The present invention relates to methods and uses of antibodies against ELR + CXC
chemokines for preventing and/or treating respiratory diseases, e.g., acute respiratory
5 distress syndrome (ARDS). The present invention also relates to doses and dosing
regimens for the methods and uses of antibodies against ELR+ CXC chemokines for
preventing and/or treating respiratory diseases, e.g., ARDS.
ELR+ CXC chemokines (so-called because members of the chemokine family all
possess an E-L-R amino acid motif immediately adjacent to their CXC motif) play an
10 important role in a variety of 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.
Chemokines are grouped into four subfamilies: CXC, CC, (X)C, and CX3C. In the
CXC chemokines, one amino acid separates the first two cysteines ("the CXC motif").
15 ELR+ CXC chemokines are ligands for CXCR 1 and/or CXCR2 chemokine receptors,
which are G-protein coupled seven transmembrane domain-type 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
20 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 CXCL 7 or human neutrophil activating protein-2), and human IL-8 (also known
as CXCL8 or human interleukin-8). All ELR+ CXC chemokines bind the CXCR2
receptor; moreover, some ELR + CXC chemokines bind both CXCR 1 and CXCR2
25 receptors (i.e., CXCL6 and CXCL8), all of which contributes to redundancy in the
activation pathways. Neutralizing all seven ELR+ CXC chemokines could impact the
ability of CXCR1 +or CXCR2+ cells to migrate to sites of inflammation.
Antibodies that bind and neutralize all seven human ELR + CXC chemokines have
been previously described, e.g., in WO 2014149733, EP 2970447B1, US 9290570. Given
30 their ability to bind and neutralize all seven human ELR+ CXC chemokines, those
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antibodies offer advantages over monotherapies targeting single human ELR+ CXC
chemokines and combination therapies targeting multiple human ELR+ CXC chemokines.
One of such antibodies that bind all seven human ELR + CXC chemokines is Antibody 1
that comprises light chain complementarity determining regions ("LCDR") LCDR1,
5 LCDR2, LCDR3, and heavy chain complementarity determining regions ("HCDR")
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. Antibody 1
comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID
10 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. It was shown
that Antibody 1 binds an epitope that is common to all seven human ELR+ CXC
chemokines and neutralize the activities of all seven human ELR + CXC chemokines. By
15 binding to all seven ELR+ CXC chemokines, both the CXCR1 and the CXCR2 pathways
can be blocked, which may result in more effective inhibition of neutrophil trafficking.
ARDS is a life-threatening respiratory disease characterized by inflammation of the
lungs, which can be widespread and rapid in onset. ARDS is caused by damage to the
alveolar epithelial and endothelial barriers, leading to accumulation of fluid and innate
20 inflammatory cells that trigger further inflammation and tissue injury. This culminates in
pulmonary edema and progressive pulmonary failure/death. ARDS has a mortality rate
reported as high as 30AO?o. Symptoms associated v-rith ARDS include shortness ofbreath,
rapid breathing and bluish skin coloration, in association with disease or injury. Formal
diagnosis of ARDS is challenging as scientifi.c and rnedical definitions have evolved. One
25 definition, known as the "Berlin definition'', relies on radiological imagining of lung and
Pa02/Fi02 ratios (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 following lung insult; unexplained bilateral opacities on chest
imaging; respiratory failure (not explained by heart failure or volume overload); decreased
30 Pa02/Fi02 ratio. The Berlin definition also allows for staging of ARDS according to:
mild ARDS· 201 - 300 rnmHg (~~ 39.9 kPa); moderate ARDS: 101 - 200 mmHg (:S 26.6
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kPa); and severe ARDS: ~-:; 100 mmHg (~-:; 13.3 kPa). However, even in those who recover,
although lung function may gradually improve over a period of six months to a year,
patients may be left with significant scarring and lower than normal lung volumes.
There are presently no approved treatments for preventing and/or treating ARDS.
5 A complicating factor in developing a therapy for ARDS is that ARDS and associated
mortalities develop from a number of diseases and injuries, including interstitial lung
disease, viral insult such as coronavirus disease 2019 (i.e., COVID-19), caused by SAJ~SCoV-
2 virus, and Jniddle eastern respiratory syndrome (J\.'fERS), and therapy induced insult
such as CAR~T therapy induced ARDS. Additionally, ARDS involves a number of
10 molecular path\vays involving numerous immune and epithelial targets. Further, complex
dysregulation of the body's own immune response, following disease or injury (for
example, as in COVID-19), leading to a phenomenon known as cytokine storm has also
been associated v-rith ARDS. As such, there remains an urgent and unmet need for the
prevention and/or treatment of A.RDS.
