WO2021243396A1

WO2021243396A1 - Therapeutic methods of using cd 14 antagonistic antibodies in treating conditions associated with a coronavirus infection including sars-cov-2 (covid-19)

Info

Publication number: WO2021243396A1
Application number: PCT/AU2021/050292
Authority: WO
Inventors: Garry REDLICH
Original assignee: Implicit Bioscience Limited
Priority date: 2020-06-01
Filing date: 2021-03-31
Publication date: 2021-12-09

Abstract

The present application is directed to treating diseases associated with a coronavirus infection, specifically SARS-CoV-2 (COVID-19) in a human subject by administering an effective amount of a CD14 antagonist antibody. The present application is further directed to methods of treating inflammation induced hypercoagulopathy in a human subject by administering an effective amount of a CD 14 antagonist antibody.

Description

TITLE OF THE INVENTION

THERAPEUTIC METHODS OF USING CD 14 ANTAGONISTIC ANTIBODIES IN TREATING CONDITIONS ASSOCIATED WITH A CORONAVIRUS INFECTION

INCLUDING SARS-COV-2 (COVID-19)

[0001] This application claims priority to Australian Provisional Application No. 2020901800 entitled "Therapeutic methods and agents" filed 1 June 2020 and Australian Provisional Application No. 2020901854 entitled "Therapeutic methods and agents" filed 5 June 2020, the contents of each of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] This disclosure relates generally to methods and agents for treating or preventing a disease associated with a virus infection, and in particular infection with a coronavirus. More particularly, the present disclosure relates to the use of CD14 antagonist antibodies for treating or preventing disease associated with a coronavirus infection. The disclosure also relates to methods and agents for treating or preventing coagulopathies.

BACKGROUND OF THE INVENTION

[0003] Coronaviruses, which are enveloped positive-sense RNA viruses characterized by club-like spikes that project from their surface, have been the source of many of the recent pandemics and smaller outbreaks that have had significant health and economic impacts. These include, for example, Middle East respiratory syndrome coronavirus (MERS-CoV), which causes Middle East respiratory syndrome (MERS); severe acute respiratory syndrome coronavirus (SARS-CoV), which causes severe acute respiratory syndrome (SARS); and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19).

[0004] The COVID-19 pandemic has led to more than 360,000 deaths worldwide to 1 June 2020, from nearly 6 million confirmed infections. The severity of COVID-19 ranges from asymptomatic infection (estimated to be around 80% of infected individuals) to critical illness. The Chinese Center for Disease Control and Prevention reported that 14% of infected individuals developed severe disease (with dyspnoea, hypoxia or greater than 50% lung involvement on imaging tests) and 5% developed critical disease (characterized by respiratory failure, systemic shock or multi- organ failure). It has been estimated that up to one third of hospitalized patients require mechanical ventilation in an intensive care unit, and mortality among those that are ventilated is approximately 80%. [0005] One of the notable characteristics of COVID-19 is the complexity and heterogeneity of the disease, and the number of organs that it affects. SARS-CoV-2 typically enters the subject by the nose and/or throat, where it can attach to the cell surface receptor angiotensin-converting enzyme 2 (ACE2) and enter the cell. As the virus multiplies in the early phase, symptoms may be absent or may include fever, dry cough, loss of smell or taste, and sore throat, for example. If the infection progresses and the virus enters the lungs, the disease can worsen significantly, potentially resulting in sepsis, pneumonia and acute respiratory distress syndrome (ARDS), and requiring oxygen support and/or ventilation. In biopsy or autopsy studies, diffuse alveolar damage with the formation of hyaline membranes, mononuclear cells, and macrophages infiltrating air spaces, and a diffuse thickening of the alveolar wall was observed (for review, see Li et al. 2020, Lancet 395: 1517-1520).

[0006] However, it is not only the lung that is affected in COVID-19. The disease appears to affect the brain, with some patients presenting with encephalitis, seizures, loss of consciousness, or stroke; the heart and blood vessels, with some patients presenting with blood clots, cardiac inflammation and scarring, or cardiac arrest; the liver, with liver dysfunction evidenced by elevated levels of alanine aminotransferase and aspartate aminotransferase (AST); and the kidneys, with kidney damage evidenced by high levels of protein in the urine, requiring dialysis in some instances.

