WO2023235795A2

WO2023235795A2 - Granulocyte-macrophage colony-stimulating factor-based treatments for pulmonary or respiratory diseases or disorders

Info

Publication number: WO2023235795A2
Application number: PCT/US2023/067754
Authority: WO
Inventors: Edwin ROCK; Ila JOSHI; Hillard LAZARUS
Original assignee: Partner Therapeutics Inc
Current assignee: Partner Therapeutics Inc
Priority date: 2022-06-01
Filing date: 2023-06-01
Publication date: 2023-12-07
Anticipated expiration: 2024-12-01
Also published as: WO2023235795A3

Abstract

The present disclosure relates to the treatment of respiratory or pulmonary diseases or disorders with granulocyte-macrophage colony-stimulating factor.

Description

GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-BASED

TREATMENTS FOR PULMONARY OR RESPIRATORY DISEASES OR DISORDERS

FIELD

[0001] This disclosure relates, in part, to treatment and/or mitigation of pulmonary or respiratory diseases or disorders, as well as diagnostic, prognostic and patient selection methods.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63/347,781 , filed on June 1 , 2022, the entire contents of which are hereby incorporated in their entirety.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0003] This application contains a Sequence Listing in XML format submitted electronically herewith via Patent Center. The contents of the XML copy, created on May 31 , 2023, is named “PNR-010PC_127114-501 O.xml” and is 4,866 bytes in size. The Sequence Listing is incorporated herein by reference in its entirety.

BACKGROUND

[0004] Pulmonary or respiratory diseases of the airways and other structures of the lung are among the leading causes of morbidity and mortality worldwide. The Forum of the International Respiratory Society identified, in 2017, five major lung diseases, the “big five’’, which include asthma, chronic obstructive pulmonary disease (COPD), acute lower respiratory tract infections, lung cancer and tuberculosis. These diseases are among the most common causes of severe illness and death worldwide See WHO: Chronic respiratory diseases report 2020. Other pulmonary diseases and disorders that cause considerable worldwide morbidity and mortality include (but not limited to) PAP including aPAP (autoimmune pulmonary alveolar proteinosis), occupational lung diseases, idiopathic pulmonary fibrosis (IPF), pneumonia, sepsis including pediatric sepsis, cystic fibrosis, sleep apnea, chronic bronchitis, emphysema, pleural effusion, interstitial lung disease, pulmonary sarcoidosis, pneumoconiosis including silicosis and asbestosis, and pulmonary hypertension.

[0005] Amongst all diseases, lower respiratory tract infections have the greatest burden on human health, with two and six-fold greater disability-adjusted life years compared to ischemic heart disease and diabetes mellitus, respectively. Infections of the upper respiratory tract, such as laryngitis, pharyngitis, nasopharyngitis, and rhinitis, are among the most common diseases in primary medical care. Pulmonary diseases or illnesses can be caused by an infection with a viral, bacterial or a fungal agent.

[0006] Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant. It may result from mutations in surfactant proteins or granulocyte macrophage-colony stimulating factor (GM-CSF) receptor genes, it may be secondary to toxic inhalation or hematological disorders, or it may be auto-immune, with anti-GM-CSF antibodies blocking activation of alveolar macrophages. Auto-immune pulmonary alveolar proteinosis (aPAP) is the most frequent form of pulmonary alveolar proteinosis (PAP), representing 90% of cases. Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia (IIP) and is characterized by diffuse, progressive remodeling of the lung parenchyma with extracellular matrix deposition and irreversible scarring. See Salamo C et al. Chest 2007. 131 : 60-67; Ferlay J et al. Int J Cancer. 2010; 127:2893-2917; Borie R et al. European Resp Rev. 2011. 20:98-107; King PE Jr. et al. Lancet. 2011. 378(9807): 1949-61 ; Hasegawa K et al. 2015; 34(7): 681-5; GBD 2017: a fragile world; The Global Impact of Respiratory Disease. 2nd edition Sheffield, European Respiratory Society; 2017; Lancet 2018; 392: 1683; Ann Res Hosp 2018; 2:12; Incze M et al. JAMA Intern Med. 2018: 178(9): 1288; Forum of International Respiratory Societies; WHO: Chronic respiratory diseases report 2020.

[0007] Pulmonary diseases or disorders can be broadly classified by their clinical presentations, and having one or more of fever, cough, headache, confusion, shortness of breath, chest pain, myalgia, tachypnea, diarrhea, nausea, chronic mucus hypersecretion or excess/chronic sputum production, upper respiratory symptoms including stuffy nose, rhinorrhea, sneezing, sore throat, lower respiratory symptoms, pharyngitis, epiglottitis, laryngotracheitis, sinusitis, tonsillitis, pneumonia, immunoparalysis, hyperinflammation, and acute respiratory syndrome.

[0008] The lung is a vital organ for providing mandatory oxygen for all organs in the body, and excessive inflammation or an imbalance can be life threatening. Therefore, a delicate balance between inflammation and anti-inflammation is essential for lung homeostasis. Inflammation, especially chronic inflammation, can play a critical role in pulmonary diseases and disorders. Chronically inflamed tissues typically proceed to evoke immune cells from the bloodstream to amplify the inflammatory response. They can destroy healthy tissues in a misdirected attempt at initiating the healing process. Airway inflammation is usually caused by pathogens or by exposure to toxins, pollutants, irritants, and allergens. Different factors have been identified that affect the inflammatory response including tissue microenvironment, disease, energy, stress, neighborhood, and seasonal change. Several cytokines, growth factors and chemokines, including GM-CSF, interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-a), matrix metalloproteinase-9 (MMP-9). See Lee G et al. Curr Opin Pulm Med. 2009. 15(4): 303-7; Lumb AB. Elseview Health Sciences, ebook. 2016. Chronic inflammation and a dysfunctional immune response have been shown to play a crucial role in various pulmonary disorders including COPD, asthma and cystic fibrosis. See Ashasafari, P et al. 2019. Inflamm Res. 68(1 ): 59- 74; Arai T et al. Intern Med. 2020. 59(20): 2539-2546.

[0009] Since therapeutic response can vary on the basis of heterogeneous clinical and molecular phenotypes, a shift toward personalized or precision medicine approaches, including biomarker development and validation, has been thought to improve the management of many pulmonary or respiratory diseases or disorders. Substantial progress in molecular immunology, coupled with an increased focus on translational research and personalized medicine, has resulted in a rapid expansion in the field of immune biomarkers in recent years. Such biomarkers might be used as either an objective measure of normal versus pathogenic processes or an indicator of pharmacological responses to therapeutic inventions. See Biomarkers Definitions Working Group. Clin Pharmacol Then 2001. 69(3): 89-95; Willis JCD and Lord GM. Nat Rev Immunol. 2015. 15:323-329; Renert-Yuval Y et al. J Allergy Clin Immunol. 2021. 147(4): 1174-1190.

[0010] Cluster of Differentiation-26 (CD26) is a 110 kD cell-surface glycoprotein and a known T-cell activation molecule. CD26 has a known dipeptidyl-peptidase IV (DPP- IV) activity in its extracellular domain. This ecto-enzyme is capable of cleaving amino terminal dipeptides from polypeptides with either L-proline or L-alanine in the penultimate position. On human T cells, CD26 expression appears late in thymic differentiation and is preferentially restricted to the CD4+ helper/memory population, and CD26 can deliver a potent co-stimulatory T-cell activation signal. CD26 is also present on epithelial cells of various tissues, including the liver, kidney and intestine. Detailed analysis of subsets of human CD4+ lymphocytes indicates that CD26 appears to be more restricted than most other accessory molecules since it is expressed only on the CD4 memory/helper (CD45RO+CD29+) populations. This unique population of human CD4 cells is the only one that can respond to recall antigens, induce immunoglobulin G (IgG) synthesis, and activate MHC-restricted cytotoxic T cells. In inflammatory diseases such as rheumatoid arthritis (RA), T cells at sites of inflammation express CD26 molecule strongly on the cell surface. See Morimoto C and Schlossman SF. Immunol Rev. 1998. 161 : 55-70.

[0011] C-X-C Motif Chemokine Receptor 4 (CXCR4) is one of the most widely expressed chemokine receptors and participates in numerous physiological and pathological processes. CXCR4 is expressed by most cells, including hematopoietic and endothelial cells (ECs), neurons, and stem cells (embryonic and adult). CXCR4 is activated by CXCL12. In the lung, CXCR4 expression is thought to contribute to cellular trafficking from vessels into the interstitium and to contribute to fibrotic disorders, including asthma and pulmonary fibrosis. See Gomperts BN and Stricter RM. J Leukoc Biol. 2007. 82(3):449-56; Bianchi ME and Mezzepelle R. Front Immunol. 2020 (11 ); Jaffar J et al. Respiratory Research. 2020. 21 :221.

[0012] Toll Like Receptor 4 (TLR4) is the prototypic member of a key immune signaling system that recognizes diverse pathogen associated molecular patterns (PAMPS) and initiates acute inflammation through production of inflammatory cytokines. TLR4 efficiently senses gram-negative bacterial infections through recognition of the bacterial membrane component, lipopolysaccharides (LPS). Binding of LPS to TLR4 triggers signaling cascades (e.g., NFkB and MAPK) that culminate in production of proinflammatory cytokines (TNFa, IL-1 p, IL-6, IL-12) and type-l interferons required for propagation of the inflammatory response and ultimately pathogen destruction. Although many components of the TLR-signaling pathway have been well characterized, regulatory mechanisms that intricately balance proinflammatory and anti-inflammatory responses remain incompletely understood. Certain viruses (e.g. IAV, RSV) encode glycoproteins that activate both TLR2/6 and TLR4, which also contribute to inflammatory cytokine/chemokine production, polymorphonuclear leukocyte (PMN) influx, and viral clearance. TLR4, among other TLRs, has been implicated in allergic airway inflammation leading to asthma. See Moynagh PN. Trends Immunol. 2005. 26:469-476; Lu YC et al. Cytokine. 2008. 42:145-151 ; Murawski MR et al. J Virol. 2009. 83:1492-500; Kovach MA and Standiford TJ. Int Immunopharmacol. 2011. 11 (10): 1399-1406; Swanson L et al. PNAS. 2020. 117(43):26895:26906.

