for use of claim 218, wherein the safety outcome is selected from the group consisting of: incidence and severity of adverse events; incidence and severity of adverse events with severity determined according to NCI CTCAE v5.0; change from baseline in targeted vital signs; and change from baseline in targeted clinical laboratory test results.

220. The IL-22 Fc fusion protein of any one of claims 193-219, wherein the SOC comprises supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s).

221 . The IL-22 Fc fusion protein of any one of claims 147, 149-174, 182, 184-193, 201 , and 203- 220, wherein the anti-bacterial epithelial factors comprise one or more of REG3A, Lipocalin 2, INFAR1 , INFA11 , CXCL10, DEFA1 , DEFB14, MDK, PTN, and CRP.

222. An IL-22 Fc fusion protein for use in treating or preventing CRS in a patient.

223. The IL-22 Fc fusion protein for use of claim 222, wherein the IL-22 Fc fusion protein is to be administered at a dose of between about 30 pg/kg to about 120 pg/kg.

224. The IL-22 Fc fusion protein for use of claim 222 or 223, wherein the IL-22 Fc fusion protein is to be administered at a dose of about 30 pg/kg, about 60 pg/kg, about 90 pg/kg, or about 120 pg/kg.

225. The IL-22 Fc fusion protein for use any one of claims 222-224, wherein the IL-22 Fc fusion protein is to be administered at a dose of about 90 pg/kg.

226. The IL-22 Fc fusion protein for use of any one of claims 222-224, wherein the IL-22 Fc fusion protein is to be administered at a dose of about 60 pg/kg.

227. The IL-22 Fc fusion protein for use of any one of claims 222-226, wherein the CRS is caused by a viral infection (e.g., COVID-19) or is CAR T cell-induced CRS.

228. The IL-22 Fc fusion protein for use of any one of claims 140-227, wherein the IL-22 Fc fusion protein comprises an IL-22 polypeptide linked to an Fc region by a linker.

229. The IL-22 Fc fusion protein for use of claim 228, wherein the IL-22 polypeptide is glycosylated and/or the Fc region is not glycosylated.

230. The IL-22 Fc fusion protein for use of claim 229, wherein: (i) the amino acid residue at position 297 as in the EU index of the Fc region is Gly or Ala; and/or (ii) the amino acid residue at position 299 as in the EU index of the Fc region is Ala, Gly, or Val.

231 . The IL-22 Fc fusion protein for use of any one of claims 228-230, wherein the Fc region is an IgG 1 Fc region, an lgG2 Fc region, or an lgG4 Fc region.

232. The IL-22 Fc fusion protein for use of claim 231 , wherein the Fc region comprises the CH2 and CH3 domain of lgG4.

233. The IL-22 Fc fusion protein for use of any one of claims 140-232, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:8.

234. The IL-22 Fc fusion protein for use of claim 233, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:8.

235. The IL-22 Fc fusion protein for use of claim 234, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:8.

236. The IL-22 Fc fusion protein for use of claim 235, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:8.

237. The IL-22 Fc fusion protein for use of claim 236, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8.

238. The IL-22 Fc fusion protein for use of any one of claims 140-237, wherein the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:8, SEQ ID NO:10, or SEQ ID NO:16.

239. The IL-22 Fc fusion protein for use of claim 238, wherein the IL-22 Fc fusion protein comprises or consists of the amino acid sequence of SEQ ID NO:8.

240. The IL-22 Fc fusion protein for use of any one of claims 140-232, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:12.

241 . The IL-22 Fc fusion protein for use of claim 240, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 96% sequence identity to the amino acid sequence of SEQ ID NO:12.

242. The IL-22 Fc fusion protein for use of claim 241 , wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 97% sequence identity to the amino acid sequence of SEQ ID NO:12.

243. The IL-22 Fc fusion protein for use of claim 242, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:12.

244. The IL-22 Fc fusion protein for use of claim 243, wherein the IL-22 Fc fusion protein comprises an amino acid sequence having at least 99% sequence identity to the amino acid sequence of SEQ ID NO:12.

245. The IL-22 Fc fusion protein for use of any one of claims 140-232 and 240-244, wherein the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:12, SEQ ID NO:14, or SEQ ID NQ:20.