[0007] SARS-CoV-2 infection results in coagulopathy in many patients, with the incidence of thrombotic complications estimated as being between 16-49% in patients with COVID-19 admitted to intensive care (Editorial, 2020, Lancet Haematology, 7:

E425). The coagulopathy associated with COVID-19, which is generally characterized by increased levels of D-dimers (fibrin degradation products) and fibrinogen, and coagulation abnormalities (e.g. prolongation of the prothrombin time) has been reported to be a combination of low-grade disseminated intravascular coagulation (DIC) and localised pulmonary thrombotic microangiopathy (Levi et al., 2020 Lancet Haematol.

2020 Jun; 7(6): e438-e440; Oudkerk et al. 2020 Radiology, 297: E216-E222). Increased levels of D-dimers are associated with poor prognosis, and the coagulation changes associated with COVID-19 suggest the presence of a hypercoagulable state that may increase the risk of thromboembolic complications (e.g. stroke, and pulmonary embolism). Microthrombi of the lungs, lower limbs, hands, brain, heart, liver and kidneys have been described in patients with COVID-19, and it is been suggested that respiratory failure in COVID-19 is not driven only by the development of ARDS alone, but that microvascular thrombotic processes may play a role as well. [0008] The complexity of COVID-19 is also apparent when considering the effect on children compared to adults. The risk of severe disease and death is highest in older adults and in those with underlying conditions such as hypertension, cardiac disease, chronic lung disease and cancer, and clinical manifestations of COVID-19 are generally milder in children compared with adults. However, some children do require hospitalisation, and a cohort of these present with a multisystem inflammatory condition (referred to as pediatric multisystem inflammatory syndrome (PIMS) or multisystem inflammatory syndrome in children (MIS-C)) with some features similar to those of Kawasaki disease and toxic shock syndrome (Viner and Whittaker, 2020, Lancet, 20:31129; Chiotos et al. 2020, J Ped Inf Dis Soc, 9(6):701-715). While these patients do not typically present with respiratory symptoms, they have fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes.

[0009] The precise mechanisms that ultimately result in the variety of symptoms observed in subjects with COVID-19 have not been fully elucidated. An excessive inflammatory response to SARS-CoV-2 has been postulated to be a cause of disease severity and death, and is associated with high levels of circulating cytokines, lymphopenia and mononuclear cell infiltration in the lungs, heart, spleen, lymph nodes and kidney. Proinflammatory cytokines and chemokines including tumour necrosis factor (TNF) a, interleukin 1b (IL-1β), IL-6, granulocyte-colony stimulating factor, interferon gamma-induced protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory proteins 1-α are significantly elevated in COVID-19 patients, and some have postulated that this "cytokine storm" plays an important role in the immunopathology of COVID-19. However, targeting some of these cytokines, such as IL- 6, for the treatment of COVID-19 has had mixed results (Xu et al. 2020, Proc. Natl Acad. Sci. USA, 117 (20) 10970-10975; Gritti, G. et al. 2020 medRxiv doi.org/10.1101/2020.04.01.20048561), illustrating the complexity of the disease.

[0010] Accordingly, there remains a need for additional agents and methods for treating disease caused by coronavirus infection.

SUMMARY OF THE INVENTION

[0011] In one aspect, provided is a method for treating a disease associated with a coronavirus infection in a human subject, comprising, consisting or consisting essentially of administering an effective amount of a CD14 antagonist antibody to the subject. In some examples, the disease is characterized by systemic inflammatory response syndrome or sepsis. In further examples, the disease is characterized by hypercoagulopathy, multi-organ failure, pneumonia, adult respiratory distress syndrome (ARDS), and/or a pediatric multisystem inflammatory syndrome. In particular examples, the coronavirus is SARS-CoV-2 and the disease is COVID-19.

[0012] In some embodiments, administration of the CD14 antagonist antibody increases lung function, increases liver function, increases kidney function, reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time.

[0013] Also provided is a method for treating an inflammation-induced hypercoagulopathy in a human subject, comprising, consisting or consisting essentially of administering an effective amount of a CD14 antagonist antibody to the subject. In some embodiments, administration of the CD14 antagonist antibody reduces levels of D- dimers, reduces levels of fibrinogen, and/or reduces prothrombin time.

[0014] In some examples, the CD14 antagonist antibody is administered systemically.

[0015] Also provided is use of a CD14 antagonist antibody for the preparation of a medicament for treating a disease associated with a coronavirus infection in a human subject. In some examples, the disease is characterized by systemic inflammatory response syndrome or sepsis. In further examples, the disease is characterized by hypercoagulopathy, multi-organ failure, pneumonia, adult respiratory distress syndrome (ARDS), and/or a pediatric multisystem inflammatory syndrome. In particular examples, the coronavirus is SARS-CoV-2 and the disease is COVID-19.