15 The present disclosure provides methods and uses for the prevention and/or
treatment of ARDS. In one aspect, provided herein are methods of preventing and/or
treating ARDS in a human patient in need thereof by administering to the human patient a
therapeutically effective amount of an antibody that binds all seven human ELR+ CXC
chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an
20 antibody. In some embodiments, provided herein are methods 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 growthregulated
oncogene ("Gro")-alpha, human Gro-beta, human Gro-gamma, human epithelial
neutrophil activating peptide-78, human granulocyte chemotactic protein-2, human
25 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 ("LCDR") LCDR1, LCDR2, LCDR3, and heavy chain
complementarity determining regions ("HCDR") HCDR1, HCDR2, HCDR3, wherein
LCDR1 comprises SEQ ID NO: 7, LCDR2 comprises SEQ ID NO: 8, LCDR3 comprises
30 SEQ ID NO: 9, HCDR1 comprises SEQ ID NO: 10, HCDR2 comprises SEQ ID NO: 11,
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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
5 SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 3.
IL-8 is highly correlated with adverse outcomes in ARDS. IL-8 and other ELR+
chemokines attract neutrophils into the injured alveolus. Once neutrophils enter the
inflamed lung, they secrete proteases, reactive oxygen species, neutrophil extracellular
traps (NETs), and other pro-inflammatory mediators that cause tissue injury and further
10 contribute to inflammation. Neutrophil NETs could uniquely contribute to ARDS by
inducing IL-1b (cytokine storm), M1 alveolar macrophage polarization, mucosal
secretions, and microthrombi. Multiple ELR+ chemokines are elevated in ARDS patients
in general and COVID-19 patients in particular (plasma and bronchoalveolar fluid
[BALF]) and IL-8 is elevated in patients infected with the related coronaviruses that cause
15 SARS and MERS (plasma and BALF). The ELR+ chemokines that bind to CXCR1 and
CXCR2 are involved in angiogenesis and neutrophil migration. Neutralizing all seven
CXCR1/2 ligands can potentially decrease mortality in ARDS, in general, and ARDS
associated with coronaviral infections (SARS, MERS, COVID-19, etc.) in particular, by
blocking neutrophil trafficking to the lung, decreasing multiple neutrophil-mediated
20 contributions to this disease. In contrast to other molecules that target individual ligands or
receptors in the CXCR1/2 network, Antibody 1 is uniquely able to bind to and neutralize
all seven CXCR1/2ligands.
In some embodiments, a method of preventing ARDS in a patient is provided,
comprising administering to said patient a therapeutically effective amount of an antibody
25 that binds all seven human ELR+ CXC chemokines, e.g., 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 insult. In some
embodiments, the respiratory insult is a respiratory disease. According to some
embodiments, the respiratory insult is a respiratory injury.
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In some embodiments, a method of treating ARDS in a patient is provided
comprising administering to said patient a therapeutically effective amount of an antibody
that binds 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
5 as having mild ARDS. In some embodiments, the patient is diagnosed as having moderate
ARDS. In some embodiments, the patient is diagnosed as having severe ARDS. In some
embodiments, the patient is diagnosed as having one of mild, moderate or severe ARDS
according to the Berlin definition.
According to some embodiments of the methods provided herein, the patient has a
10 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
15 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.
Also provided herein are antibodies that bind all seven human ELR+ CXC
20 chemokines, e.g., 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 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
25 protein-2, and human interleukin-8, wherein the antibody comprises light chain
complementarity determining regions ("LCDR") LCDR1, LCDR2, LCDR3 and heavy
chain complementarity determining regions ("HCDR") 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
30 NO: 11, and HCDR3 comprises SEQ ID NO: 12, or a pharmaceutical composition
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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
5 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.
Also provided herein are uses of antibodies that bind all seven human ELR+ CXC
chemokines, e.g., Antibody 1, in the manufacture of a medicament for in the prevention
and/or treatment of ARDS. In some embodiments, provided herein is use of an antibody
10 that binds human growth-regulated oncogene ("Gro")-alpha, human Gro-beta, human Grogamma,
human epithelial 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 ("LCDR") LCDR1,
LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR")
15 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 the
manufacture of a medicament for in the prevention and/or treatment of ARDS. In some
embodiments, the antibody comprises a heavy chain variable region comprising the amino
20 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.
