Pan-ELR+CXC chemokine antibodies for treatment of respiratory disease

Abstract

To meet an urgent need for the prevention and / or treatment of ARDS.SOLUTION: Provided herein are methods and uses of antibodies that bind all seven human ELR+CXC chemokines with high affinity for preventing and / or treating respiratory diseases, e.g., acute respiratory distress syndrome (ARDS). The present invention also relates to doses and dosing regimens for the methods and uses of antibodies that bind all seven human ELR+CXC chemokines with high affinity for preventing and / or treating respiratory diseases, e.g., ARDS.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to methods and uses of antibodies against ELR+CXC chemokines for preventing and / or treating respiratory diseases, such as acute respiratory distress syndrome (ARDS). The present invention also relates to dosage and dosing regimens for methods and uses of antibodies against ELR+CXC chemokines for preventing and / or treating respiratory diseases, such as ARDS. [Background technology]

[0002] ELR+CXC chemokines (so named because all members of the chemokine family have an ELR amino acid motif immediately adjacent to the CXC motif) play important roles in various pathogenic mechanisms, including the migration of neutrophils to sites of inflammation and angiogenesis. Neutrophils contribute to the pathogenesis of several acute and chronic inflammatory and autoimmune diseases.

[0003] Chemokines are classified into four subfamilies: CXC, CC, (X)C, and CX3C. In CXC chemokines, one amino acid separates the first two cysteines (the "CXC motif"). ELR+CXC chemokines are ligands for the CXCR1 and / or CXCR2 chemokine receptors, which are G protein-coupled, seven-transmembrane domain receptors that specifically bind ELR+CXC chemokines. The seven human ELR+CXC chemokines are human growth-regulated oncogene ("Gro")-alpha (also known as CXCL1), human Gro-beta (also known as CXCL2), human Gro-gamma (also known as CXCL3), human ENA-78 (also known as CXCL5, or human epithelial neutrophil-activating peptide-78), human GCP-2 (also known as CXCL6, or human granulocyte chemotactic protein-2), human NAP-2 (also known as CXCL7, or human neutrophil-activating protein-2), and human IL-8 (also known as CXCL8, or human interleukin-8). All ELR+CXC chemokines bind to the CXCR2 receptor, and furthermore, some ELR+CXC chemokines bind to both the CXCR1 and CXCR2 receptors (i.e., CXCL6 and CXCL8), all of which contribute to the redundancy of the activation pathway. Neutralization of all seven ELR+CXC chemokines may affect the ability of CXCR1+ or CXCR2+ cells to migrate to sites of inflammation.

[0004] Antibodies that bind and neutralize all seven human ELR+CXC chemokines have been previously described, for example in WO2014149733, EP2970447B1, US9290570. Given their ability to bind and neutralize all seven human ELR+CXC chemokines, these antibodies are superior to monotherapies targeting a single human ELR+CXC chemokine and combination therapies targeting multiple human ELR+CXC chemokines. One such antibody that binds to all seven human ELR+CXC chemokines is Antibody 1, which comprises light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, where LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:12. Antibody 1 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4. Antibody 1 comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:3. Antibody 1 has been shown to bind to an epitope common to all seven human ELR+CXC chemokines and neutralize the activity of all seven human ELR+CXC chemokines. Binding to all seven ELR+CXC chemokines may block both the CXCR1 and CXCR2 pathways, which may result in more effective inhibition of neutrophil trafficking.

[0005] ARDS is a life-threatening respiratory disease characterized by lung inflammation that can be widespread and rapid in onset. ARDS is caused by damage to the alveolar epithelium and endothelial barrier, leading to the accumulation of fluid and innate inflammatory cells, causing further inflammation and tissue damage. This leads to pulmonary edema and progressive lung failure / death. Mortality from ARDS has been reported to reach 30-40%. Symptoms associated with ARDS include disease- or injury-related shortness of breath, rapid breathing, and pale skin. Formal diagnosis of ARDS is difficult because scientific and medical definitions are evolving. One definition, known as the "Berlin definition," relies on radiological imaging of the lungs and the PaO2 / FiO2 ratio (Ranieri et al., 2012, JAMA, 307(23):2526-33). According to the Berlin definition, ARDS is characterized according to the following factors: acute onset respiratory symptoms secondary to lung injury, bilateral opacities of unknown etiology on chest imaging, respiratory failure (not explained by cardiac failure or volume overload), and a decreased PaO2 / FiO2 ratio. The Berlin definition also allows for staging of ARDS according to mild ARDS: 201-300 mmHg (≤39.9 kPa), moderate ARDS: 101-200 mmHg (≤26.6 kPa), and severe ARDS: ≤100 mmHg (≤13.3 kPa). However, even in recovered patients, patients may be left with significant scarring and have lower than normal lung volumes, although lung function may improve gradually over a period of 6 months to 1 year.