[0016] In some examples, the medicament increases lung function, increases liver function, increases kidney function, reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time in the subject.

[0017] Also provided is use of a CD14 antagonist antibody for the preparation of a medicament for treating an inflammation-induced hypercoagulopathy in a human subject. In some examples, the medicament reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time in the subject.

[0018] In the methods and uses of the present disclosure, the CD14 antagonist antibody may be selected from:

(i) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence [SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises

the sequence

[SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence

[SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 11] (3C10 H-CDR2); and H- CDR3 comprises the sequence

[SEQ ID NO: 12] (3C10 H-CDR3);

(ii) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 15] (28C5 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence

[SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (28C5 H-CDR2); and H- CDR3 comprises the sequence

[SEQ ID NO: 18] (28C5 H-CDR3);

(iii) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 27] (IC14 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence

[SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (IC14 H-CDR2); and H- CDR3 comprises the sequence

[SEQ ID NO: 18] (IC14 H-CDR3); and

(iv) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence

[SEQ ID NO: 22] (18E12 H-CDR1); H- CDR2 comprises the sequence [SEQ ID NO: 23] (18E12 H-CDR2);

and H-CDR3 comprises the sequence

[SEQ ID NO: 24] (18E12 H-CDR3).

[0019] In other examples, the CD14 antagonist antibody is selected from:

(i) an antibody comprising: a VL domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 1] (3C10 VL); and

a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 2] (3C10 VH);

(ii) an antibody comprising: a VL domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 3]

(28C5 VL); and a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 4] (28C5 VH); and

(iii) an antibody comprising: a VL domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 25] (IC14 VL); and a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 26] (IC14 VH); and

(iv) an antibody comprising : a VL domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 5] (18E12 VL); and

a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 6] (18E12 VH).

[0020] In particular examples, the CD14 antagonist antibody is humanized or chimeric.

[0021] In one embodiment, the CD14 antagonist antibody comprises a light chain and a heavy chain, wherein: the light chain comprises the amino acid sequence:

[SEQ ID NO: 28]; and the heavy chain comprises the amino acid sequence:

[SEQ ID NO: 29].

[0022] In some embodiments, the CD14 antagonist antibody or medicament is administered in a single dose.

[0023] In other embodiments, the CD14 antagonist antibody or medicament is administered in multiple doses (e.g. every 1, 2, 3, 4, 5, 6, 7 or 8 days; or every 2, 3, 4, or 5 weeks).

[0024] In some examples, the CD14 antagonist antibody or medicament is administered in combination with (e.g. simultaneously or sequentially) an ancillary agent (e.g. an antiviral, an anti-inflammatory, or an anti-malarial).

DETAILED DESCRIPTION OF THE INVENTION

1. Definitions

[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0026] The articles "a" and "an" are used herein to refer to one or to more than one (/.e., to at least one) of the grammatical object of the article. By way of example,

"an element" means one element or more than one element. [0027] As used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0028] The terms "active agent" and "therapeutic agent" are used interchangeably herein and refer to agents that prevent, reduce or amelioriate at least one symptom of a disease or disorder.

[0029] The terms "administration concurrently" or "administering concurrently" or "co-administering" and the like refer to the administration of a single composition containing two or more agents, or the administration of each agent as separate compositions and/or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such agents are administered as a single composition. By "simultaneously" is meant that the agents are administered at substantially the same time, and desirably together in the same formulation. By "contemporaneously" it is meant that the agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful. However, it will often be the case that when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and suitably within less than about one to about four hours. When administered contemporaneously, the agents are suitably administered at the same site on the subject. The term "same site" includes the exact location, but can be within about 0.5 to about 15 centimeters, preferably from within about 0.5 to about 5 centimeters. The term "separately" as used herein means that the agents are administered at an interval, for example at an interval of about a day to several weeks or months. The agents may be administered in either order. The term "sequentially" as used herein means that the agents are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks. If appropriate the agents may be administered in a regular repeating cycle.