[0013] Interferon Regulatory Factor 4 (IRF4) is one of nine IRF family members. All IRF proteins share similar structure containing an N-terminal DBD and, except IRF1 and IRF2, carry a C-terminal IRF-associated domain (IAD) that is responsible for interactions with other family members or other transcription factors including ETS factors and AP1 (activator protein 1 ) family members. IRF4 is a critical regulator of many aspects of B- and T-cell differentiation and cell metabolism. In DCs, Irf4 is highly expressed in the CD4⁺ subset and in a fraction of pDCs. In line with this expression pattern, tissue-resident CD4⁺ DCs and nearly half the pDC population are absent from the spleen of Irf4~‘~ mice. IRF-4 is a hemopoietic transcription factor critical for activation of microglia/macrophages and modulation of inflammatory responses. Effects of IRF4 signaling on inflammation are pleiotropic and vary depending on immune cell types and the local pathological microenvironment that is regulated by both pro- and anti-inflammatory cytokines. Mechanistically, IRF4 is a quintessential ‘context-dependent’ transcription factor that regulates distinct groups of inflammatory mediators in a differential manner depending on their activation in different cell types including phagocytes, T-cell subtypes. See Seillet C and Belz GT Advances in Immunology. 2013. V120: 185-210. [0014] Vitamin D Receptor (VDR) is a nuclear, ligand-dependent transcription factor that in complex with hormonally active vitamin D, 1 ,25(OH)2D3 regulates expression of more than 900 genes involved in an array of physiological functions. VDR has been shown to be expressed on immune cells. VDR protein level is decreased in lungs of patients with COPD. Vitamin D has also been implicated in reversal of steroid resistance and airway remodeling, which are the hallmarks of chronic obstructive pulmonary disease (COPD) and severe asthma. VDR deficient mice develop an abnormal lung phenotype with characteristics of COPD, such as airspace enlargement and decline in lung function associated with increased lung inflammatory cellular influx, and immune- lymphoid aggregates formation. See Hewison M et al. J Immunol. 2003. 170:5382-5390; Sundar IK and Rahman I. Front. Pharmacol. 2011. V2; Kongsbak et al. Front. Immunol. 2013. V4.

[0015] Peroxisome Proliferator-Activated Receptor Gamma (PPAR-y or PPARG) is a subtype of PPARs. PPARs are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising three subtypes: PPARa, PPARy, and PPARp/5. PPARy is expressed in both alveolar macrophages and neutrophils, and ligand-dependent activation of this receptor results in suppression of leukocyte effector responses, including cytokine production, elaboration of reactive oxygen and nitrogen species, and migratory responses. See Tyagi S et al. J Adv. Pharm. Tech. Res. 2011 . V2 (4); Standiford TJ et al. Proc Am Thorac Soc. 2005. 2(3): 226-31 .

[0016] Nuclear receptor subfamily 3 group C, member 1 or glucocorticoid receptor (NR3C1 , GR). NR3C1 is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, and immune response. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body. NR3C1 has been shown to exert antifibrotic effects on fibroblast gene expression, fibronectin deposition, and collagen gel compaction when its expression was enhanced in IPF fibroblasts. See Bray PJ and Cotton RG. Hum. Mutat. 2003. 21 (6):557- 68; Han H and Lagares D. 2021. 64(4):401 -402.

[0017] Cluster of Differentiation 80 (CD80), also known as B7-1 plays a key role in regulating T cell activation and tolerance. Engagement of CD80 with its receptors, CD28 or CTLA-4, can deliver a critical second signal that can promote and sustain or downregulate T cell responses. This dual role of CD80 can contribute to T cell activation and survival or T cell inhibition respectively. See Greenwald RJ et al. Annu Rev Immunol. 2005. 23:515-48; Chen L and Flies DB. Nat Rev Immunol. 2013. 13(4):227-242. Reduced expression of CD80 in alveolar macrophages (AM) of COPD patients suggests that cell- mediated immune function of AMs may be abnormal in these patients. See Pns AR et al. Eur Respir J.2005. 25:647-652.

[0018] Human Leukocyte Antigen-DR isotype (HLA-DR) is part of the Human Leukocyte Antigen (HLA) system, also known as the human Major Histocompatibility Complex (MHC). The HLA system is classically divided into three regions: Class I, II, and III regions. The class I transmembrane proteins are encoded by the HLA-A, HLA-B and HLA-C loci. Three isoforms of class II MHC molecules, denoted HLA-DR, HLA-DQ, and HLA-DP are currently recognized. The MHC class II molecules have been implicated in pathogenesis of a number of autoimmune diseases, due to their central roles in presentation of antigenic peptides to helper T cells. Mature eosinophils in idiopathic disorders such as chronic esosinophilic pneumonia have been shown to express HLA- DR and have been implicated in potentially contributing to inflammatory lung injury. See Beninati W et al. J Allergy Clin Immunol. 1993. 92(3):442-449; Klein J. In: Gotze D, ed. The Major Histocompatibility System in Man and Animals, New York: Springer-Verlag, 1976: 339-378; Choo SY Yonsei. 2007. 48(1 ): 11-23.

[0019] Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) is a hematological growth factor that regulates production, migration, proliferation, differentiation and function of hematopoietic cells. It was first identified as being able to induce, in vitro, proliferation and differentiation of bone marrow progenitors into granulocytes and macrophages. In response to inflammatory stimuli, GM-CSF is released by various cell types including T lymphocytes, macrophages, fibroblasts and endothelial cells. GM-CSF then activates and enhances the production and survival of neutrophils, eosinophils, and macrophages. Native GM-CSF is usually produced near the site of action where it modulates in vitro proliferation, differentiation, and survival of hematopoietic progenitor cells. It is present in circulating blood at picomolar concentrations (10^-10 to 10'¹² M). Several studies have shown that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches have indicated its potential as an important therapeutic target in several inflammatory and autoimmune disorders. See A Metcalf D. Immunol Cell Biology. 1987, 65:35-43; Gasson JC. Blood. 1991 , 77:1131 -1145; Shannon MF et al. Crit Rev Immunol. 1997, 17:301-323; Alexander WS. Int Rev Immunol. 1998, 16:651-682; Barreda DR et al. Dev Comp Immunol. 2004, 28:509-554; Lee KMC et al. Immunotargets Ther. 2020. 9:225-240.

[0020] Recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) has been approved by the FDA for treatment of neutropenia, blood dyscrasias and malignancies like leukemia in combination with chemotherapies. In the clinic, GM-CSF used for treatment of neutropenia and aplastic anemia following chemotherapy greatly reduces infection risk associated with bone marrow transplantation. Its utility in myeloid leukemia treatment and as a vaccine adjuvant is also well established. See Dorr RT. Clin Therapeutics. 1993. 15(1 ): 19-29; Armitage JO. Blood 1998, 92:4491 -4508; Kovacic JC et al. J Mol Cell Cardiol. 2007, 42:19-33; Jacobs PP et al. Microbial Cell Factories 2010, 9:93.

[0021] Specific biomarkers can be used for diagnosis, prognosis, or theranosis of respiratory or pulmonary diseases or disorders. They can also be used to identify respiratory or pulmonary diseases or disorders and ailments that do not respond to monotherapy alone, and those that might benefit from combination therapies. Such combination therapies can potentially increase the percentage of patients who respond to treatments. Hence, there remains a need for new and more effective biomarkers and treatments, e.g. combination treatments, of respiratory or pulmonary diseases or disorders.

SUMMARY

[0022] Accordingly, in aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by an increased or high expression and/or activity of Cluster of Differentiation 26 (CD26), e.g. relative to an undiseased and/or untreated state. [0023] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by an increased or high expression and/or activity of C-X-C Motif Chemokine Receptor 4 (CXCR4), e.g. relative to an undiseased and/or untreated state.

[0024] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by an increased or high expression and/or activity of Toll Like Receptor 4 (TLR4), e.g. relative to an undiseased and/or untreated state.

[0025] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by a decreased or low expression and/or activity of Interferon Regulatory Factor-4 (IRF-4), e.g. relative to an undiseased and/or untreated state.

[0026] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by a decreased or low expression and/or activity of Vitamin D Receptor (VDR), e.g. relative to an undiseased and/or untreated state.

[0027] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by a decreased or low expression and/or activity of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-y or PPARG), e.g. relative to an undiseased and/or untreated state.

[0028] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by a decreased or low expression and/or activity of Nuclear receptor subfamily 3 group C, member 1 (NR3C1 ), e.g. relative to an undiseased and/or untreated state.

[0029] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by an decreased or low expression and/or activity of Cluster of Differentiation 80 (CD80), e.g. relative to an undiseased and/or untreated state.

[0030] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF to a patient in need thereof, wherein the patient is characterized by a decreased or low expression and/or activity of Human Leukocyte Antigen-DR isotype (HLA-DR), e.g. relative to an undiseased and/or untreated state.

[0031] In aspects, the present disclosure provides a method for treating a respiratory or pulmonary disease or disorder, comprising: (a) identifying a patient undergoing or having undergone treatment with an agent for a respiratory or pulmonary disease or disorder and presenting or presented as failed, intolerant, resistant, or refractory to the treatment with an immunomodulatory or pulmonary agent; (b) determining the presence, absence or amount of CD26, and/or CXCR4, and/or TLR4, and/or IRF-4 and/or VDR and/or PPAR-y and/or NR3C1 and/or CD80, and/or HLA-DR in a sample from the patient; and (c) administering an effective amount of a granulocytemacrophage colony-stimulating factor (GM-CSF) agent to a patient demonstrating (i) an increased or high expression and/or activity of CD26 and/or CXCR4 and/or TLR4 relative to a pre-treated and/or undiseased state, and/or (ii) a decreased or low expression and/or activity of IRF4 and/or VDR and/or PPAR-y and/or NR3C1 and/or CD80 and/or HLA-DR relative to a pre-treated and/or undiseased state.

[0032] In aspects, the present disclosure provides a method for selecting a patient for treatment with GM-CSF for a respiratory or pulmonary disease or disorder based on the presence, absence or amount of CD26, and/or CXCR4, and/or TLR4, and/or IRF-4 and/or VDR, and/or PPAR-y and/or NR3C1 and/or CD80, and/or HLA-DR in a sample from the patient.

BRIEF DESCRIPTION OF DRAWINGS

[0033] FIG. 1A is a graph depicting the kinetics of expression of CD26 induced by sargramostim (LEUKINE). Monocytes and lymphocytes from a human donor were treated with sargramostim (LEUKINE) at various concentrations 0.001 pM to 10pM. Expression of CD26 was assessed on day 1 on both monocytes and lymphocytes.

[0034] FIG. 1 B is a graph depicting the kinetics of expression of CD26 induced by sargramostim (LEUKINE). Monocytes from multiple healthy human donors were treated with sargramostim (LEUKINE) at various concentrations 0.33pM to 33.33pM. Expression of CD26 was assessed on day 1 on monocytes. In the graph, each curve represents monocytes from individual donors.

[0035] FIG. 2A is a graph depicting the kinetics of expression of CXCR4 induced by sargramostim (LEUKINE). Monocytes from a human donor were treated with sargramostim (LEUKINE) at various concentrations 0.001 pM to 10pM. Expression of CXCR4 was assessed on day 1 on monocytes and lymphocytes.

[0036] FIG. 2B is a graph depicting the kinetics of expression of CXCR4 induced by sargramostim (LEUKINE). Monocytes from multiple healthy human donors were treated with sargramostim (LEUKINE) at various concentrations 0.33pM to 33.33pM. Expression of CXCR4 was assessed on day 1 on monocytes. In the graph, each curve represents monocytes from individual donors.