[0006] Currently, there are no approved therapies to prevent and / or treat ARDS. Complicating the development of therapies for ARDS is that ARDS and associated mortality arise from several diseases and injuries, including interstitial lung disease, viral insults such as coronavirus disease 2019 (i.e., COVID-19) caused by the SARS-CoV-2 virus, and Middle East Respiratory Syndrome (MERS), as well as therapy-induced insults such as CAR-T therapy-induced ARDS. In addition, ARDS involves several molecular pathways with numerous immune and epithelial targets. Furthermore, complex dysregulation of the body's own immune response following disease or injury (e.g., as with COVID-19), which causes a phenomenon known as a cytokine storm, is also associated with ARDS. Thus, there remains an urgent unmet need for the prevention and / or treatment of ARDS. Summary of the Invention

[0007] The present disclosure provides methods and uses for the prevention and / or treatment of ARDS. In one aspect, provided herein is a method for preventing and / or treating ARDS in a human patient by administering to the human patient in need of such prevention and / or treatment a therapeutically effective amount of an antibody that binds to all seven human ELR+CXC chemokines, such as antibody 1, or a pharmaceutical composition comprising such an antibody. In some embodiments, provided herein is a method of preventing and / or treating ARDS in a human patient in need thereof, comprising administering to the human patient a therapeutically effective amount of an antibody that binds human growth-regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epithelial neutrophil-activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil-activating protein-2, and human interleukin-8, or a pharmaceutical composition comprising such an antibody, wherein the antibody comprises light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:12. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] IL-8 is highly correlated with adverse outcomes in ARDS. IL-8 and other ELR+ chemokines attract neutrophils to damaged alveoli. When neutrophils enter the inflamed lung, they secrete proteases, reactive oxygen species, neutrophil extracellular traps (NETs), and other proinflammatory mediators that cause tissue damage and further contribute to inflammation. Neutrophil NETs may specifically contribute to ARDS by inducing IL-1b (cytokine storm), M1 alveolar macrophage polarization, mucus secretion, and microthrombi. Multiple ELR+ chemokines are generally elevated in ARDS patients, particularly COVID-19 patients (plasma and bronchoalveolar fluid [BALF]), and IL-8 is elevated in patients infected with related coronaviruses that cause SARS and MERS (plasma and BALF). ELR+ chemokines that bind to CXCR1 and CXCR2 are involved in angiogenesis and neutrophil trafficking. Neutralizing all seven CXCR1 / 2 ligands may reduce mortality in ARDS in general, and in ARDS associated with coronavirus infections (e.g., SARS, MERS, COVID-19), in particular, by blocking neutrophil trafficking to the lungs and reducing the multiple neutrophil-mediated contributions to the disease. In contrast to other molecules that target individual ligands or receptors within the CXCR1 / 2 network, Antibody 1 can specifically bind and neutralize all seven CXCR1 / 2 ligands.

[0009] In some embodiments, a method of preventing ARDS in a patient is provided, comprising administering to the patient a therapeutically effective amount of an antibody that binds to all seven human ELR+CXC chemokines, such as antibody 1, or a pharmaceutical composition comprising such an antibody. In some embodiments, the patient is at risk of developing ARDS. In some embodiments, the patient has a respiratory injury. In some embodiments, the respiratory injury is a respiratory disease. According to some embodiments, the respiratory injury is a respiratory injury.