[0030] The term "antagonist antibody" is used in the broadest sense, and includes an antibody that inhibits or decreases the biological activity of an antigen to which the antibody binds (e.g., CD14). For example, an antagonist antibody may partially or completely block interaction between a receptor (e.g., CD14) and a ligand (e.g., a DAMP or PAMP), or may practically decrease the interaction due to tertiary structure change or down regulation of the receptor. Thus, a CD14 antagonist antibody encompasses antibodies that bind to CD14 and that block, inhibit, nullify, antagonize, suppress, decrease or reduce (including significantly), in any meaningful degree, a CD14 agonist activity, including activation of downstream pathways such as Toll-like receptor (TLR) signaling pathways ( e.g ., TLR4 signaling pathway) and the TIR-domain-containing adapter-inducing IFN-β (TRIF) pathway, or elicitation of a cellular response (e.g., production of pro-inflammatory mediators including pro-inflammatory cytokines) to CD14 binding by a CD14 ligand (e.g., a DAMP or PAMP).

[0031] The term "antibody" herein is used in the broadest sense and specifically covers naturally occurring antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, or any other antigen-binding molecule so long as they exhibit the desired immuno-interactivity. A naturally occurring "antibody" includes within its scope an immunoglobulin comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised specific CH domains (e.g., CH1, CH2 and CH3). Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementary determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed 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 constant regions of the antibodies may mediate the binding of an immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), subclass or modified version thereof (e.g., IgG1 isotype, which carries L234A and L235A double mutations (igG1-LALA)). The antibodies can be of any species, chimeric, humanized or human. In other embodiments, the antibody is a homomeric heavy chain antibody (e.g., camelid antibodies) which lacks the first constant region domain (CH1) but retains an otherwise intact heavy chain and is able to bind antigens through an antigen-binding domain. The variable regions of the heavy and light chains in the antibody-modular recognition domain (MRD) fusions will contain a functional binding domain that interacts with an antigen of interest.

[0032] The "variable domain" (variable domain of a light chain (VL), variable domain of a heavy chain (VH)) as used herein denotes each of the pair of light and heavy chain domains which are involved directly in binding the antibody to the antigen. The variable light and heavy chain domains have the same general structure and each domain comprises four FRs whose sequences are widely conserved, connected by three CDRs or "hypervariable regions". The FRs adopt a β-sheet conformation and the CDRs may form loops connecting the β-sheet structure. The CDRs in each chain are held in their three-dimensional structure by the FRs and form together with the CDRs from the other chain the antigen binding site.

[0033] The term "antigen-binding portion" when used herein refer to the amino acid residues of an antibody which are responsible for antigen-binding generally, which generally comprise amino acid residues from the CDRs. Thus, "CDR" or "complementarity determining region" (also referred to as "hypervariable region") are used interchangeably herein to refer to the amino acid sequences of the light and heavy chains of an antibody which form the three-dimensional loop structure that contributes to the formation of an antigen binding site. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated "CDR1", "CDR2", and "CDR3", for each of the variable regions. The term "CDR set" as used herein refers to a group of three CDRs that occur in a single variable region that binds the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat ( Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as "Kabat CDRs". Chothia and coworkers (Chothia and Lesk, 1987. J. Mot. Biol. 196: 901-917; Chothia et al., 1989. Nature 342: 877-883) found that certain sub- portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as "L1", "L2", and "L3", or "H1", "H2", and "H3", where the "L" and the "H" designate the light chain and the heavy chain regions, respectively. These regions may be referred to as "Chothia CDRs", which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995. FASEB J. 9: 133-139) and MacCallum (1996. J. Mol. Biol. 262(5): 732-745). Still other CDR boundary definitions may not strictly follow one of these systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. [0034] As used herein, the term "framework region" or "FR" refers to the remaining sequences of a variable region minus the CDRs. Therefore, the light and heavy chain variable domains of an antibody comprise from N- to C-terminus the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDRs and FRs are typically determined according to the standard definition of Kabat, E. A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991) and/or those residues from a "hypervariable loop".

[0035] As used herein, the terms "light chain variable region" ("VL") and "heavy chain variable region" (VH) refer to the regions or domains at the N-terminal portion of the light and heavy chains respectively which have a varied primary amino acid sequence for each antibody. The variable region of an antibody typically consists of the amino terminal domain of the light and heavy chains as they fold together to form a three- dimensional binding site for an antigen. Several subtypes of VH and VL, based on structural similarities, have been defined, for example as set forth in the Kabat database.

[0036] The term "chimeric antibody" refers to antibodies that comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.