In some embodiments, the antibody that binds all seven human ELR+ CXC
25 chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an
antibody, is administered intravenously. In some embodiments, the antibody that binds all
seven human ELR+ CXC chemokines, e.g., Antibody 1, or a pharmaceutical composition
comprising such an antibody, is administered subcutaneously.
In some embodiments, the antibody that binds all seven human ELR+ CXC
30 chemokines, e.g., Antibody 1, or a pharmaceutical composition comprising such an
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antibody, is administered to the patient for two to three doses. In some embodiments, the
antibody that binds all seven human ELR+ CXC chemokines, e.g., Antibody 1, or a
pharmaceutical composition comprising such an antibody, is administered intravenously to
the patient for two to three doses.
In some embodiments, the antibody that binds 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,
10 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).
As shown below, the bioavailability for subcutaneous injection of Antibody 1 is
15 estimated to be approximately 65% of intravenous injection of Antibody 1. In some
embodiments, the antibody that binds all seven human ELR+ CXC chemokines, e.g.,
Antibody 1, or a pharmaceutical composition comprising such an antibody, is administered
subcutaneously at a dose 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
20 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, 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,
25 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).
As used herein, the term "human ELR + CXC chemokines" refers to the seven
known CXC chemokines that have an E-L-R motif and that bind to CXCR 1 and/or
CXCR2 receptor. The human ELR+ CXC chemokines are human Gro-alpha (also known
30 as CXCL1) (SEQ ID NO: 13), human Gro-beta (also known as CXCL2) (SEQ ID NO: 14),
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human Gro-gamma (also known as CXCL3) (SEQ ID NO: 15), human ENA-78 (also
known as CXCL5) (SEQ ID NO: 16), human GCP-2 (also known as CXCL6) (SEQ ID
NO: 17), human NAP-2 (also known as CXCL 7) (SEQ ID NO: 18), and human IL-8 (also
known as CXCL8) (SEQ ID NO: 19). Collectively, all seven human ELR+ CXC
5 chemokines are called "human pan-ELR+ CXC chemokines" herein.
The term "antibody," as used herein, refers to monoclonal immunoglobulin
molecules comprising four polypeptide chains, two heavy (H) chains and two light (L)
chains inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain
variable region (HCVR) and a heavy chain constant region. The heavy chain constant
10 region comprises three domains, CHI, CH2, and CH3. Each light chain is comprised of a
light chain variable region (LCVR) and a light chain constant region, CL. The HCVR and
LCVR regions can be further subdivided into regions of hypervariability, termed
complementarity determining regions (CDRs), interspersed with regions that are more
conserved, termed framework regions (FR). Each HCVR and LCVR is composed of three
15 CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following
order: FRI, CDRI, FR2, CDR2, FR3, CDR3, FR4. The CDR regions in HCVR are termed
HCDRl, HCDR2, and HCDR3. The CDR regions in LCVR are termed LCDRl, LCDR2,
and LCDR3. The CDRs contain most of the residues which form specific interactions with
the antigen. There are currently three systems of CDR assignments for antibodies that are
20 commonly used for sequence delineation. The Kabat CDR definition (Kabat et al.,
"Sequences of Proteins oflmmunological Interest," National Institutes ofHealth,
Bethesda, Md. (1991)) is based upon antibody sequence variability. 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
25 al., "Standard conformations for the canonical structures of immunoglobulins", Journal of
Molecular Biology, 273, 927-948 (1997)) is based on three-dimensional structures of
antibodies and topologies of the CDR loops. The Chothia CDR definitions are identical to
the Kabat CDR definitions with the exception ofHCDRl and HCDR2. For the purposes of
the present invention, a hybrid of the Kabat and Chothia definitions are used to define
30 CDRs. The assignment of amino acids in the HCVR and LCVR regions is in accordance
with the Kabat numbering convention. It is further understood that the term "antibody"
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encompasses any cellular post-translational modifications to the antibody including, but
not limited to, acylation and glycosylation.
As used herein, the term "septa-specific antibody" refers to an antibody that binds
all seven human ELR+ CXC chemokines with high affinity (e.g., with binding affinity
5 (Kn) in the range of from about 5 x 10"11 M to about 1 x 10"9 M).
As used herein, a "patient," "individual," "subject," refers to a human with a
disease, disorder, or condition that would benefit from a decreased level of human ELR+
CXC chemokines or decreased bioactivity induced by human ELR + CXC chemokines.