[0010] In some embodiments, a method of treating ARDS in a patient is provided, comprising administering to the patient a therapeutically effective amount of an antibody that binds to all seven human ELR+CXC chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an antibody. In some embodiments, the patient is diagnosed with mild ARDS. In some embodiments, the patient is diagnosed with moderate ARDS. In some embodiments, the patient is diagnosed with severe ARDS. In some embodiments, the patient is diagnosed with one of mild, moderate, or severe ARDS according to the Berlin definition.

[0011] According to some embodiments of the methods provided herein, the patient has a viral infection. In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus is SARS-CoV-2. According to some embodiments of the methods provided herein, the patient has COVID-19. According to some embodiments of the methods provided herein, the patient has pneumonia. According to some embodiments of the methods provided herein, the patient has asthma. According to some embodiments of the methods provided herein, the patient has chronic obstructive pulmonary disease (COPD). According to some embodiments of the methods provided herein, the patient has pulmonary fibrosis. According to some embodiments of the methods provided herein, the patient has interstitial lung disease.

[0012] Also provided herein is an antibody that binds to all seven human ELR+CXC chemokines, such as Antibody 1, or a pharmaceutical composition comprising such an antibody, for use in the prevention and / or treatment of ARDS. In some embodiments, provided herein is an antibody that binds to human growth-regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epidermal neutrophil-activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil-activating protein-2, and human interleukin-8, the antibody comprising light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, where LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:12, or a pharmaceutical composition comprising such an antibody, for use in the prevention and / or treatment of ARDS. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:3.

[0013] Also provided herein is the use of an antibody that binds to all seven human ELR+CXC chemokines, e.g., antibody 1, in the manufacture of a medicament for the prevention and / or treatment of ARDS. In some embodiments, provided herein is the use of an antibody that binds to human growth-regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epidermal neutrophil-activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil-activating protein-2, and human interleukin-8, in the manufacture of a medicament for the prevention and / or treatment of ARDS, the antibody comprising light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:12. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 3.

[0014] In some embodiments, an antibody that binds to all seven human ELR+CXC chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an antibody, is administered intravenously. In some embodiments, an antibody that binds to all seven human ELR+CXC chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an antibody, is administered subcutaneously.

[0015] In some embodiments, an antibody that binds to all seven human ELR+CXC chemokines, e.g., antibody 1, or a pharmaceutical composition comprising such an antibody, is administered to a patient two or three times. In some embodiments, an antibody that binds to all seven human ELR+CXC chemokines, e.g., antibody 1, or a pharmaceutical composition comprising such an antibody, is administered intravenously to a patient two or three times.

[0016] In some embodiments, an antibody that binds to all seven human ELR+CXC chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an antibody, is administered intravenously at a dose of about 100 mg to about 1200 mg (e.g., about 100 mg to about 1200 mg, about 200 mg to about 1150 mg, about 300 mg to about 1100 mg, about 600 mg to about 1000 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg).

[0017] As shown below, the bioavailability of subcutaneous injection of Antibody 1 is estimated to be approximately 65% ​​of that of intravenous injection of Antibody 1. In some embodiments, an antibody that binds to all seven human ELR+CXC chemokines, such as Antibody 1, or a pharmaceutical composition comprising such an antibody, is administered in a dose range of about 150 mg to about 1800 mg (e.g., about 150 mg to about 1800 mg, about 200 mg to about 1700 mg, about 300 mg to about 1600 mg, about 400 mg to about 1500 mg, about 500 mg to about 1400 mg, about 600 mg to about 1300 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg). , about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg.

[0018] As used herein, the term "human ELR+CXC chemokines" refers to the seven known CXC chemokines that have an ELR motif and bind to the CXCR1 and / or CXCR2 receptors. The human ELR+CXC chemokines are human Gro-alpha (aka CXCL1) (SEQ ID NO: 13), human Gro-beta (aka CXCL2) (SEQ ID NO: 14), human Gro-gamma (aka CXCL3) (SEQ ID NO: 15), human ENA-78 (aka CXCL5) (SEQ ID NO: 16), human GCP-2 (aka CXCL6) (SEQ ID NO: 17), human NAP-2 (aka CXCL7) (SEQ ID NO: 18), and human IL-8 (aka CXCL8) (SEQ ID NO: 19). Collectively, all seven human ELR+CXC chemokines are referred to herein as "human pan-ELR+CXC chemokines."