[0037] FIG. 3A is a graph depicting the kinetics of expression of TLR4 induced by sargramostim (LEUKINE). Monocytes from a human donor were treated with sargramostim (LEUKINE) at various concentrations 0.33pM to 33.33pM. Expression of TLR4 was assessed on day 1 on monocytes and lymphocytes.

[0038] FIG. 3B is a graph depicting the kinetics of expression of TLR4 induced by sargramostim (LEUKINE). Monocytes from multiple healthy human donors were treated with sargramostim (LEUKINE) at various concentrations 0.33pM to 33.33pM. Expression of TLR4 was assessed on day 1 on monocytes. In the graph, each curve represents monocytes from individual donors.

[0039] FIG. 4 is a graph depicting the kinetics of expression of IRF-4 induced by sargramostim (LEUKINE). Monocytes and lymphocytes from a human donor were treated with sargramostim (LEUKINE) at various concentrations 1 pM to 10³pM. Expression of IRF-4 was assessed on day 1 on both monocytes and lymphocytes.

[0040] FIG. 5 is a graph depicting the kinetics of expression of VDR induced by sargramostim (LEUKINE). Monocytes and lymphocytes from a human donor were treated with sargramostim (LEUKINE) at various concentrations 1 pM to 10³pM. Expression of VDR was assessed on day 1 on both monocytes and lymphocytes.

[0041] FIG. 6 is a graph depicting the kinetics of expression of PPAR-yand NR3C1 (induced by sargramostim (LEUKINE). Monocytes and lymphocytes from a human donor were treated with sargramostim (LEUKINE) at various concentrations 0.05pM to 0.6pM. Expression of PPAR-g and NR3C1 was assessed on day 1 on monocytes.

[0042] FIG. 7A is a graph depicting the normalized expression of CD80 induced by sargramostim (LEUKINE). Monocytes from 2 human donors were treated with sargramostim (LEUKINE) at various concentrations 0.01 pM to 100pM. Expression of CD80 was assessed on day 1 on monocytes and lymphocytes.

[0043] FIG. 7B is a graph depicting the kinetics of expression of CD80 induced by sargramostim (LEUKINE). Monocytes from 2 human donors were treated with sargramostim (LEUKINE) at various concentrations 0.01 pM to 100pM. Expression of CD80 was assessed on day 1 on monocytes and lymphocytes.

[0044] FIG. 8 is a graph showing expression of HLA-DR on monocytes and lymphocytes was measured on day 1 , day 2 and day 3 following treatment with various concentrations of GM-CSF.

DETAILED DESCRIPTION

[0045] The present disclosure relates, in part, to the use of GM-CSF as an effective treatment for specific respiratory or pulmonary diseases or disorders. [0046] In aspects, there is provided a method of patient selection for treatment with GM-CSF specific respiratory or pulmonary diseases or disorders, selected using CD26 and/or CXCR4, and/or TLR4, and/or IRF-4 and/or VDR and/or PPAR-y and/or NR3C1 and/or CD80, and/or HLA-DR as a predictive marker of disease sequelae and responsiveness to current therapy, e.g. with an agent to treat a respiratory or pulmonary disease or disorder.

[0047] In aspects, the present disclosure relates to improved treatments for respiratory or pulmonary diseases or disorders in a patient that has failed, is intolerant, is resistant, or is refractory to a current treatment in use. For instance, in embodiments, evaluation of the presence, absence, levels or activity of CD26, and/or CXCR4, and/or TLR4, and/or IRF-4 and/or VDR, and/or PPAR-y and/or NR3C1 and/or CD80 and/or HLA- DR informs or predicts the disease state in the and, without limitation, the administration of GM-CSF converts the patient that has failed, is intolerant, is resistant, or is refractory to current treatment(s) for the respiratory or pulmonary indication to a patient who responds to current treatment(s) for the respiratory or pulmonary indication. In embodiments, the GM-CSF modulates CD26, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates CXCR4, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM- CSF modulates TLR4, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates IRF-4, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates VDR, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates PPAR-y, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates NR3C1 , or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates CD80, or cells expressing the same, to improve a patient’s treatment outcome. In embodiments, the GM-CSF modulates HLA-DR, or cells expressing the same, to improve a patient’s treatment outcome.

[0048] Accordingly, in aspects, the disclosure provides methods for treating respiratory or pulmonary diseases or disorders. In embodiments, the respiratory or pulmonary disease or illness is caused by an infection with a viral, bacterial or fungal agent, optionally selected from alphacoronaviruses including human coronaviruses (HCoV): HCoV-NL63 and HCoV-229E, betacoronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East respiratory syndrome-coronavirus (MERS-CoV), HCoV-HKU1 , and HCoV-OC43, orthomyxoviruses including influenza viruses; paramyxoviruses including human respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human parainfluenza viruses (HPIV), picornaviruses including human rhinoviruses (HRV), foot-and-mouth disease virus (FMDV), parvoviruses including human bocavirus (HBoV), human adenoviruses A-G (HAdV-A through HAdV-G), herpes simplex virus (HSV); Rickettsia typhi, Haemophilus influenzae type b, Mycoplasma pneumoniae, Chlamydia species, Legionella species including Legionella pneumophilia, Coxiella burnetti; Streptococcus pneumoniae; Pseudomonas aeruginosa, Escherichia coli species, Enterobacter, Proteus species, and Klebsiella species, Francisella tularensis, Yersinia pestis, Neisseria meningitidis, Xanthomonas pseudomallei, Mycobacterium tuberculosis, Actinomyces, Bacteroides, Peptostreptococcus, Veilonella, Propionibacterium, Eubacterium, Fusobacterium species; Cryptococcus neoformans, Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Aspergillus species and Candida species.

[0049] In aspects, the disclosure provides methods for treating respiratory or pulmonary diseases or disorders, wherein the respiratory or pulmonary disease or disorder is selected from pneumonia, sepsis including pediatric sepsis, chronic obstructive pulmonary disease (COPD), asthma, PAP including aPAP (autoimmune pulmonary alveolar proteinosis), occupational lung diseases, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, sleep apnea, chronic bronchitis, emphysema, pleural effusion, interstitial lung disease, pulmonary sarcoidosis, pneumoconiosis including silicosis and asbestosis, and pulmonary hypertension. Compositions of Immunomodulatory and/or Pulmonary Agents

[0050] In embodiments, the present disclosure pertains to pharmaceutical compositions comprising the compositions, e.g. GM-CSF and/or an additional therapeutic to treat a respiratory or pulmonary disease or disorder.

[0051] In embodiments, the patient is treated with an additional agent(s) comprising: administering an effective amount of drug(s) or therapeutics to treat a respiratory or pulmonary disease or illness.

[0052] In embodiments, the additional immunomodulatory or respiratory or pulmonary agent is optionally selected from anti-virals including, but not limited to, remdesivir; favipiravir; galidesivir; prezcobix; lopinavir; ritonavir; arbidol lopinavir/ritonavir; ribavirin; IFN-beta; xiyanping; anti-VEGF-A; fingolimod; carrimycin; hydroxychloroquine; darunavir and cobicistat; methylprednisolone; brilacidin; leronlimab; and thalidomide; anti-bacterials including, but not limited to, caspofungin macrolides roxithromycin, azithromycin, erythromycin, clarithromycin; second-generation cephalosporins such as cefuroxime, cefaclor; third-generation cephalosporins such as cefdinir, cefixime; fluoroquinolones such as levofloxacin; penicillin; third-generation quinolones such as levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, beta-lactamase inhibitors; and trimethoprim; anti-fungals/anti-mycotics including, but no limited to azoles such as fluconazole, itraconazole, miconazole, ketoconazole, clotrimazole, voriconazole, Posaconazole, sulfamethoxazole; echinocandins such as caspofungin; and compounds with anti-mycotic capabilities such as flucytosine; nystatin; and amphotericin B; inhaled corticosteroids such as prednisone; inhaled brochodialators; diuretics; pyridones such as pirfenidone; small molecules tyrosine-kinase inhibitors (TKI) such as nintedanib; hydroxychloroquine; tumor necrosis factor-alpha (TNF-a) inhibitors; immunosuppressive drugs such as azathioprine and methotrexate; and anticoagulants such as rivaroxaban, dabigatran, apixaban and edoxaban.

[0053] In embodiments, the immunoregulatory or respiratory or pulmonary agent is an antibody or antibody format which is selected from one or more of a monoclonal antibody, polyclonal antibody, antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and fusion protein comprising the antigen-binding portion of an antibody.

Compositions of GM-CSF

[0054] GM-CSF, in embodiments, includes any pharmaceutically safe and effective GM-CSF, or any derivative thereof having the biological activity of GM-CSF. In embodiments, the GM-CSF is rhu GM-CSF, such as sargramostim (LEUKINE). Sargramostim is a biosynthetic, yeast-derived, recombinant human GM-CSF, having a single 127 amino acid glycoprotein that differs from endogenous human GM-CSF by having a leucine instead of a proline at position 23. Other natural and synthetic GM-CSFs, and derivatives thereof having the biological activity of natural human GM-CSF, may be equally useful in embodiments.

[0055] In embodiments, the GM-CSF is produced or producible in bacteria, yeasts, plants, insect cells, and mammalian cells. In embodiments, the GM-CSF is produced or producible in Escherichia coli cells. In embodiments, the GM-CSF is produced or producible in yeast cells. In embodiments, the GM-CSF is produced or producible in Chinese hamster ovary cells (CHO). In embodiments, the GM-CSF is not produced in E. coli cells. In embodiments, the GM-CSF is produced in a cell that allows for glycosylation, e.g. yeast or CHO cells.

[0056] In embodiments, the GM-CSF has an amino acid sequence of SEQ ID NO: 1 , or a variant of at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In embodiments, the GM-CSF has an amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO:4, or a variant of at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In embodiments, the GM-CSF is one of sargramostim, molgramostim, and regramostim. In embodiments, the GM-CSF is sargramostim.

[0057] Without wishing to be bound by theory, the core of hGM-CSF consists of four helices that pack at angles. Crystal structures and mutagenic analysis of rhGM-CSF (Rozwarski D A et al., Proteins 26:304-13, 1996) showed that, in addition to apolar side chains in the protein core, 10 buried hydrogen bonding residues involve intramolecular hydrogen bonding to main chain atoms that were better conserved than residues hydrogen bonding to other side chain atoms; 24 solvation sites were observed at equivalent positions in the two molecules in the asymmetric unit, and the strongest among these was located in clefts between secondary structural elements. Two surface clusters of hydrophobic side chains are located near the expected receptor binding regions. Mutagenesis of residues on the helix A/helix C face confirmed the importance of certain Glu, Gly, and Gin residues. These residues are therefore not to be substituted in the functional substitution variants of hGM-CSF for use in the present disclosure and these helices are to be retained in a functional fragments or deletion variants of hGM-CSF for use in this disclosure. Further, in embodiments, one of ordinary skill can reference UniProtKB entry P04141 for structure information to inform the identity of variants.