As used herein, "prevention", "prevent", and I or "preventing", which are used
10 interchangeably herein, are intended to refer to all processes wherein there may be a
slowing, interrupting, arresting, controlling, stopping, alleviating symptoms or
complications or reversing of the progression of a respiratory disease, for example, caused
by an injury, insult such as SARS-CoV-2 viral infection or disease such as COVID-19
disease, or therapy induced insult such as CAR-T therapy, whereby the respiratory disease
15 does not progress to ARDS or does not progress to a more severe stage of ARDS, for
example, as defined by the Berlin definition. As used herein, prevention is not intended to
necessarily indicate a total elimination of all disorder symptoms.
As used interchangeably herein, "treatment" and/or "treating" and/or "treat" are
intended to refer to all processes wherein there may be a slowing, interrupting, arresting,
20 controlling, stopping, alleviating symptoms or complications or reversing of the
progression of ARDS, but does not necessarily indicate a total elimination of all disorder
symptoms.
As may be used herein, the terms "about" or "approximately", when used in
reference to a particular recited numerical value or range of values, means that the value
25 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 in between
(e.g., 91, 92, 93, 94, etc.).
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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 explore the safety and tolerability of a
5 single dose of Antibody 1 in healthy subjects, including Japanese subjects, in order to
define an appropriate dose range for further clinical research. The endpoints for this
objective are 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 estimation of the bioavailability following
10 subcutaneous (SC) administration of a single dose of Antibody 1, in healthy subjects,
including Japanese subjects. The endpoints include Cmax (maximum observed drug
concentration), tmax (time to reach Cmax), AUCs (area under the concentration-time curve
during dosing interval at steady) and the presence of antidrug antibodies.
In this study, Antibody 1 has been administered to 39 healthy subjects in a single-
15 ascending dose study in which doses of 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 700
mg of Antibody 1 were administered as a slow intravenous (IV) infusion; or the dose of
100 mg of Antibody 1 was administered by SC injection to assess the bioavailability. In
addition, skin blisters were induced in subjects who received IV doses of 10 mg, 30 mg,
100 mg, 200 mg, and 400 mg of Antibody 1 to assess neutrophil chemotaxis and
20 accumulation.
25
There were no deaths or serious adverse events (SAEs) reported. Adverse events
(AEs) reported were graded using the Common Terminology Criteria for Adverse Events
(CTCAE). All AEs reported were Grade 1, except for 1 subject who reported a Grade 2
event, which the investigator considered to be unrelated to study drug.
There were no clinically significant changes in hematology (including peripheral
blood neutrophil counts) or urinalysis.
There were no clinically significant changes in vital signs or electrocardiograms
(ECG).
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Antibody 1 exhibited linear PK in the dose range tested, with an estimated terminal
half-life (tl/2) of approximately 2 weeks. The estimated bioavailability for SC injection of
Antibody 1 is approximately 65% ofiV injection.
The preliminary pharmacodynamic (PD) assessment was focused on the percentage
5 of neutrophils present in the blister fluid. The neutrophil data were highly variable, but a
trend of dose-dependent decreases of neutrophils in the blister fluid was observed.
Example 2: Clinical Study of Antibody 1 for prevention and/or treatment of ARDS in
COVID-19 Patients
A clinical study comparing prevention and/or treatment of ARDS in patients with
10 COVID-19 with Antibody 1, can be undertaken as described herein. Briefly, patients
positive for COVID-19 can be administered intravenously with 1200 mg of Antibody 1 or
placebo for two to three doses on Day 0, Day 2 or 3, and Day 7. Day 7 dose will be
administered only if the patient is in respiratory distress. Day 28 will be the primary
endpoint. The primary endpoint can be all cause mortality at Day 28, or proportion of
15 patients alive and respiratory failure free at Day 28. There will be 11 weeks of follow up
time. The secondary endpoints can be number of days alive and ventilator-free; number of
days in ICU; number of days in hospital; and/or number of days before patient returns to
baseline oxygen requirement. Patients can be assessed for respiratory disease presence,
ARDS presence, or respiratory disease or ARDS progression during and following
20 treatment. Assessment may include chest imagining and Pa02/Fi02 ratio assessment.