[0019] The term "antibody" as used herein refers to a monoclonal immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds. Each of the heavy chains comprises a heavy chain variable region (HCVR) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each of the light chains consists of a light chain variable region (LCVR) and a light chain constant region CL. The HCVR and LCVR regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions ("FRs"). Each of the HCVR and LCVR consists of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The CDR regions of the HCVR are referred to as HCDR1, HCDR2, and HCDR3. The CDR regions of LCVR are called LCDR1, LCDR2, and LCDR3. CDRs contain most of the residues that form specific interactions with antigen. Currently, there are three CDR assignment systems for antibodies that are commonly used for sequence delineation. The Kabat CDR definition (Kabat et al., "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991)) is based on the variability of antibody sequences. The Chothia CDR definition (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)) is based on the three-dimensional structure of the antibody and the topology of the CDR loops.The Chothia CDR definitions are identical to the Kabat CDR definitions, except for HCDR1 and HCDR2. For the purposes of the present invention, a hybrid of the Kabat and Chothia definitions is used to define the CDRs. The assignment of amino acids in the HCVR and LCVR regions follows the Kabat numbering convention. It is further understood that the term "antibody" encompasses any cellular post-translational modifications to antibodies, including, but not limited to, acylation and glycosylation.

[0020] As used herein, the term "septa-specific antibody" refers to an antibody that specifically binds to all seven human ELR+CXC chemokines with high affinity (e.g., approximately 5×10 -11 M ~ approx. 1×10 -9 Binding affinity (K D ) refers to an antibody that binds to

[0021] As used herein, "patient," "individual," or "subject" refers to a human having a disease, disorder, or condition that would benefit from a reduction in the levels of human ELR+CXC chemokines or a reduction in the biological activity induced by human ELR+CXC chemokines.

[0022] As used herein, "prevention," "preventing," and / or "preventing" are used interchangeably herein and are intended to refer to any process in which symptoms or complications may be delayed, interrupted, arrested, controlled, halted, alleviated, or reversed in the progression of a respiratory disease, e.g., caused by an injury, insult such as SARS-CoV-2 viral infection, or disease such as COVID-19 disease, or therapy-induced injury such as CAR-T therapy, such that the respiratory disease does not progress to ARDS or to a more severe stage of ARDS, e.g., ARDS as defined by the Berlin definition. As used herein, prevention is not necessarily intended to indicate the complete elimination of all symptoms of the disorder.

[0023] As used interchangeably herein, "treatment" and / or "treating" and / or "treat" refer to any process in which there may be a delay, interruption, arrest, control, halt, alleviation of symptoms or complications, or reversal of the progression of ARDS, but are not necessarily intended to indicate a complete elimination of all symptoms of the disorder.

[0024] As may be used herein, the terms "about" or "approximately," when used in reference to a particular recited numerical value or range of values, mean that the value may vary from the recited value by no more than 10% (e.g., ±10%). For example, as used herein, the expression "about 100" includes 90 and 110, and all values ​​therebetween (e.g., 91, 92, 93, 94, etc.). EXAMPLES

[0025] Example 1: A Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Antibody 1 in Healthy Subjects (NCT02148627) The primary objective of this study is to investigate the safety and tolerability of a single dose of antibody 1 in healthy subjects, including Japanese subjects, and to define an appropriate dose range for further clinical studies. Endpoints for this objective are the incidence of SAEs (serious adverse events) and TEAEs (treatment-emergent adverse events). The secondary objective of this study is to characterize the pharmacokinetics (PK) of antibody 1, including an estimate of the bioavailability following a single subcutaneous (SC) dose of antibody 1 in healthy subjects, including Japanese subjects. Endpoints include Cmax (maximum observed drug concentration), tmax (time to reach Cmax), AUC (area under the concentration-time curve during the dosing interval at steady state), and the presence of anti-drug antibodies.