[0058] The N-terminal helix of hGM-CSF governs high affinity binding to its receptor (Shanafelt A B et al., EMBO J 10:4105-12, 1991 ). Transduction of the biological effects of GM-CSF requires interaction with at least two cell surface receptor components (one of which is shared with the cytokine IL-5). The above study identified receptor binding determinants in GM-CSF by locating unique receptor binding domains on a series of human-mouse hybrid GM-CSF cytokines. The interaction of GM-CSF with the shared subunit of their high affinity receptor complexes was governed by a very small part of the peptide chains. The presence of a few key residues in the N-terminal a-helixwas sufficient to confer specificity to the interaction.

[0059] In embodiments, the amino acid mutations are amino acid substitutions, and may include conservative and/or non-conservative substitutions.

[0060] “Conservative substitutions” may be made, for instance, on the basis of similarity in polarity, charge, size, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the amino acid residues involved. The 20 naturally occurring amino acids can be grouped into the following six standard amino acid groups: (1 ) hydrophobic: Met, Ala, Vai, 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; and (6) aromatic: Trp, Tyr, Phe. [0061] As used herein, “conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed within the same group of the six standard amino acid groups shown above. For example, the exchange of Asp by Glu retains one negative charge in the so modified polypeptide. In addition, glycine and proline may be substituted for one another based on their ability to disrupt a-helices.

[0062] As used herein, “non-conservative substitutions” are defined as exchanges of an amino acid by another amino acid listed in a different group of the six standard amino acid groups (1 ) to (6) shown above.

[0063] In embodiments, the substitutions may also include non-classical amino acids (e.g. selenocysteine, pyrrolysine, /V-formylmethionine p-alanine, GABA and 6- Aminolevulinic acid, 4-aminobenzoic acid (PABA), D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2- amino butyric acid, y-Abu, s-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3- amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosme, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, [3-alanine, fluoro-amino acids, designer amino acids such as [3 methyl amino acids, C o-methyl amino acids, N a-methyl amino acids, and amino acid analogs in general).

[0064] Modification of the amino acid sequences may be achieved using any known technique in the art e.g., site-directed mutagenesis or PCR based mutagenesis. Such techniques are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Plainview, N.Y., 1989 and Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., 1989. Without wishing to be bound by theory, the degree of glycosylation of biosynthetic GM-CSFs appears to influence half-life, distribution, and elimination. (Lieschke and Burgess, N. Engl. J. Med. 327:28-35, 1992; Dorr, R. T., Clin. Ther. 15:19-29, 1993; Horgaard et al., Eur. J. Hematol. 50:32-36, 1993). In embodiments, the present GM-CSF molecules are glycosylated. Biomarker

[0065] In aspects, the present methods relate to the utility of a predictive biomarkers to determine the use of GM-CSF in the treatment of respiratory or pulmonary diseases or disorders.

[0066] In aspects, the present disclosure relates to a method of treating a patient in need of therapy wherein the patient is characterized by having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent. In other aspects, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring of a biomarker in a sample of the patient.

[0067] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring a variety of patient parameters. In embodiments, the patient sample may be analyzed using, e.g. immunohistochemical or immunofluorescence techniques may be used to evaluate the immune infiltrate, for example, immune subsets such as, CD4⁺ Th cells (T helper cells), IL-17-producing CD4⁺ Th cells (Th17 cells), CD8⁺ T cells (cytotoxic T cells), and systemic or circulating intermediate monocytes. In embodiments, polychromatic flow cytometry can be used to measure multiple surface and intracellular markers, allowing characterization of cell phenotype and activation state. In embodiments, whole blood can be used to evaluate changes in cell count with therapy or changes in cytokine levels, for example IL-1 , IL-4, IL-6, IL-10, IL-12, IL-18, IL-33, IFN- y, IP-10, M-CSF, TGF-p, VEGF, and TNFa. In embodiments, deep sequencing techniques can be used to yield quantification of changes in individual cell clonotypes.

[0068] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of CD26 isotype in a sample of the patient.

[0069] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of CXCR4 isotype in a sample of the patient.

[0070] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of TLR4 isotype in a sample of the patient.

[0071] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of IRF-4 isotype in a sample of the patient.

[0072] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of VDR isotype in a sample of the patient.

[0073] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of PPAR-y isotype in a sample of the patient.

[0074] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of NR3C1 isotype in a sample of the patient.

[0075] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of CD80 isotype in a sample of the patient.

[0076] In embodiments, an assessment of the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent comprises measuring the presence, absence, or amount of HLA-DR isotype in a sample of the patient.

[0077] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder, wherein CD26 is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0078] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder, wherein CXCR4 is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0079] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein TLR4 is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0080] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein IRF-4 is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0081] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein VDR is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0082] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein PPAR-y is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0083] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein NR3C1 is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0084] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein CD80 is used as a biomarker for predicting or determining the need for treatment with GM-CSF. [0085] In embodiments, the present disclosure relates to a method for treating a pulmonary disease or disorder wherein HLA-DR is used as a biomarker for predicting or determining the need for treatment with GM-CSF.

[0086] In embodiments, the presence, absence or amount of CD26, CXCR4, TLR4, IRF-4, VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR by detection of protein and/or nucleic acids in a sample of the patient.

[0087] In embodiments, the presence, absence or amount of CD26, CXCR4, TLR4, IRF-4, VDR, PPAR-y, NR3C1 , CD80, HLA-DR is determined by ELISA, immunohistochemical staining, western blotting, in-cell western, immunofluorescent staining, or fluorescent activating cell sorting (FACS), or the like, in a sample of the patient.

[0088] In embodiments, the method for determining the presence, absence or amount of CD26, CXCR4, TLR4, IRF-4, VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR is a method of characterizing a patient or selecting a patient for the treatment comprising GM-CSF.

[0089] In embodiments, the method of determining the levels of CD26, CXCR4, TLR4, IRF-4, VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR, involves assaying the levels of CD26, CXCR4, TLR4, IRF-4 VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR in a biological sample from the patient.

[0090] In embodiments, the present methods, e.g., the method of determining CD26, CXCR4, TLR4, IRF-4, VDR, PPAR-y, NR3C1 , CD80, HLA-DR presence, absence, levels or activity for the purposes of patient selection, employs a biological sample, the biological sample is or comprises blood, plasma, serum, mucus, stool, sputum, saliva, nasal secretion, lavage fluid, respiratory fluid blood, and/or other body fluids.

[0091] In embodiments, the method of patient selection is undertaken using a sample of the patient, where the sample is selected from blood, skin sample or tissue sample, tissue biopsy, a formalin-fixed or paraffin-embedded tissue specimen, cytological sample, cultured cells, blood, plasma, serum, mucus, stool, sputum, saliva, nasal secretion, lavage fluid, respiratory fluid blood, and/or other body fluids. [0092] In embodiments, the respiratory fluid is from an oropharyngeal (OP) or nasopharyngeal (NP) swab. In embodiments, the respiratory fluid is lavage fluid, optionally wherein the lavage fluid comprises a bronchial washing. In embodiments, the respiratory fluid is sputum. In embodiments, the respiratory fluid is a nasal secretion. In embodiments, the respiratory fluid is saliva.

[0093] In embodiments, the present methods direct patient treatment decisions. For instance, in embodiments, the method comprises the step of monitoring the expression and/or activity of CD26, CXCR4 and/or TLR4 during the course of treatment. In embodiments, the methods may detect a high or increased expression and/or activity of CD26, CXCR4 and/or TLR4, and this is correlative with the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent. In such embodiments, without limitation, this directs treatment of the patient with GM-CSF agents. In embodiments, the patient with an increased expression and/or activity of CD26, CXCR4 and/or TLR4 directs continued administration of GM-CSF. In embodiments, the patient with an increased or high expression or activity of CD26, CXCR4 and/or TLR4 receives, for example, a greater dose of GM-CSF, and/or additional pulmonary therapies. In embodiments, the patient with a decreased expression and/or activity of CD26, CXCR4 and/or TLR4 directs discontinuation of administration of GM- CSF.

[0094] In embodiments, the present method comprises the step of monitoring the expression and/or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR during the course of treatment. In embodiments, the methods may detect a low or decreased expression and/or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR, and this is correlative with the patient having failed or being intolerant or refractory to a treatment with an immunomodulatory or pulmonary agent. In such embodiments, without limitation, this directs treatment of the patient with GM-CSF agents. In embodiments, the patient with an decreased expression and/or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR directs continued administration of GM-CSF. In embodiments, the patient with an decreased or low expression or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR receives, for example, a greater dose of GM-CSF, and/or additional pulmonary therapies. In embodiments, the patient with an increased expression and/or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR directs discontinuation of administration of GM-CSF.

[0095] In embodiments, the GM-CSF agents, as described herein, potentiate treatment with an immunomodulatory or pulmonary agent. In embodiments, GM-CSF agents, as described herein, are used to modulate the patient’s immune system, e.g. by decreasing or increasing expression and/or activity of CD26, CXCR4, TLR4, IRF-4 VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR.

Methods of Treatment

[0096] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition GM-CSF to a patient in need thereof.

[0097] In aspects, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF in conjunction with an immunomodulatory or pulmonary agent to a patient in need thereof, wherein the patient is characterized by the presence, absence or amount of CD26, CD26, CXCR4, TLR4, IRF-4, VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR in a sample of the patient.

[0098] In aspects, the present disclosure relates to methods for treating a respiratory or pulmonary disease or disorder, comprising: (a) identifying a patient undergoing or having undergone treatment with an agent for pulmonary issues and presenting as failed, intolerant, resistant, or refractory to the treatment with an immunomodulatory or pulmonary agent; (b) determining the presence, absence or amount of CD26, CXCR4, TLR4, IRF-4 VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR in a sample from the patient; and (c) (i) administering an effective amount of a granulocytemacrophage colony-stimulating factor (GM-CSF) agent to a patient demonstrating an increased or high expression and/or activity of CD26, CXCR4 and/or TLR4 relative to a pre-treated and/or undiseased state, or (c) (ii) administering an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent to a patient demonstrating an decreased or low expression and/or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR relative to a pre-treated and/or undiseased state.

[0099] In aspects, the present disclosure relates to methods of treating a respiratory or pulmonary disease or disorder, comprising: (a) selecting a patient having pulmonary disease or disorder and one or more of (i) increased expression and/or activity of CD26 relative to a non-diseased state; (ii) increased expression and/or activity of CXCR4 relative to a non-diseased state; (iii) increased expression and/or activity of TLR4 relative to a non-diseased state; (iv) decreased expression and/or activity of IRF4 relative to a non-diseased state; (v) decreased expression and/or activity of VDR relative to a non-diseased state; (vi) decreased expression and/or activity of PPAR-y relative to a nondiseased state; (vii) decreased expression and/or activity of NR3C1 relative to a nondiseased state; (viii) decreased expression and/or activity of CD80 relative to a nondiseased state; (ix) decreased expression and/or activity of HLA-DR relative to a nondiseased state, and (b) administering an effective amount of a composition comprising GM-CSF to the patient.