[0037] "Flumanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Thus, the FRs and CDRs of a humanized antibody need not correspond precisely to the parental (i.e., donor) sequences, e.g., a donor antibody CDR or the consensus framework may be mutagenized by substitution, insertion, and/or deletion of at least one amino acid residue so that the CDR or FR at that site does not correspond to either the donor antibody or the consensus framework. Typically, such mutations, however, will not be extensive and will generally avoid "key residues" involved in binding to an antigen. Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region in the consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (see, for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, 1987)). A "consensus immunoglobulin sequence" may thus comprise a "consensus framework region(s)" and/or a "consensus CDR(s)". In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non- human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will generally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al. (1986. Nature 321:522- 525), Riechmann et al. (1988. Nature 332:323-329) and Presta (1992. Curr. Op. Struct. Biol. 2:593-596). A humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including without limitation IgG1, IgG2, IgG3, and IgG4. A humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains may be selected to optimize desired effector functions using techniques well known in the art. As used herein, the term "key residue" refers to certain residues within the variable region that have more impact on the binding specificity and/or affinity of an antibody, in particular a humanized antibody. A key residue includes, but is not limited to, one or more of the following: a residue that is adjacent to a CDR, a potential glycosylation site (can be either N- or O-glycosylation site), a rare residue, a residue capable of interacting with the antigen, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region, a residue within the Vernier zone, and a residue in the region that overlaps between the Chothia definition of a variable heavy chain CDR1 and the Kabat definition of the first heavy chain framework.

[0038] As used herein, "Vernier" zone refers to a subset of framework residues that may adjust CDR structure and fine-tune the fit to antigen as described by Foote and Winter (1992. J. Mol. Biol. 224: 487-499). Vernier zone residues form a layer underlying the CDRs and may impact on the structure of CDRs and the affinity of the antibody.

[0039] As used herein, the term "canonical" residue refers to a residue in a CDR or framework that defines a particular canonical CDR structure as defined by Chothia et al. (1987. J. Mol. Biol. 196: 901-917; 1992. J. Mol. Biol. 227: 799-817), both are incorporated herein by reference). According to Chothia et al., critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.

[0040] As used herein, the terms "donor" and "donor antibody" refer to an antibody providing one or more CDRs to an "acceptor antibody". In some embodiments, the donor antibody is an antibody from a species different from the antibody from which the FRs are obtained or derived. In the context of a humanized antibody, the term "donor antibody" refers to a non-human antibody providing one or more CDRs.

[0041] As used herein, the terms "acceptor" and "acceptor antibody" refer to an antibody providing at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the FRs. In some embodiments, the term "acceptor" refers to the antibody amino acid sequence providing the constant region(s). In other embodiments, the term "acceptor" refers to the antibody amino acid sequence providing one or more of the FRs and the constant region(s). In specific embodiments, the term "acceptor" refers to a human antibody amino acid sequence that provides at least 80%, preferably, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the FRs. In accordance with this embodiment, an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues that does (do) not occur at one or more specific positions of a human antibody. An acceptor framework region and/or acceptor constant region(s) may be, for example, derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well-known in the art, antibodies in development, or antibodies commercially available).

[0042] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. Flowever, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. [0043] The terms "heavy chain variable region CDR1" and "H-CDR1" are used interchangeably, as are the terms "heavy chain variable region CDR2" and "H-CDR2", the terms "heavy chain variable region CDR3" and "H-CDR3", the terms "light chain variable region CDR1" and "L-CDR1"; the terms "light chain variable region CDR2" and "L-CDR2" and the terms "light chain variable region CDR3" and "L-CDR3" antibody fragment. Throughout the specification, complementarity determining regions ("CDR") are defined according to the Kabat definition unless specified otherwise. The Kabat definition is a standard for numbering the residues in an antibody and it is typically used to identify CDR regions (Kabat et al., (1991), 5th edition, NIH publication No. 91-3242).

[0044] Antigen binding can be performed by "fragments" or "antigen-binding fragments" of an intact antibody. Herein, both terms are used interchangeably. Examples of binding fragments encompassed within the term "antibody fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single domain antibody (dAb) fragment (Ward et al., 1989. Nature 341:544- 546), which consists of a VH domain; and an isolated complementary determining region (CDR). In a particular embodiment, the antibody of the present disclosure is an antigen- binding fragment that lacks all or a portion of the Fc region.