[0026] In this study, antibody 1 was administered to 39 healthy subjects in a single ascending dose study where bioavailability was assessed at doses of 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 700 mg of antibody 1 administered by slow intravenous (IV) infusion or at a dose of 100 mg of antibody 1 administered by SC injection. Additionally, skin blistering was induced in subjects receiving 10 mg, 30 mg, 100 mg, 200 mg, and 400 mg of antibody 1 IV, and neutrophil chemotaxis and accumulation was assessed.

[0027] No deaths or serious adverse events (SAEs) were reported. Reported adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events (CTCAE). All reported AEs were grade 1, except for one subject who reported a grade 2 event that the investigator deemed unrelated to study drug.

[0028] There were no clinically significant changes in hematology (including peripheral blood neutrophil count) or urinalysis.

[0029] There were no clinically significant changes in vital signs or electrocardiograms (ECGs).

[0030] Antibody 1 exhibited linear PK within the dose range tested, with an estimated terminal half-life (t1 / 2) of approximately 2 weeks. The estimated bioavailability of Antibody 1 following SC injection is approximately 65% ​​of that following IV injection.

[0031] Preliminary pharmacodynamic (PD) evaluation focused on the percentage of neutrophils present in the blister fluid. Although neutrophil data were highly variable, a trend towards a dose-dependent decrease in neutrophils in the blister fluid was observed.

[0032] Example 2: Clinical Study of Antibody 1 for the Prevention and / or Treatment of ARDS in COVID-19 Patients A clinical study comparing the prevention and / or treatment of ARDS in COVID-19 patients to Antibody 1 can be conducted as described herein. Briefly, COVID-19 positive patients can receive 2-3 doses of 1200 mg of Antibody 1 or placebo intravenously on days 0, 2 or 3, and 7. The day 7 dose is administered only if the patient is in respiratory distress. Day 28 is the primary endpoint. The primary endpoint can be all-cause mortality at day 28, or the proportion of patients alive and free of respiratory failure at day 28. There is an 11 week follow-up period. Secondary endpoints can be days alive and ventilator-free, days in ICU, days hospitalized, and / or days until the patient returns to baseline oxygen requirements. Patients can be evaluated during and after treatment for the presence of respiratory disease, the presence of ARDS, or progression of respiratory disease or ARDS. Evaluations can include chest imaging and evaluation of the PaO2 / FiO2 ratio.