[00100] In embodiments, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF alone or in conjunction with an immunomodulatory or pulmonary agent to a patient in need thereof, wherein the patient is characterized by as a partial responder or a non-responder to a pulmonary treatment. In embodiments, the method of treatment causes a decrease in the expression and/or activity of CD26. In embodiments, the method of treatment causes a decrease in the expression and/or activity of CXCR4. In embodiments, the method of treatment causes a decrease in the expression and/or activity of TLR4.

[00101] In embodiments, the present disclosure relates to a method for treating a respiratory or pulmonary disease or disorder, comprising: administering an effective amount of a composition comprising GM-CSF alone or in conjunction with an immunomodulatory or pulmonary agent to a patient in need thereof, wherein the patient is characterized by as a partial responder or a non-responder to a pulmonary treatment. In embodiments, the method of treatment causes a decrease in the expression and/or activity of CD26. In embodiments, the method of treatment causes a decrease in the expression and/or activity of CXCR4. In embodiments, the method of treatment causes a decrease in the expression and/or activity of TLR4.

[00102] In embodiments, the method of treatment causes an increase in the expression and/or activity of IRF4. In embodiments, the method of treatment causes an increase in the expression and/or activity of VDR. In embodiments, the method of treatment causes an increase in the expression and/or activity of PPAR-y. In embodiments, the method of treatment causes an increase in the expression and/or activity of NR3C1. In embodiments, the method of treatment causes an increase in the expression and/or activity of CD80. In embodiments, the method of treatment causes an increase in the expression and/or activity of HLA-DR.

[00103] In embodiments, the dose of GM-CSF administered to a patient is dependent on the expression and/or activity of CD26 and/or one CXCR4 and/or TLR4 and/or IRF4 and/or VDR and/or PPAR-y and/or NR3C1 and/or CD80 and/or HLA-DR.

[00104] In embodiments, the method of treatment prevents, treats, and/or mitigates progression and/or development of the respiratory or pulmonary disease or disorder in the patient. In embodiments, the method of treatment improves the respiratory or pulmonary disease or disorder in the patient. In embodiments, the method of treatment elicits a disease-modifying response in the patient. In embodiments, the method of treatment elicits temporarily or permanently reverses or treats hypoxia in the patient. In other embodiments, the method of treatment elicits temporarily or permanently reverses or treats respiratory distress in the patient. In still other embodiments, the method of treatment causes an amelioration of the respiratory or pulmonary disease or disorder symptoms. In yet other embodiments, the method of treatment prevents, treats, slows and/or mitigates the onset, progression and/or development of the respiratory or pulmonary disease or illness in the patient.

[00105] In embodiments, the method of treatment decreases, mitigates, reverses or prevents chronic inflammation in the pulmonary or respiratory system. In embodiments, the method of treatment decreases or mitigates the development of systemic inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS) in the patient. In embodiments, the method improves oxygenation in the patient. In embodiments, the method prevents or mitigates a transition from respiratory distress to cytokine imbalance in the patient. In embodiments, the method reverses or prevents a cytokine storm in the lungs or systemically. In embodiments, the method of treatment causes an improvement in one or more of oxygen saturation, clinical indicators, PaO2/FiO2 ratio, and enhanced immunological effects, as well as improvements in major endpoints like reduction in mortality and days of hospitalization. In embodiments, the method of treatment causes a decrease in the sequelae of a respiratory or pulmonary disease or illness in the patient relative to before treatment.

[00106] In embodiments, the method decreases or mitigates the dysfunction of endogenous or exogenous pulmonary immune cells.

[00107] In embodiments, the method of treatment prevents or reverses the cytokine storm which is selected from one or more of systemic inflammatory response syndrome, cytokine release syndrome, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis.

[00108] In embodiments the method of treatment reverses or prevents excessive production of one or more inflammatory cytokines, wherein the inflammatory cytokine is one or more of IL-6, IL-1 , IL-1 receptor antagonist (IL-1 ra), IL-2ra, IL-10, IL-18, TNFa, interferon-y, CXCL10, and CCL7.

[00109] In embodiments, the method of treatment the method causes a decrease in viral, bacterial or fungal load in the patient relative to before treatment.

[00110] In embodiments, the agent that stimulates the survival, proliferation and activation of neutrophils, macrophages and/or dendritic cells is administered at a time selected from (i) the same time as an immunomodulatory or pulmonary agent; (ii) within about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about 96 hours or about 1 week or about 2 weeks following administration of said pulmonary agent; (iii) at least about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 36 hours, about 72 hours, or about 96 hours, or about 1 week or about 2 weeks prior to administration of the pulmonary agent; (iv) after at least an about 10%, about 20%, about 30%, about 40% or about 50% decrease in expression of a marker such as CD26, CXCR4 and/or TLR4; and/or (v) after at least an about 10%, about 20%, about 30%, about 40% or about 50% increase in expression of a marker such as IRF-4, VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR.

[00111] In embodiments, the respiratory or pulmonary disease or illness is caused by an infection with a viral, bacterial or fungal agent, optionally selected from alphacoronaviruses including human coronaviruses (HCoV): HCoV-NL63 and HCoV- 229E, betacoronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East respiratory syndrome-coronavirus (MERS- CoV), HCoV-HKU1 , and HCoV-OC43, orthomyxoviruses including influenza viruses; paramyxoviruses including human respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human parainfluenza viruses (HPIV), picornaviruses including human rhinoviruses (HRV), foot-and-mouth disease virus (FMDV), parvoviruses including human bocavirus (HBoV), human adenoviruses A-G (HAdV-A through HAdV-G), herpes simplex virus (HSV); Rickettsia typhi, Haemophilus influenzae type b, Mycoplasma pneumoniae, Chlamydia species, Legionella species including Legionella pneumophilia, Coxiella burnetii; Streptococcus pneumoniae; Pseudomonas aeruginosa, Escherichia coli species, Enterobacter, Proteus species, and Klebsiella species, Francisella tularensis, Yersinia pestis, Neisseria meningitidis, Xanthomonas pseudomallei, Mycobacterium tuberculosis, Actinomyces, Bacteroides, Peptostreptococcus, Veilonella, Propionibacterium, Eubacterium, Fusobacterium species; Cryptococcus neoformans, Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Aspergillus species and Candida species.

[00112] In embodiments, the respiratory or pulmonary disease or disorder is selected from pneumonia, sepsis including pediatric sepsis, chronic obstructive pulmonary disease (COPD), asthma, PAP including aPAP (autoimmune pulmonary alveolar proteinosis), occupational lung diseases, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, sleep apnea, chronic bronchitis, emphysema, pleural effusion, interstitial lung disease, pulmonary sarcoidosis, pneumoconiosis including silicosis and asbestosis, and pulmonary hypertension. [00113] In embodiments, the patient is afflicted with an acute or chronic respiratory or pulmonary disease or illness.

[00114] In embodiments, the patient is characterized by having one or more of fever, cough, headache, confusion, shortness of breath, chest pain, myalgia, tachypnea, diarrhea, nausea, chronic mucus hypersecretion or excess/chronic sputum production, upper respiratory symptoms including stuffy nose, rhinorrhea, sneezing, sore throat, lower respiratory symptoms, pharyngitis, epiglottitis, laryngotracheitis, sinusitis, tonsillitis, pneumonia, immunoparalysis, hyperinflammation, and acute respiratory syndrome.

[00115] In embodiments, the patient is characterized by being hypoxic. In embodiments, the patient is afflicted with respiratory distress.

[00116] In embodiments, the method further comprises administering one or more additional therapeutic agents, optionally selected from anti-virals including, but not limited to, remdesivir; favipiravir; galidesivir; prezcobix; lopinavir; ritonavir; arbidol lopinavir/ritonavir; ribavirin; IFN-beta; xiyanping; anti-VEGF-A; fingolimod; carrimycin; hydroxychloroquine; darunavir and cobicistat; methylprednisolone; brilacidin; leronlimab; and thalidomide; anti-bacterials including, but not limited to, caspofungin macrolides roxithromycin, azithromycin, erythromycin, clarithromycin; second-generation cephalosporins such as cefuroxime, cefaclor; third-generation cephalosporins such as cefdinir, cefixime; fluoroquinolones such as levofloxacin; penicillin; third-generation quinolones such as levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, beta-lactamase inhibitors; and trimethoprim; anti-fungals/anti-mycotics including, but no limited to azoles such as fluconazole, itraconazole, miconazole, ketoconazole, clotrimazole, voriconazole, Posaconazole, sulfamethoxazole; echinocandins such as caspofungin; and compounds with anti-mycotic capabilities such as flucytosine; nystatin; and amphotericin B; inhaled corticosteroids such as prednisone; inhaled brochodialators; diuretics; pyridones such as pirfenidone; small molecules tyrosine-kinase inhibitors (TKI) such as nintedanib; hydroxychloroquine; tumor necrosis factor-alpha (TNF-a) inhibitors; immunosuppressive drugs such as azathioprine and methotrexate; and anticoagulants such as rivaroxaban, dabigatran, apixaban and edoxaban. Pharmaceutically Acceptable Salts and Excipients

[00117] The compositions described herein can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[00118] Pharmaceutically acceptable salts include, by way of non-limiting example, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene- 2-benzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-1 ,4-dicarboxylate, hexyne-1 ,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2- hydroxyethylsulfonate, methylsulfonate, naphthalene-1 -sulfonate, naphthalene-2- sulfonate, naphthalene-1 ,5-sulfonate, xylenesulfonate, and tartarate salts.

[00119] The term “pharmaceutically acceptable salt” also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxysubstituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N- methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert- butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

[00120] In embodiments, the compositions described herein are in the form of a pharmaceutically acceptable salt.

Pharmaceutical Compositions and Formulations

[00121] In embodiments, the present disclosure pertains to pharmaceutical compositions comprising the compositions, e.g. GM-CSF and/or an additional therapeutic agent, e.g. the therapeutic agent described herein, and a pharmaceutically acceptable carrier or excipient.