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Sequence Listing
Antibody 1 Heavy chain amino acid sequence: SEQ ID NO: 1
QVQL VQSGAEVKKPGASVKVSCKASGYEFTSYWIHWVRQAPGQGLEWMGNISP
NSGSANYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDT AVYYCAREGPYSYYPS
REYYGSDL WGQGTL VTVSSASTKGPSVFPLAPCSRSTSEST AALGCL VKDYFPEP
VTVSWNSGALTSGVHTFP A VLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSN
TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS
QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY
KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCL VKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRL TVDKSRWQEGNVFSCSVMH
EALHNHYTQKSLSLSLG
Antibody 1 Heavy chain variable region: SEQ ID NO: 2
QVQL VQSGAEVKKPGASVKVSCKASGYEFTSYWIHWVRQAPGQGLEWMGNISP
NSGSANYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDT AVYYCAREGPYSYYPS
REYYGSDL WGQGTL VTVSS
Antibody 1 Light chain amino acid sequence: SEQ ID NO: 3
EIVLTQSPA TLSLSPGERA TLSCRASQSISNNLHWYQQKPGQAPRLLIYYTSRSVS
GIPARFSGSGSGTDFTL TISSLEPEDFAVYYCGQNNEWPEVFGGGTKVEIKRTV AA
PSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD
SKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC
Antibody 1 Light chain variable region: SEQ ID NO: 4
EIVLTQSPA TLSLSPGERA TLSCRASQSISNNLHWYQQKPGQAPRLLIYYTSRSVS
GIPARFSGSGSGTDFTL TISSLEPEDF A VYYCGQNNEWPEVFGGGTKVEIK
Antibody 1 Heavy chain DNA sequence: SEQ ID NO: 5
CAGGTGCAGCTGGTGCAGTCTGGTGCTGAAGTGAAGAAGCCTGGGGCCTCAG
TGAAGGTGTCCTGCAAGGCATCTGGCTACGAGTTCACCAGCTACTGGATTCAC
TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAATATTTCTC
CTAATAGTGGTAGTGCTAACTACAATGAGAAGTTCAAGAGCAGAGTCACCAT
GACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGA
TCTGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGGCCCTTACAGTTATTA
TCCGAGTAGGGAGTACTATGGCTCTGACCTCTGGGGGCAAGGGACCCTAGTC
ACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTG
CTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGAC
TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCG
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GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC
AGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCA
ACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCA
AATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCA
TCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACAC TCTCATGATCTCCCGGAC
CCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTC
CAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGC
CGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT
CCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAAC
AAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC
CCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAA
GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC
GCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG
CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGT
GGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCAT
GAGGCTCTGCACAACCACTACACACAGAAGAGCC TCTCCCTGTCTCTGGGT
Antibody 1 Light chain DNA sequence: SEQ ID NO: 6
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAG
AGCCACCCTCTCCTGCAGGGCCAGTCAAAGTATCAGCAATAACCTACACTGG
TACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTATACTTCCCG
GTCCGTCTCTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACT
TCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGT
GGACAGAATAACGAGTGGCCTGAGGTGTTCGGCGGAGGGACCAAGGTGGAG
ATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGA
GCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC
CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAA
CTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC
GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCA
ACAGGGGAGAGTGC
Antibody 1 LCDR1: SEQ ID NO: 7
RASQSISNNLH
Antibody 1 LCDR2: SEQ ID NO: 8
YTSRSVS
Antibody 1 LCDR3: SEQ ID NO: 9
GQNNEWPEV
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Antibody 1 HCDR1: SEQ ID NO: 10
GYEFTSYWIH
Antibody 1 HCDR2: SEQ ID NO: 11
NISPNSGSANYNEKFKS
Antibody 1 HCDR3: SEQ ID NO: 12
EGPYSYYPSREYYGSDL
Human Gro-alpha (CXCL1): SEQ ID NO: 13
PCT/US2021/027776
ASV ATELRCQCLQTLQGIHPKNIQSVNVKSPGPHCAQTEVIATLKNGRKACLNPA
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
AA VLRELRCVCLQTTQGVHPKMISNLQVF AIGPQCSKVEVV ASLKNGKEICLDPE
APFLKKVIQKILDGGNKEN
Human GCP-2 (CXCL6): SEQ ID NO: 17
VSAVLTELRCTCLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQVCLD
PEAPFLKKVIQKILDSGNKKN
Human NAP-2 (CXCL 7): SEQ ID NO: 18
AELRCMCIKTTSGIHPKNIQSLEVIGKGTHCNQVEVIATLKDGRKICLDPDAPRIK
KIVQKKLAGDESAD
Human IL-8 (CXCL8): SEQ ID NO: 19
SAKELRCQCIKTYSKPFHPKFIKELRVIESGPHCANTEIIVKLSDGRELCLDPKENW
VQRVVEKFLKRAENS

CLAIMS:
1. A method of preventing acute respiratory distress syndrome (ARDS) in a patient in need
thereof, 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 epithelial 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 ("LCDR") LCDR1, LCDR2,
LCDR3, and heavy chain complementarity determining regions ("HCDR") 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 insult.