[0033] Sequence Listing Antibody 1 heavy chain amino acid sequence: SEQ ID NO:1 QVQLVQSGAEVKKPGASVKVSCKASGYEFTSYWIHWVRQAPGQGLEWMGNISP NSGSANYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDT AVYYCAREGPYSYYPS REYYGSDLWGQGTL VTVSSASTKGPSVFPLAPCSRSTSEST AALGCLVKDYFPEP VTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCL VKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQEGNVFSCSVMH EALHNHYTQKSLSLSLG Antibody 1 heavy chain variable region: SEQ ID NO:2 QVQLVQSGAEVKKPGASVKVSCKASGYEFTSYWIHWVRQAPGQGLEWMGNISP NSGSANYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDT AVYYCAREGPYSYYPS REYYGSDLWGQGTLVTVSS Antibody 1 light chain amino acid sequence: SEQ ID NO:3 EIVLTQSPA TLSLSPGERATLSCRASQSISNNLHWYQQKPGQAPRLLIYYTSRSVS GIPARFSGSGSGTDFTL TISSLEPEDFAVYYCGQNNEWPEVFGGGTKVEIKRTV AA PSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC Antibody 1 light chain variable region: SEQ ID NO: 4 EIVLTQSPA TLSLSPGERATLSCRASQSISNNLHWYQQKPGQAPRLLIYYTSRSVS GIPARFSGSGSGTDFTL TISSLEPEDFAVYYCGQNNEWPEVFGGGTKVEIK Antibody 1 heavy chain DNA sequence: SEQ ID NO:5 CAGGTGCAGCTGGTGCAGTCTGGTGCTGAAGTGAAGAAGCCTGGGGCCTCAG TGAAGGTGTCCTGCAAGGCATCTGGCTACGAGTTCACCAGCTACTGGATTCAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAATATTTCTC CTAATAGTGGTAGTGCTAACTACAATGAGAAGTTCAAGAGCAGAGTCACCAT GACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGA TCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGGCCCTTACAGTTATTA TCCGAGTAGGGAGTACTATGGCTCTGACCTCTGGGGGCAAGGGACCCTAGTC ACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTG CTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCG GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC AGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCA ACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCA AATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCA TCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACAC TCTCATGATCTCCCGGAC CCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTC CAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT CCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAA GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACAT C GCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGT GGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCAT GAGGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGT Antibody 1 light chain DNA sequence: SEQ ID NO: 6 GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAG AGCCACCTCTCCTGCAGGGCCAGTCAAAGTATCAGCAATAACCTACACTGG TACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTATACTTCCCG GTCCGTCTCTGGCATCCCAGCCAGGTTCAGTGGCAGTGGTCTGGGACAGACT TCACTTCCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTATTACTGT GGACAGAATAACGAGT GGCCTGAGGTGTTCGGCGAGGACCAAGGT GGAG ATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGA GCAGTTGAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAA CTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACC TACAGCCTC AGCAGCACCC TGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCA ACAGGGGAGAGTGC Antibodies1 LCDR1: sejjak nomjekti7 RASQSISNNLH Antibodies1 LCDR2: அக்க்கியுக்க்கி8 YTSRSVS Antibodies1 LCDR3: sejjak nomko9 GQNNEWPEV Antibodies1 HCDR1: sejjak nomikum10 GYEFTSYWIH Antibodies1 HCDR2: sejjak nomdek11 NISPNSGSANYNEKFKS Antibodies1 HCDR3: sejjak nomdek12 EGPYSYYPSREYYGSDL Human Gro-alpha (CXCL1): SEQ ID NO: 13 ASVATELRCQCLQTLQGIHPKNIQSVNVKSPGPHCAQTEVIATLKNGRKACLNPA SPIVKKIIEKMLNSDKSN Human Gro-beta (CXCL2): SEQ ID NO: 14 APLATELRCQCLQTLQGIHLKNIQSVKVKSPGPHCAQTEVIATLKNGQKACLNPA SPMVKKIIEKMLKNGKSN Human Gro-gamma (CXCL3): SEQ ID NO: 15 ASVVTELRCQCLQTLQGIHLKNIQSVNVRSPGPHCAQTEVIATLKNGKKACLNPA SPMVQKIIEKILNKGSTN Human ENA-78 (CXCL5): SEQ ID NO: 16 AAVLRELRCVCLQTTQGVHPKMISNLQVFAIGPQCSKVEVVASLKNGKEICLDPE APFLKKVIQKILDGGNKEN Human GCP-2 (CXCL6): SEQ ID NO: 17 VSAVLTELRCTCLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQVCLD PEAPFLKKVIQKILDSGNKKN Human NAP-2 (CXCL7): SEQ ID NO: 18 AELRCMCIKTTSGIHPKNIQSLEVIGKGTHCNQVEVIATLKDGRKICLDPDAPRIK KIVQKKLAGDESAD Human IL-8 (CXCL8): SEQ ID NO: 19 SAKELRCQCIKTYSKPFHPKFIKELRVIESGPHCANTEIIVKLSDGRELCLDPKENW VQRVVEKFLKRAENS

Claims

1. 1. A method of preventing respiratory distress syndrome (ARDS) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an antibody that binds to human growth regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epidermal neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil activating protein-2, and human interleukin-8, wherein the antibody comprises light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:

12.

2. The method of claim 1 , wherein the patient is at risk of developing ARDS.

3. The method of claim 1 or 2, wherein the patient has a respiratory disorder.

4. The method according to any one of claims 1 to 3, wherein the respiratory disorder is a respiratory disease.

5. The method according to any one of claims 1 to 3, wherein the respiratory injury is a respiratory injury.

6. 1. A method of treating respiratory distress syndrome (ARDS) in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of an antibody that binds human growth regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epidermal neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil activating protein-2, and human interleukin-8, wherein the antibody comprises light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:

12.

7. The method of claim 6, wherein the patient is diagnosed with mild ARDS.

8. The method of claim 6, wherein the patient is diagnosed with moderate ARDS.

9. The method of claim 6 , wherein the patient is diagnosed with severe ARDS.

10. The method of any one of claims 7 to 9, wherein the patient is diagnosed as having one of mild, moderate, or severe ARDS according to the Berlin definition.