[00122] In embodiments, the additional therapeutic agent comprises and/or is selected from anti-virals including, but not limited to, remdesivir; favipiravir; galidesivir; prezcobix; lopinavir; ritonavir; arbidol lopinavir/ritonavir; ribavirin; IFN-beta; xiyanping; anti-VEGF-A; fingolimod; carrimycin; hydroxychloroquine; darunavir and cobicistat; methylprednisolone; brilacidin; leronlimab; and thalidomide; anti-bacterials including, but not limited to, caspofungin macrolides roxithromycin, azithromycin, erythromycin, clarithromycin; second-generation cephalosporins such as cefuroxime, cefaclor; third- generation cephalosporins such as cefdinir, cefixime; fluoroquinolones such as levofloxacin; penicillin; third-generation quinolones such as levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, beta-lactamase inhibitors; and trimethoprim; anti-fungals/anti- mycotics including, but no limited to azoles such as fluconazole, itraconazole, miconazole, ketoconazole, clotrimazole, voriconazole, Posaconazole, sulfamethoxazole; echinocandins such as caspofungin; and compounds with anti-mycotic capabilities such as flucytosine; nystatin; and amphotericin B; inhaled corticosteroids such as prednisone; inhaled brochodialators; diuretics; pyridones such as pirfenidone; small molecules tyrosine-kinase inhibitors (TKI) such as nintedanib; hydroxychloroquine; tumor necrosis factor-alpha (TNF-a) inhibitors; immunosuppressive drugs such as azathioprine and methotrexate; and anticoagulants such as rivaroxaban, dabigatran, apixaban and edoxaban.

[00123] Any pharmaceutical compositions described herein can be administered to a patient as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.

[00124] In embodiments, pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a patient. Water is a useful excipient when any agent described herein is administered intravenously or intranasally. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[00125] The present disclosure includes the described pharmaceutical compositions (and/or additional therapeutic agents) in various formulations. Any inventive pharmaceutical composition (and/or additional therapeutic agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, gelatin capsules, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, lyophilized powder, frozen suspension, desiccated powder, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule. In another embodiment, the composition is in the form of a tablet. In yet another embodiment, the pharmaceutical composition is formulated in the form of a soft-gel capsule. In embodiments, the pharmaceutical composition is formulated in the form of a gelatin capsule. In yet another embodiment, the pharmaceutical composition is formulated as a liquid.

[00126] Where necessary, the inventive pharmaceutical compositions (and/or additional therapeutic agents) can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device.

[00127] The formulations comprising the inventive pharmaceutical compositions (and/or additional therapeutic agents) of the present disclosure may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

[00128] In embodiments, any pharmaceutical compositions (and/or additional therapeutic agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[00129] Routes of administration include, for example: topical, oral, intradermal, transdermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intranasal, epidural, sublingual, intracerebral, intravaginal, rectal, or by inhalation. Administration can be local or systemic. In embodiments, the administering is by an intravenous or intranasal route, or by inhalation. The mode of administration can be left to the discretion of the practitioner, and depends in-part upon the site of the medical condition. In most instances, administration results in the release of any agent described herein onto or into the affected site.

[00130] In embodiments, the GM-CSF is administered to the lung. In embodiments, the GM-CSF is administered via aerosol or nebulizer. In embodiments, the GM-CSF is administered via aerosol or nebulizer. In embodiments, the aerosol or nebulizer is selected from liquid nebulization, dry powder dispersion and meter-dose administration.

[00131] In specific embodiments, the GM-CSF (and/or additional therapeutic agents) is administered by inhalation.

[00132] In one embodiment, the pharmaceutical compositions (and/or additional therapeutic agents) described herein are formulated in accordance with routine procedures as a composition adapted for administration. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol), and suitable mixtures thereof.

[00133] Dosage forms suitable for parenteral administration (e.g. intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art. Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. [00134] Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of Wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.

[00135] Compositions for topical delivery can be in the form of a cream, gel, ointment, lotion, spray, aqueous or oily suspensions, powders, or emulsions, for example. Increased skin permeability and penetration may be achieved by non-invasive methods, for example, with the use of any nanocarriers combined with any pharmaceutical composition (and/or additional therapeutic agents) described herein. The skin can act as a reservoir, and can be used to deliver the compositions (and/or additional therapeutic agents) described herein for more extended periods in a sustained manner.

[00136] Any inventive pharmaceutical compositions (and/or additional therapeutic agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591 ,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropyl cellulose, hydropropylmethyl cellulose, polyvinylpyrrolidone, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the agents described herein. The disclosure thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release. [00137] Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[00138] In another embodiment, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used.

[00139] Pharmaceutical formulations preferably are sterile. Sterilization can be accomplished, for example, by filtration through sterile filtration membranes. Where the composition is lyophilized, filter sterilization can be conducted prior to or following lyophilization and reconstitution.

Administration and Dosage

[00140] It will be appreciated that the actual dose of the composition to be administered according to the present disclosure will vary according to the particular dosage form, and the mode of administration. Many factors that may modify the action of the composition (e.g., body weight, gender, diet, time of administration, route of administration, rate of excretion, condition of the patient, drug combinations, genetic disposition and reaction sensitivities) can be taken into account by those skilled in the art. Administration can be carried out continuously or in one or more discrete doses within the maximum tolerated dose. Optimal administration rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage administration tests.

[00141] In embodiments, the GM-CSF is administered at a total dose of about 125 pg, about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg. In embodiments, the GM-CSF is administered at a total dose of about 250 pg.

[00142] In embodiments, the GM-CSF is administered at a dose of about 125 pg, about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg. [00143] In embodiments, the GM-CSF is administered at a dosing schedule of once monthly, or twice monthly, or once weekly, or twice weekly, or once daily or twice daily. In embodiments, the GM-CSF is administrated weekly.

[00144] In embodiments, the GM-CSF is sargramostim, administered at a dose of about 125 pg, once weekly.

Combination Therapy and Additional Therapeutic Agents

[00145] In embodiments, the pharmaceutical composition of the present disclosure is co-administered in conjunction with additional agent(s), for example an immunomodulatory or pulmonary agent, such as a checkpoint inhibitor. Co-administration can be simultaneous or sequential.

[00146] In one embodiment, the additional immunomodulatory or pulmonary agent and the GM-CSF of the present disclosure are administered to a patient simultaneously. The term “simultaneously” as used herein, means that the immunomodulatory or pulmonary agent and the GM-CSF are administered with a time separation of no more than about 60 minutes, such as no more than about 30 minutes, no more than about 20 minutes, no more than about 10 minutes, no more than about 5 minutes, or no more than about 1 minute. Administration of the immunomodulatory or pulmonary agent and the GM-CSF can be by simultaneous administration of a single formulation (e.g., a formulation comprising the additional therapeutic agent and the GM-CSF composition) or of separate formulations (e.g., a first formulation including the immunomodulatory or pulmonary agent and a second formulation including the GM-CSF composition).

[00147] Co-administration does not require therapeutic agents to be administered simultaneously, if timing of their administration is such that pharmacological activities of the immunomodulatory or pulmonary agent and the GM-CSF overlap in time, thereby exerting a combined therapeutic effect. For example, the immunomodulatory or pulmonary agent and the targeting moiety, the GM-CSF composition can be administered sequentially. The term “sequentially” as used herein means that the immunomodulatory or pulmonary agent and the GM-CSF are administered with a time separation of more than about 60 minutes. For example, the time between the sequential administration of the immunomodulatory or pulmonary agent and the GM-CSF can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, more than about 3 days, more than about 1 week apart, more than about 2 weeks apart, or more than about one month apart. The optimal administration times will depend on the rates of metabolism, excretion, and/or the pharmacodynamic activity of the additional therapeutic agent and the GM-CSF being administered. Either the immunomodulatory or pulmonary agent or the GM-CSF composition may be administered first.

[00148] Co-administration also does not require the therapeutic agents to be administered to the patient by the same route of administration. Rather, each therapeutic agent can be administered by any appropriate route, for example, parenterally or non- parenterally.

[00149] In embodiments, the GM-CSF described herein acts synergistically when co-administered with the immunomodulatory or pulmonary agent. In such embodiments, the targeting moiety, the GM-CSF composition and the immunomodulatory or pulmonary agent may be administered at doses that are lower than the doses employed when the agents are used in the context of monotherapy.

Samples

[00150] In embodiments, the sample is selected from a biopsy, a tissue and/or a body fluid.

[00151] In embodiments, the sample is selected from blood, skin sample or tissue sample, tissue biopsy, a formalin-fixed or paraffin- embedded tissue specimen, cytological sample, cultured cells, plasma, serum, pus, urine, perspiration, tears, mucus, sputum, saliva and/or other body fluids.

Sequences

[00152] SEQ ID NO: 1 is wild type GM-CSF:

[00153] APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDL

QEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKE NLKDFLLVIPFDCWEPVQE

[00154] SEQ ID NO: 2 is sargramostim: [00155] APARSPSPSTQPWEHVNAIQEALRLLNLSRDTAAEMNETVEVISEMFDL

QEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKE

NLKDFLLVIPFDCWEPVQE

[00156] SEQ ID NO: 3 is molgramostim:

[00157] APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDL

QEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKE NLKDFLLVIPFDCWEPVQE

[00158] SEQ ID NO: 4 is regramostim:

[00159] APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDL

QEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQTTFESFKE NLKDFLLVIPFDCWEPVQE

Definitions

[00160] The following definitions are used in connection with the subject matter disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this subject matter belongs.

[00161] An “effective amount,” when used in connection with an agent effective for the treatment of a coronavirus infection is an amount that is effective for treating or mitigating a coronavirus infection.

[00162] As used herein, “a,” “an,” or “the” can mean one or more than one. Further, the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language “about 50” covers the range of 45 to 55.

[00163] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[00164] Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the present subject matter, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.”

EXAMPLES

Example 1 : Expression and Kinetics of CD26, CXCR4, TLR4, IRF-4 VDR, PPAR-y, NR3C1, CD80, and/or HLA-DR on Human Monocytes

[00165] Blood was collected in healthy volunteers, and a whole blood stain, lyse-no- wash protocol was used to prepare stained cell samples for analysis. Human monocytes and lymphocytes from the donors were incubated with sargramostim (LEUKINE) at various concentrations from 0.01 pM to 100nM. The expression of CD26, CXCR4, TLR4, IRF-4 VDR, PPAR-y, NR3C1 , CD80, and/or HLA-DR on monocytes and lymphocytes was measured on day 1 or days 1 , 2 and 3 following treatment. Treatment with sargramostim (LEUKINE) decreased the expression of CD26 (FIG. 1A and 1B), CXCR4 (FIG. 2A and 2B) and TLR4 (FIG. 3A and 3B). However, treatment with sargramostim (LEUKINE) increased the expression of IRF4 (FIG. 4), VDR (FIG. 5), PPAR-y and NR3C1 (FIG. 6), CD80 (FIG. 7A and 7B) and HLA-DR (FIG. 8, e.g., showing enhanced kinetics of HLA- DR) on monocytes but not lymphocytes.

EQUIVALENTS

[00166] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

[00167] All patents and publications referenced herein are hereby incorporated by reference in their entireties. [00168] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

Claims

CLAIMS What is claimed is:

1. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Cluster of Differentiation 26 (CD26) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating an increased or high expression and/or activity of CD26 relative to a pre-treated and/or undiseased state.

2. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of C-X-C Motif Chemokine Receptor 4 (CXCR4) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating an increased or high expression and/or activity of CXCR4 relative to a pre-treated and/or undiseased state.

3. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Toll Like Receptor 4 (TLR4) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating an increased or high expression and/or activity of TLR4 relative to a pre-treated and/or undiseased state.

4. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Interferon Regulatory Factor-4 (IRF-4) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating a decreased or low expression and/or activity of IRF-4 relative to a pre-treated and/or undiseased state.

5. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Vitamin D Receptor (VDR) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating a decreased or low expression and/or activity of VDR relative to a pre-treated and/or undiseased state.

6. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-y or PPARG) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating a decreased or low expression and/or activity of PPAR-y relative to a pre-treated and/or undiseased state.

7. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Nuclear receptor subfamily 3 group C, member 1 (NR3C1 ) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating a decreased or low expression and/or activity of NR3C1 relative to a pre-treated and/or undiseased state.

8. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Cluster of Differentiation 80 (CD80) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating a decreased or low expression and/or activity of CD80 relative to a pre-treated and/or undiseased state.

9. A method of selecting a patient for treatment with an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent for a respiratory or pulmonary disease or illness, comprising: determining the presence, absence or amount of Human Leukocyte Antigen-DR isotype (HLA-DR) in a sample from the patient, wherein the patient is suitable for the treatment if demonstrating a decreased or low expression and/or activity of HLA-DR relative to a pre-treated and/or undiseased state.

10. The method of any one of claims 1-9, wherein the patient is treated with an additional agent(s) comprising: administering an effective amount of drug(s) or therapeutics to treat a respiratory or pulmonary disease or illness.

11. A method for treating or preventing a respiratory or pulmonary disease or illness, comprising:

(a) identifying a patient undergoing or having undergone treatment with an agent for a respiratory or pulmonary disease or illness and presenting as failed, intolerant, resistant, or refractory to the treatment with the agent for a respiratory or pulmonary disease or illness;

(b) determining the presence, absence or amount of CD26, CXCR4, TLR4, IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR in a sample from the patient; and

(c) administering an effective amount of a granulocyte-macrophage colonystimulating factor (GM-CSF) agent to a patient

(i) demonstrating an increased or high expression and/or activity of CD26, CXCR4, and/or TLR4 relative to a pre-treated and/or undiseased state; and/or

(ii) patient demonstrating a decreased or low expression and/or activity of IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR relative to a pre-treated and/or undiseased state.

12. The method of any one of claims 1 -11 , wherein the respiratory or pulmonary disease or illness is caused by an infection with a viral, bacterial or fungal agent, optionally selected from alphacoronaviruses including human coronaviruses (HCoV): HCoV-NL63 and HCoV-229E, betacoronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East respiratory syndrome-coronavirus (MERS-CoV), HCoV-HKU1 , and HCoV-OC43, orthomyxoviruses including influenza viruses; paramyxoviruses including human respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human parainfluenza viruses (HPIV), picornaviruses including human rhinoviruses (HRV), foot-and-mouth disease virus (FMDV), parvoviruses including human bocavirus (HBoV), human adenoviruses A-G (HAdV-A through HAdV-G), herpes simplex virus (HSV); Rickettsia typhi, Haemophilus influenzae type b, Mycoplasma pneumoniae, Chlamydia species, Legionella species including Legionella pneumophilia, Coxiella burnetti; Streptococcus pneumoniae; Pseudomonas aeruginosa, Escherichia coli species, Enterobacter, Proteus species, and Klebsiella species, Francisella tularensis, Yersinia pestis, Neisseria meningitidis, Xanthomonas pseudomallei, Mycobacterium tuberculosis, Actinomyces, Bacteroides, Peptostreptococcus, Veilonella, Propionibacterium, Eubacterium, Fusobacterium species; Cryptococcus neoformans, Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Aspergillus species and Candida species.

13. The method of any one of claims 1 -12, wherein the respiratory or pulmonary disease or illness is selected from pneumonia, sepsis including pediatric sepsis, chronic obstructive pulmonary disease (COPD), asthma, PAP including aPAP (autoimmune pulmonary alveolar proteinosis), occupational lung diseases, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, cystic fibrosis, sleep apnea, chronic bronchitis, emphysema, pleural effusion, interstitial lung disease, pulmonary sarcoidosis, pneumoconiosis including silicosis and asbestosis, and pulmonary hypertension.

14. The method of any one of claims 1 -13, wherein the patient is afflicted with an acute or chronic respiratory or pulmonary disease or illness.

15. The method of any one of claims 1-14, wherein the patient is characterized by having one or more of fever, cough, headache, confusion, shortness of breath, chest pain, myalgia, tachypnea, diarrhea, nausea, chronic mucus hypersecretion or excess/chronic sputum production, upper respiratory symptoms including stuffy nose, rhinorrhea, sneezing, sore throat, lower respiratory symptoms, pharyngitis, epiglottitis, laryngotracheitis, sinusitis, tonsillitis, pneumonia, immunoparalysis, hyperinflammation, and acute respiratory syndrome.

16. The method of any one of claims 1 -15, wherein the patient is hypoxic.

17. The method of any one of claims 1-16, wherein the patient is afflicted with respiratory distress.

18. The method of any one of claims 1 -17, wherein the biological sample is or comprises blood, plasma, serum, mucus, stool, sputum, saliva, nasal secretion, lavage fluid, respiratory fluid blood, and/or other body fluids.

19. The method of claim 18, wherein the respiratory fluid is from an oropharyngeal (OP) or nasopharyngeal (NP) swab.

20. The method of claim 18, wherein the respiratory fluid is lavage fluid, optionally wherein the lavage fluid comprises a bronchial washing.

21 . The method of claim 18, wherein the respiratory fluid is sputum.

22. The method of claim 18, wherein the respiratory fluid is a nasal secretion.

23. The method of claim 18, wherein the respiratory fluid is saliva.

24. The method of any one of claims 1 -23, wherein the method prevents, treats, and/or mitigates the onset, progression and/or development of the respiratory or pulmonary disease or illness in the patient.

25. The method of any one of claims 1-24, wherein the method prevents or mitigates development of systemic inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS) in the patient.

26. The method of any one of claims 1 -25, wherein the method improves oxygenation in the patient.

27. The method of any one of claims 1-26, wherein the method prevents or mitigates a transition from respiratory distress to cytokine imbalance in the patient.

28. The method of any one of claims 1-27, wherein the method reverses or prevents a cytokine storm.

29. The method of claim 28, wherein the method reverses or prevents a cytokine storm in the lungs or systemically.

30. The method of claim 28 or 29, wherein the cytokine storm is selected from one or more of systemic inflammatory response syndrome, cytokine release syndrome, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis.

31 . The method of claim 28 or 29, wherein the method reverses or prevents excessive production of one or more inflammatory cytokines.

32. The method of claim 31 , wherein the inflammatory cytokine is one or more of IL-6, IL-1 , IL-1 receptor antagonist (IL-1 ra), IL-2ra, IL-10, IL-18, TNFa, interferon-y, CXCL10, and CCL7.

33. The method of any one of claims 1-32, wherein the method causes a decrease in viral, bacterial or fungal load in the patient relative to before treatment.

34. The method of any one of claims 1 -33, wherein the GM-CSF has an amino acid sequence of SEQ ID NO: 1 , or a variant of at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto.

35. The method of any one of claims 1 -33, wherein the GM-CSF has an amino acid sequence of one of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, or a variant of at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto.

36. The method of any one of claims 1 -35, wherein the GM-CSF is one of molgramostim, sargramostim, and regramostim.

37. The method of claim 36, wherein the GM-CSF is sargramostim.

38. The method of any one of claims 1-37, wherein the GM-CSF is administered at a total dose of about 125 pg, about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg.

39. The method of claim 38, wherein the GM-CSF is administered at a total dose of about 250 pg.

40. The method of any one of claims 1-39, wherein the GM-CSF is administered at a dose of about 125 pg, about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg.

41 . The method of any one of claims 38-40, wherein the GM-CSF is administered twice daily.

42. The method of claim 41 , wherein the GM-CSF is sargramostim, administered at a dose of about 125 g, twice daily.

43. The method of any one of claims 1 -42, wherein the GM-CSF is administered via an intravenous or intranasal route, or by inhalation.

44. The method of any one of claims 1 -42, wherein the GM-CSF is administered to the lung.

45. The method of claim 44, wherein the GM-CSF is administered via aerosol or nebulizer.

46. The method of claim 45, wherein the aerosol or nebulizer is selected from liquid nebulization, dry powder dispersion and meter-dose administration.

47. The method of any one of claims 1 -42, wherein the GM-CSF is administered by inhalation.

48. The method of any one of claims 1-47, wherein the method further comprises administering one or more additional therapeutic agents, optionally selected from antivirals including, but not limited to, remdesivir; favipiravir; galidesivir; prezcobix; lopinavir; ritonavir; arbidol lopinavir/ritonavir; ribavirin; IFN-beta; xiyanping; anti-VEGF-A; fingolimod; carrimycin; hydroxychloroquine; darunavir and cobicistat; methylprednisolone; brilacidin; leronlimab; and thalidomide; anti-bacterials including, but not limited to, caspofungin macrolides roxithromycin, azithromycin, erythromycin, clarithromycin; second-generation cephalosporins such as cefuroxime, cefaclor; third- generation cephalosporins such as cefdinir, cefixime; fluoroquinolones such as levofloxacin; penicillin; third-generation quinolones such as levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, beta-lactamase inhibitors; and trimethoprim; anti-fungals/anti- mycotics including, but no limited to azoles such as fluconazole, itraconazole, miconazole, ketoconazole, clotrimazole, voriconazole, Posaconazole, sulfamethoxazole; echinocandins such as caspofungin; and compounds with anti-mycotic capabilities such as flucytosine; nystatin; and amphotericin B; inhaled corticosteroids such as prednisone; inhaled brochodialators; diuretics; pyridones such as pirfenidone; small molecules tyrosine-kinase inhibitors (TKI) such as nintedanib; hydroxychloroquine; tumor necrosis factor-alpha (TNF-a) inhibitors; immunosuppressive drugs such as azathioprine and methotrexate; and anticoagulants such as rivaroxaban, dabigatran, apixaban and edoxaban.

49. The method of any one of claims 1-48, wherein the method elicits a diseasemodifying response.

50. The method of any one of claims 1-49, wherein the method causes an amelioration of the respiratory or pulmonary disease or illness symptoms.

51 . The method of any one of claims 1 -50, wherein the method slows the onset and/or development of the respiratory or pulmonary disease or illness.

52. The method of any one of the claims 1 -51 , wherein the method reverses or prevents chronic inflammation in the respiratory or pulmonary system.

53. The method of any one of the claims 1-52, wherein the method decreases or mitigates the dysfunction of endogenous or exogenous pulmonary immune cells.