[0045] A "single chain variable Fragment (scFv)" is a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1988. Science 242:423-426; and Huston et al., 1988. Proc. Natl. Acad. Sci. 85:5879-5883). Although the two domains VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by an artificial peptide linker that enables them to be made as a single protein chain. Such single chain antibodies include one or more antigen binding moieties. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0046] The term "monoclonal antibody" and abbreviations "MAb" and "mAb", as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each mAb is directed against a single determinant on the antigen. The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. Monoclonal antibodies may be produced, for example, by a single clone of antibody- producing cells, including hybridomas. The term "hybridoma" generally refers to the product of a cell-fusion between a cultured neoplastic lymphocyte and a primed B- or T- lymphocyte which expresses the specific immune potential of the parent cell.

[0047] An antibody "that binds" an antigen of interest ( e.g ., CD14) is one that binds the antigen with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins. In such embodiments, the extent of binding of the antibody to a "non-target" protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined, for example, by fluorescence activated cell sorting (FACS) analysis, enzyme- linked immunosorbent assay (ELISA), immunoprecipitation or radioimmunoprecipitation (RIA). Thus, an antibody that antagonizes CD14 suitably inhibits or decreases production of pro-inflammatory mediators, including pro-inflammatory cytokines/chemokines. With regard to the binding of an antibody to a target molecule, the term "specific binding" or "specifically binds to" or is "specific for" a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non- specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The specific region of the antigen to which the antibody binds is typically referred to as an "epitope". The term "epitope" broadly includes the site on an antigen which is specifically recognized by an antibody or T-cell receptor or otherwise interacts with a molecule. Generally epitopes are of active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and generally may have specific three-dimensional structural characteristics, as well as specific charge characteristics. As will be appreciated by one of skill in the art, practically anything to which an antibody can specifically bind could be an epitope.

[0048] The term "Acute Respiratory Distress Syndrome" or ARDS refers to an acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue with hypoxemia and bilateral radiographic opacities, associated with increased venous admixture, increased physiological dead space and decreased lung compliance. ARDS may be defined by, for example, the following criteria: acute, with onset over 1 week or less; bilateral opacities consistent with pulmonary edema must be present; they may be detected on CT or chest radiograph; PF ratio <300mmHg with a minimum of 5 cmH20 PEEP; must not be fully explained by cardiac failure or fluid overload, in the physician's best estimation using available information — an "objective assessment" (e.g. echocardiogram) should be performed in most cases if there is no clear cause such as trauma or sepsis.

[0049] Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. Thus, use of the term "comprising" and the like indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0050] The term "characterized by" with reference to a disease and a symptom or presentation means that the symptom or presentation (e.g. headache, cough, shortness of breath (dyspnea), tachychardia, pneumonia, systemic inflammatory response syndrome, sepsis, hypercoagulopathy, multi-organ failure, adult respiratory distress syndrome (ARDS), a pediatric multisystem inflammatory syndrome) is a characteristic of the disease. It is understood that the symptom or presentation need not be observed in all subjects with the disease (i.e. not all subjects with the disease will develop the symptom or presentation), but that at least some subjects with the disease will have the symptom or presentation. In some instances, subjects in a particular cohort may be more likely to exhibit the symptom or presentation, e.g. subjects of a certain age, or with certain underlying conditions.

[0051] The phrase "disease associated with a coronavirus infection" means a disease or condition in a subject that results from, or is caused by, infection of the subject with a coronavirus. The disease or condition may be characterized by one or multiple symptoms or presentations, such as for example, headache, cough, shortness of breath (dyspnea), tachychardia, pneumonia, systemic inflammatory response syndrome, sepsis, hypercoagulopathy, multi-organ failure, adult respiratory distress syndrome (ARDS), a pediatric multisystem inflammatory syndrome. For example, COVID-19 is a disease associated with SARS-CoV-2 infection; SARS is a disease associated with SARS- CoV infection; and MERS is a disease associated with MERS-CoV infection.

[0052] The term "hypercoagulopathy" refers to a condition in which the ability of the blood to coagulate is increased or elevated, and may be characterised by, for example, prolonged prothrombin time, elevated levels of D-dimer and/or fibrinogen. An "inflammation-induced hypercoagulopathy" refers to a hypercoagulopathy that is associated with inflammation, and is typically initiated or induced by tissue factor (TF)- expressing inflammatory monocytes (such as those recruited by activated endothelial cells) in response to mediators such as tumor necrosis factor-α (TNF-α) or other inflammatory cytokines, lipoproteins, C-reactive protein (CRP), or bacterial endotoxins. Inflammation-induced hypercoagulopathy includes, for example, hypercoagulopathy resulting from infection or sepsis (sepsis-induced coagulopathy or sepsis-induced disseminated intravascular coagulation (DIC)), pancreatitis, trauma, immune-mediated diseases, and neoplasia (e.g. as reviewed in, for example, Beristain-Covarrubias et al. (2019) Front. Immunol. 10:2569; Simmons and Pittet, 2015, Curr Opin Anaesthesiol. 28(2): 227-236; Dumnicka et al. 2017, Int J Mol Sci. 18(2): 354).