11. The method of any one of claims 1 to 10, wherein the patient has a viral infection.

12. The method of claim 11 , wherein the viral infection is a coronavirus infection.

13. The method of claim 12, wherein the coronavirus is SARS-CoV-2.

14. The method of any one of claims 1 to 13, wherein the patient has pneumonia, asthma, COPD, interstitial lung disease, and / or pulmonary fibrosis.

15. The method of any one of claims 1 to 14, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

4.

16. The method of any one of claims 1 to 15, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:

3.

17. The method of any one of claims 1 to 16, wherein the antibody is administered intravenously at a dose of about 100 mg to about 1200 mg.

18. The method of any one of claims 1 to 16, wherein the antibody is administered subcutaneously at a dose of about 150 mg to about 1800 mg.

19. 18. The method of any one of claims 1 to 17, wherein the antibody is administered intravenously in a dose of about 1200 mg administered two to three times.

20. 1. An antibody that binds to human growth regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epithelial neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil activating protein-2, and human interleukin-8, for use in the prevention of ARDS, said antibody comprising light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:

12.

21. The antibody for use according to claim 20, wherein the patient is at risk of developing ARDS.

22. 22. The antibody for use according to claim 20 or 21, wherein the patient has a respiratory disorder.

23. The antibody for use according to any one of claims 20 to 22, wherein the respiratory disorder is a respiratory disease.

24. The antibody for use according to any one of claims 20 to 23, wherein the respiratory injury is a respiratory injury.

25. 1. An antibody that binds to human growth regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epithelial neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil activating protein-2, and human interleukin-8, for use in the treatment of ARDS, said antibody comprising light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:

12.

26. 26. The antibody for use according to claim 25, wherein the patient is diagnosed with mild ARDS.

27. 26. The antibody for use according to claim 25, wherein the patient is diagnosed with moderate ARDS.

28. 26. The antibody for use according to claim 25, wherein the patient is diagnosed with severe ARDS.

29. The antibody for use according to any one of claims 25 to 28, wherein the patient is diagnosed as having one of mild, moderate or severe ARDS according to the Berlin definition.

30. The antibody for use according to any one of claims 20 to 29, wherein the patient has a viral infection.

31. 31. The antibody for use according to claim 30, wherein the viral infection is a coronavirus infection.

32. The antibody for use according to claim 31, wherein the coronavirus is SARS-CoV-2.

33. The antibody for use according to any one of claims 20 to 32, wherein the patient has pneumonia, asthma, COPD, interstitial lung disease, and / or pulmonary fibrosis.

34. The antibody for use according to any one of claims 20 to 33, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

4.

35. The antibody for use according to any one of claims 20 to 34, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:

3.

36. The antibody for use according to any one of claims 20 to 35, wherein the antibody is administered intravenously at a dose of about 100 mg to about 1200 mg.

37. The antibody for use according to any one of claims 20 to 36, wherein the antibody is administered subcutaneously at a dose of about 150 mg to about 1800 mg.

38. The antibody for use according to any one of claims 20 to 36, wherein the antibody is administered intravenously in a dose of about 1200 mg administered two to three times.

39. 1. Use of an antibody that binds to human growth regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epidermal neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil activating protein-2, and human interleukin-8, in the manufacture of a medicament for the prevention of ARDS, wherein the antibody comprises light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:

12.

40. 1. Use of an antibody that binds human growth regulated oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epidermal neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human neutrophil activating protein-2, and human interleukin-8, in the manufacture of a medicament for the treatment of ARDS, wherein the antibody comprises light chain complementarity determining regions ("LCDRs") LCDR1, LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDRs") HCDR1, HCDR2, HCDR3, wherein LCDR1 comprises SEQ ID NO:7, LCDR2 comprises SEQ ID NO:8, LCDR3 comprises SEQ ID NO:9, HCDR1 comprises SEQ ID NO:10, HCDR2 comprises SEQ ID NO:11, and HCDR3 comprises SEQ ID NO:12.