54. The method of claim 53, wherein the method decreases or mitigates the activation of pulmonary eosinophils.

55. The method of claim 53, wherein the method decreases or mitigates the chronic activation of alveolar macrophages.

56. A method for treating or preventing a respiratory or pulmonary disease or illness, comprising:

(a) selecting a patient having a treating a respirator and/or pulmonary illness and one or more of

(i) increased expression and/or activity of CD26 relative to a pre-treated and/or undiseased state;

(ii) increased expression and/or activity of CXCR4 relative to a pre-treated and/or undiseased state;

(iii) increased expression and/or activity of TLR4 relative to a pre-treated and/or undiseased state; (iv) decreased expression and/or activity of IRF4 relative to a pre-treated and/or undiseased state;

(v) decreased expression and/or activity of VDR relative to a pre-treated and/or undiseased state;

(vi) decreased expression and/or activity of PPAR-y relative to a pre-treated and/or undiseased state;

(vii) decreased expression and/or activity of NR3C1 relative to a pre-treated and/or undiseased state;

(viii) decreased expression and/or activity of CD80 relative to a pre-treated and/or undiseased state; and

(ix) decreased expression and/or activity of HLA-DR relative to a pre-treated and/or undiseased state, and

(b) administering an effective amount of a composition comprising GM-CSF to the patient.

57. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of CD26 during the course of treatment.

58. The method of claim 57, wherein an increased expression and/or activity of CD26 directs continued administration of GM-CSF.

59. The method of claim 57, wherein decreased expression and/or activity of CD26 directs discontinuation of administration of GM-CSF.

60. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of CXCR4, during the course of treatment.

61. The method of claim 60, wherein an increased expression and/or activity of CXCR4 directs continued administration of GM-CSF.

62. The method of claim 60, wherein a decreased expression and/or activity of CXCR4 directs discontinuation of administration of GM-CSF.

63. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of TLR4 during the course of treatment.

64. The method of claim 63, wherein an increased expression and/or activity of TLR4 directs continued administration of GM-CSF.

65. The method of claim 63, wherein a decreased expression and/or activity of TLR4 directs discontinuation of administration of GM-CSF.

66. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of IRF4 during the course of treatment.

67. The method of claim 66, wherein a decreased expression and/or activity of IRF4 directs continued administration of GM-CSF.

68. The method of claim 66, wherein an increased expression and/or activity of IRF4 directs discontinuation of administration of GM-CSF.

69. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of VDR during the course of treatment.

70. The method of claim 69, wherein a decreased expression and/or activity of VDR directs continued administration of GM-CSF.

71. The method of claim 69, wherein an increased expression and/or activity of VDR directs discontinuation of administration of GM-CSF.

72. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of PPAR-y during the course of treatment.

73. The method of claim 72, wherein a decreased expression and/or activity of PPAR- y directs continued administration of GM-CSF.

74. The method of claim 72, wherein an increased expression and/or activity of PPAR- y directs discontinuation of administration of GM-CSF.

75. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of NR3C1 during the course of treatment.

76. The method of claim 75, wherein a decreased expression and/or activity of NR3C1 directs continued administration of GM-CSF.

77. The method of claim 75, wherein an increased expression and/or activity of NR3C1 directs discontinuation of administration of GM-CSF.

78. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of CD80 during the course of treatment.

79. The method of claim 78, wherein a decreased expression and/or activity of CD80 directs continued administration of GM-CSF.

80. The method of claim 78, wherein an increased expression and/or activity of CD80 directs discontinuation of administration of GM-CSF.

81. The method of claim 56, wherein the method further comprises the step of monitoring the expression and/or activity of HLA-DR during the course of treatment.

82. The method of claim 81 , wherein a decreased expression and/or activity of HLA- DR directs continued administration of GM-CSF.

83. The method of claim 81 , wherein an increased expression and/or activity of HLA- DR directs discontinuation of administration of GM-CSF.

84. The method of any one of claims 56-83, wherein the dose of GM-CSF administered to a patient is dependent on the expression and/or activity of CD26 and/or one CXCR4 and/or TLR4 and/or IRF4 and/or VDR and/or PPAR-y and/or NR3C1 and/or CD80 and/or HLA-DR.

85. The method of any one of claims 56-84, wherein the expression and/or activity of CD26, CXCR4, TLR4, IRF4, VDR, PPAR-y, NR3C1 , CD80 and/or HLA-DR are assayed in a biological sample from the patient.

86. The method of any one of claims 56-85, wherein the biological sample is or comprises blood, plasma, serum, mucus, stool, sputum, saliva, nasal secretion, lavage fluid, respiratory fluid blood, and/or other body fluids.

87. The method of any one of claims 56-86, wherein the respiratory or pulmonary disease or illness is caused by an infection with a viral, bacterial or fungal agent, optionally selected from alphacoronaviruses including human coronaviruses (HCoV): HCoV-NL63 and HCoV-229E, betacoronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East respiratory syndrome-coronavirus (MERS-CoV), HCoV-HKU1 , and HCoV-OC43, orthomyxoviruses including influenza viruses; paramyxoviruses including human respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human parainfluenza viruses (HPIV), picornaviruses including human rhinoviruses (HRV), foot-and-mouth disease virus (FMDV), parvoviruses including human bocavirus (HBoV), human adenoviruses A-G (HAdV-A through HAdV-G), herpes simplex virus (HSV); Rickettsia typhi, Haemophilus influenzae type b, Mycoplasma pneumoniae, Chlamydia species, Legionella species including Legionella pneumophilia, Coxiella burnetii; Streptococcus pneumoniae; Pseudomonas aeruginosa, Escherichia coli species, Enterobacter, Proteus species, and Klebsiella species, Francisella tularensis, Yersinia pestis, Neisseria meningitidis, Xanthomonas pseudomallei, Mycobacterium tuberculosis, Actinomyces, Bacteroides, Peptostreptococcus, Veilonella, Propionibacterium, Eubacterium, Fusobacterium species; Cryptococcus neoformans, Sporothrix schenckii, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Aspergillus species and Candida species.

88. The method of any one of claims 56-87, wherein the respiratory or pulmonary disease or illness is selected from pneumonia, sepsis including pediatric sepsis, chronic obstructive pulmonary disease (COPD), asthma, PAP including aPAP (autoimmune pulmonary alveolar proteinosis), occupational lung diseases, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, cystic fibrosis, sleep apnea, chronic bronchitis, emphysema, pleural effusion, interstitial lung disease, pulmonary sarcoidosis, pneumoconiosis including silicosis and asbestosis, and pulmonary hypertension.

89. The method of any one of claims 56-88, wherein the patient is characterized by having one or more of fever, cough, headache, confusion, shortness of breath, chest pain, myalgia, tachypnea, diarrhea, nausea, chronic mucus hypersecretion or excess/chronic sputum production, upper respiratory symptoms including stuffy nose, rhinorrhea, sneezing, sore throat, lower respiratory symptoms, pharyngitis, epiglottitis, laryngotracheitis, sinusitis, tonsillitis, pneumonia, immunoparalysis, hyperinflammation, and acute respiratory syndrome.

90. The method of any one of claims 56-89, wherein the method prevents, treats, and/or mitigates progression and/or development of the respiratory or pulmonary disease or illness.

91. The method of any one of claims 56-90, wherein the method improves the respiratory or pulmonary disease or illness in the patient.

92. The method of any one of claims 56-91 , wherein the method reverses or prevents excessive production of one or more inflammatory cytokines.

93. The method of claim 92, wherein the inflammatory cytokine is one or more of IL-6, IL-1 , IL-1 receptor antagonist (IL-1 ra), IL-2ra, IL-10, IL-18, TNFa, interferon-y, CXCL10, and CCL7.

94. The method of any one of claims 56-93, wherein the method causes an improvement in oxygen saturation, clinical indicators, PaO2/FiO2 ratio, and enhanced immunological effects, as well as improvements in major endpoints like reduction in mortality and days of hospitalization.

95. The method of any one of claims 56-94, wherein the method causes a decrease in the sequelae of a respiratory or pulmonary disease or illness in the patient relative to before treatment.

96. The method of any one of claims 56-95, wherein the GM-CSF has an amino acid sequence of SEQ ID NO: 1 , or a variant of at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto.

97. The method of any one of claims 56-95, wherein the GM-CSF has an amino acid sequence of one of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, or a variant of at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto.

98. The method of any one of claims 56-97, wherein the GM-CSF is one of molgramostim, sargramostim, and regramostim.

99. The method of claim 98, wherein the GM-CSF is sargramostim.

100. The method of any one of claims 56-99, wherein the GM-CSF is administered at a total dose of about 125 g, about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg.

101. The method of claim 100, wherein the GM-CSF is administered at a total dose of about 250 pg.

102. The method of any one of claims 56-99, wherein the GM-CSF is administered at a dose of about 125 pg, about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg.

103. The method of any one of claims 56-102, wherein the GM-CSF is administered twice daily.

104. The method of claim 103, wherein the GM-CSF is sargramostim, administered at a dose of about 125 pg, twice daily.

105. The method of any one of claims 94-104, wherein the GM-CSF is administered via an intravenous or intranasal route.

106. The method of any one of claims 100-104, wherein the GM-CSF is administered to the lung.

107. The method of claim 106, wherein the GM-CSF is administered via aerosol or nebulizer.

108. The method of any one of claims 53-107, wherein the method further comprises administering one or more additional therapeutic agents, optionally selected from antivirals including, but not limited to, remdesivir; favipiravir; galidesivir; prezcobix; lopinavir; ritonavir; arbidol lopinavir/ritonavir; ribavirin; IFN-beta; xiyanping; anti-VEGF-A; fingolimod; carrimycin; hydroxychloroquine; darunavir and cobicistat; methylprednisolone; brilacidin; leronlimab; and thalidomide; anti-bacterials including, but not limited to, caspofungin macrolides roxithromycin, azithromycin, erythromycin, clarithromycin; second-generation cephalosporins such as cefuroxime, cefaclor; third- generation cephalosporins such as cefdinir, cefixime; fluoroquinolones such as levofloxacin; penicillin; third-generation quinolones such as levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, beta-lactamase inhibitors; and trimethoprim; anti-fungals/anti- mycotics including, but no limited to azoles such as fluconazole, itraconazole, miconazole, ketoconazole, clotrimazole, voriconazole, Posaconazole, sulfamethoxazole; echinocandins such as caspofungin; and compounds with anti-mycotic capabilities such as flucytosine; nystatin; and amphotericin B; inhaled corticosteroids such as prednisone; inhaled brochodialators; diuretics; pyridones such as pirfenidone; small molecules tyrosine-kinase inhibitors (TKI) such as nintedanib; hydroxychloroquine; tumor necrosis factor-alpha (TNF-a) inhibitors; immunosuppressive drugs such as azathioprine and methotrexate; and anticoagulants such as rivaroxaban, dabigatran, apixaban and edoxaban.