[0053] The term "D-dimer" refers to a degradation product of cross-linked fibrin, and reflects blood clot formation and its subsequent fibrinolysis. Assessment of D- dimer levels in a subject can be performed using, for example, an enzyme-linked immunoabsorbent assay (ELISA) or microlatex agglutination assay (Riley et al. 2016, Lab Med 2016;47:90-102).

[0054] By "effective amount", in the context of treating a disease or condition is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and/or treating existing symptoms, of that condition. The effective amount will vary depending upon the age, health and physical condition of the individual to be treated and whether symptoms of disease are apparent, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the subject. Optimum dosages may vary depending on the relative potency in an individual subject, and can generally be estimated based on EC50 values found to be effective in in vitro and in vivo animal models. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.

[0055] An "increased level" or grammatical variations thereof in reference to of D-dimer or fibrinogen refers to an increase in the amount or concentration of D-dimer or fibrinogen in a sample, such as a biological sample, such as blood or serum, compared to a suitable control, e.g. a biological sample from a healthy subject. The increase may be, for example, an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 160%, 180%, 200%, 250%, 300% or more. Typically, the increase is a statistically significant increase.

[0056] The terms "reduce", "reducing", "decrease" or "decreasing" and the like, in relation to the level or concentration of D-dimer or fibrinogen in a biological sample refers to at least a small but measurable reduction in the level or amount of D-dimer, such as following administration of an anti-CD14 antagonist antibody, compared to a suitable control. Typically, the reduction is a statistically significant reduction. In embodiments, the level or concentration of D-dimer is inhibited or decreased by at least 20%, 30%, 40%, 50%, 60%, 70% 80% or more. Suitable controls may include, for example, a baseline level or concentration of D-dimer or fibrinogen in the same patient, a level or concentration of D-dimer or fibrinogen in the same patient at an earlier time- point (e.g. before a treatment), or a level or concentration of D-dimer or fibrinogen in another untreated patient.

[0057] By "isolated" is meant material that is substantially or essentially free from components that normally accompany it in its native state.

[0058] The term "ligand", as used herein, refers to any molecule which is capable of binding a receptor.

[0059] As used herein, a "pediatric multisystem inflammatory syndrome" refers to an inflammatory syndrome in children and adolescents that may be characterised by, for example, the following criteria: a) children and adolescents 0-19 years of age with fever > 3 days; b) two of the following: (i) rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet); (ii) hypotension or shock; (iii) features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP); (iv) evidence of coagulopathy (by PT, PTT, elevated d-Dimers); (v) acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain); c) elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin; d) no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes; and e) evidence or likely contact with a coronavirus, e.g. SARS-CoV-2 or other coronavirus that is characterized by SIRS or sepsis.

[0060] By "pharmaceutically acceptable carrier" is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, transfection agents and the like.

[0061] Similarly, a "pharmacologically acceptable" salt, ester, amide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.

[0062] The terms "polynucleotide," "genetic material," "genetic forms," "nucleic acids" and "nucleotide sequence" include RNA, cDNA, genomic DNA, synthetic forms and mixed polymers, both sense and antisense strands, and may be chemically or biochemically modified or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those skilled in the art.

[0063] The term "pro-inflammatory mediator" means an immunoregulatory agent that favors inflammation. Such agents include, cytokines such as chemokines, interleukins (IL), lymphokines, and tumor necrosis factor (TNF) as well as growth factors. In specific embodiments, the pro-inflammatory mediator is a "pro-inflammatory cytokine". Typically, pro-inflammatory cytokines include IL-1α, IL-1β, IL-6, and TNF-α, which are largely responsible for early responses. Other pro-inflammatory mediators include LIF, IFN-γ, IFN-β, IFN-α, OSM, CNTF, TGF-β, GM-CSF, TWEAK, IL-11, IL-12, IL- 15, IL-17, IL-18, IL-19, IL-20, IL-8, IL-16, IL-22, IL-23, IL-31 and IL-32 (Tato et al., 2008. Cell 132:900; Cell 132:500, Cell 132:324). Pro-inflammatory mediators may act as endogenous pyrogens (IL- 1, IL-6, IL-17, TNF-α), up-regulate the synthesis of secondary mediators and pro-inflammatory cytokines by both macrophages and mesenchymal cells (including fibroblasts, epithelial and endothelial cells), stimulate the production of acute phase proteins, or attract inflammatory cells. In specific embodiments, the term "pro-inflammatory cytokine" relates to TNF-α, IL- 1 α, IL-6, IFNβ, IL-1β, IL-8, IL-17 and IL-18.