4. The method of any one of claims 1-3, wherein the respiratory insult is a respiratory disease.
5. The method of any one of claims 1-3, wherein the respiratory insult is a respiratory injury.
6. A method of treating acute respiratory distress syndrome (ARDS) in a patient in need thereof,
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 epithelial 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 ("LCDR") LCDR1, LCDR2, LCDR3, and
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heavy chain complementarity determining regions ("HCDR") 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 as having mild ARDS.
8. The method of claim 6, wherein the patient is diagnosed as having moderate ARDS.
9. The method of claim 6, wherein the patient is diagnosed as having severe ARDS.
10. The method of any of claims 7-9, wherein the patient is diagnosed as having one of mild,
moderate or severe ARDS according to the Berlin definition.
11. The method of any of claims 1-10, 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 of claims 1-13, wherein the patient has pneumonia, asthma, COPD,
interstitial lung disease and I or pulmonary fibrosis.
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15. The method of any one of claims 1-14, 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 1-15, 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
SEQIDNO: 3.
17. The method of any one of claims 1-16, wherein the antibody is administered at a dose of
about 100 mg to about 1200 mg intravenously.
18. The method of any one of claims 1-16, wherein the antibody is administered at a dose of
about 150 mg to about 1800 mg subcutaneously.
19. The method of any one of claims 1-17, wherein the antibody is administered at about 1200
mg intravenously for two to three doses.
20. 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, wherein
the antibody comprises light chain complementarity determining regions ("LCDR") LCDR1,
LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR") 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, for use in the prevention of ARDS.
21. The antibody for use of claim 20, wherein the patient is at risk of developing ARDS.
22. The antibody for use of claim 20 or 21, wherein the patient has a respiratory insult.
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23. The antibody for use of any one of claims 20-22, wherein the respiratory insult is a
respiratory disease.
24. The antibody for use of any one of claims 20-23, wherein the respiratory insult is a
respiratory injury.
25. 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, wherein
the antibody comprises light chain complementarity determining regions ("LCDR") LCDR1,
LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR") 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, for use in the treatment of ARDS.
26. The antibody for use of claim 25, wherein the patient is diagnosed as having mild ARDS.
27. The antibody for use of claim 25, wherein the patient is diagnosed as having moderate
ARDS.
28. The antibody for use of claim 25, wherein the patient is diagnosed as having severe ARDS.
29. The antibody for use of any of claims 25-28, wherein the patient is diagnosed as having one
of mild, moderate or severe ARDS according to the Berlin definition.
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30. The antibody for use of any of claims 20-29, wherein the patient has a viral infection.
31. The antibody for use of claim 30, wherein the viral infection is a coronavirus infection.
32. The antibody for use of claim 31, wherein the coronavirus is SARS-CoV-2.
33. The antibody for use of any of claims 20-32, wherein the patient has pneumonia, asthma,
COPD, interstitial lung disease and I or pulmonary fibrosis.
34. The antibody for use of any of claims 20-33, 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 of any of claims 20-34, 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 of any of claims 20-35, wherein the antibody is administered at a dose
of about 100 mg to about 1200 mg intravenously.
37. The antibody for use of any of claims 20-36, wherein the antibody is administered at a dose
of about 150 mg to about 1800 mg subcutaneously.
38. The antibody for use of any of claims 20-36, wherein the antibody is administered at about
1200 mg intravenously for two to three doses.
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39. Use of an antibody that binds human growth-regulated oncogene ("Gro")-alpha, human Grobeta,
human Gro-gamma, human epithelial 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 ("LCDR") LCDR1,
LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR") 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 the manufacture of a medicament
for the prevention of ARDS.
40. Use of an antibody that binds human growth-regulated oncogene ("Gro")-alpha, human Grobeta,
human Gro-gamma, human epithelial 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 ("LCDR") LCDR1,
LCDR2, LCDR3 and heavy chain complementarity determining regions ("HCDR") 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 the manufacture of a medicament
for the treatment of ARDS.