246. The IL-22 Fc fusion protein for use of any one of claims 140-232, wherein the IL-22 Fc fusion protein comprises the amino acid sequence of SEQ ID NO:81 , SEQ ID NO:82, or SEQ ID NO:83.

247. The IL-22 Fc fusion protein for use of any one of claims 140-246, wherein the IL-22 Fc fusion protein is a dimeric IL-22 Fc fusion protein.

248. The IL-22 Fc fusion protein for use of any one of claims 140-246, wherein the IL-22 Fc fusion protein is a monomeric IL-22 Fc fusion protein.

249. The IL-22 Fc fusion protein for use of any one of claims 228-248, wherein the IL-22 polypeptide is a human IL-22 polypeptide.

250. The IL-22 Fc fusion protein for use of claim 249, wherein the IL-22 polypeptide comprises the amino acid sequence of SEQ ID NO:4.

251 . The IL-22 Fc fusion protein for use of any one of claims 228-250, wherein the linker comprises or consists of the amino acid sequence RVESKYGPP (SEQ ID NO: 44).

252. The IL-22 Fc fusion protein for use of any one of claims 140-251 , wherein the IL-22 Fc fusion protein binds to IL-22 receptor.

253. The IL-22 Fc fusion protein for use of claim 252, wherein the IL-22 receptor is human IL-22 receptor.

254. The IL-22 Fc fusion protein for use of any one of claims 140-253, wherein the IL-22 Fc fusion protein is administered to the patient in a pharmaceutical composition.

255. The IL-22 Fc fusion protein for use of claim 254, wherein the pharmaceutical composition has an average sialic acid content in the range of 8 to 12 moles of sialic acid per mole of the IL-22 Fc fusion protein.

256. The IL-22 Fc fusion protein for use of claim 255, wherein the pharmaceutical composition has an average sialic acid content in the range of 8 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein.

257. The IL-22 Fc fusion protein for use of claim 256, wherein the pharmaceutical composition has an average sialic acid content in the range of 8 to 9 moles of sialic acid per mole of the IL-22 Fc fusion protein.

258. The IL-22 Fc fusion protein for use of claim 256, wherein the pharmaceutical composition has an average sialic acid content in the range of 9 to 10 moles of sialic acid per mole of the IL-22 Fc fusion protein.

259. The IL-22 Fc fusion protein for use of any one of claims 140-258, wherein the IL-22 Fc fusion protein is to be administered to the patient as a monotherapy.

260. The IL-22 Fc fusion protein for use of any one of claims 140-258, wherein the IL-22 Fc fusion protein is to be administered to the patient as a combination therapy.

261 . The IL-22 Fc fusion protein for use of claim 260, wherein the combination therapy comprises administering tocilizumab, hydroxychloroquine, azithromycin, or a combination thereof.

262. The IL-22 Fc fusion protein for use of claim 260, wherein the combination therapy comprises administering tocilizumab.

263. The IL-22 Fc fusion protein for use of any one of claims 260-262, wherein the IL-22 Fc fusion protein is administered to the patient in combination with SOC.

264. The IL-22 Fc fusion protein for use of claim 263, wherein the IL-22 Fc fusion protein is administered to the patient prior to, concurrently with, or after the SOC.

265. The IL-22 Fc fusion protein for use of claim 263 or 264, wherein the SOC comprises supportive care, administration of one or more anti-viral agent(s), and/or administration of one or more low-dose corticosteroid(s).

266. The IL-22 Fc fusion protein for use of claim 265, wherein the supportive care comprises oxygen therapy.

267. The IL-22 Fc fusion protein for use of any one of claims 140-266, wherein the administering is to be by intravenous infusion.

268. The IL-22 Fc fusion protein for use of any one of claims 138-262, wherein the patient is a human.

269. The method of claim 126, wherein the one or more anti-viral agent(s) comprise alpha- interferon, lopinavir, ritonavir, lopinavir/ritonavir, remdesivir, ribavirin, hydroxychloroquine, chloroquine, u ifenovir, favipiravir, or a combination thereof.

270. The IL-22 Fe fusion protein for use of claim 265, wherein the one or more anti-viral agent(s) comprise alpha-interferon, lopinavir, ritonavir, lopinavir/ritonavir, remdesivir, ribavirin, hydroxychloroquine, chloroquine, umifenovir, favipiravir, or a combination thereof.