[0064] As used herein, the term "systemic inflammatory condition" refers to a disease or condition comprising a systemic inflammatory response. In some embodiments, the term encompasses systemic inflammatory response syndrome (SIRS), which may be infectious (i.e., sepsis) or non-infectious (i.e., sterile) in etiology. In some embodiments, the systemic inflammatory condition is pulmonary sepsis.

[0065] As used herein, the term SIRS ("systemic inflammatory response syndrome") refers to a clinical response arising from a non-specific insult, typically from a noxious stressor (e.g., infection, trauma, surgery, acute inflammation, ischemia or reperfusion, or malignancy), with two or more of the following measurable clinical characteristics: fever or hypothermia (temperature of 38.0° C (100.4° F) or more, or temperature of 36.0° C (96.8° F.) or less); tachycardia (at least 90 beats per minute); tachypnea (at least 20 breaths per minute or PaCC >2 less than 4.3 kPa (32.0 mm Hg) or the need for mechanical ventilation); and an altered white blood cell (WBC) count of 12 x 10⁶ cells/mL or more, or an altered WBC count of 4 x 10⁶ cells /mL or less, or the presence of more than 10% band forms (immature neutrophils). The SIRS may be sterile (e.g., resulting from trauma, surgery, acute inflammation, ischemia or reperfusion, or malignancy) or associated with an infection (e.g., a bacterial, viral, fungal, or parasitic infection).

[0066] As used herein, the term "sepsis" refers to the systemic inflammatory condition that occurs as a result of infection which may be a bacterial, viral, fungal or parasitic infection. In some embodiments, the infection is a viral infection (e.g., a coronavirus infection). "Sepsis" may be characterized as mild sepsis, severe sepsis (sepsis with acute organ dysfunction), septic shock (sepsis with refractory arterial hypotension), organ failure, multiple organ dysfunction syndrome and death.

[0067] "Mild sepsis" can be defined as the presence of sepsis without organ dysfunction.

[0068] "Severe sepsis" can be defined as the presence of sepsis and at least one of the following manifestations of organ hypoperfusion or dysfunction: hypoxemia, metabolic acidosis, oliguria, lactic acidosis, or an acute alteration in mental status without sedation. Organ hypoperfusion or dysfunction is defined as a Sequential Organ Failure Assessment (SOFA) score ≥ 2 for the organ in question.

[0069] "Septic shock" can be defined as the presence of sepsis accompanied by a sustained decrease in systolic blood pressure (90 mm Hg or less, or a drop of at least 40 mm Hg from baseline systolic blood pressure) despite fluid resuscitation, and the need for vasoactive amines to maintain adequate blood pressure.

[0070] The term "sepsis" may include pulmonary sepsis. As used herein, the term "pulmonary sepsis" refers to infection (e.g., a viral infection, suitably a coronavirus infection) in the thoracic cavity, primarily affecting the lung and pleural space (for example, but not restricted to pneumonia, lung abscess, empyema, mediastinitis, tracheobronchitis); causing organ dysfunction. Organ hypoperfusion or dysfunction is defined as a Sequential Organ Failure Assessment (SOFA) score ≥ 2 for the organ in question.

[0071] As used herein, the term "systemic administration" or "administered systemically" or "systemically administered" means introducing an agent into a subject outside of the central nervous system. Systemic administration encompasses any route of administration other than direct administration to the spine or brain. As such, it is clear that intrathecal and epidural administration as well as cranial injection or implantation, are not within the scope of the terms "systemic administration", "administered systemically" or "systemically administered". An agent ( e.g . an antibody) or pharmaceutical composition as described herein can be systemically administered in any acceptable form such as in a tablet, liquid, capsule, powder, or the like; by intravenous, intraperitoneal, intramuscular, subcutaneous or parenteral injection; by transdermal diffusion or electrophoresis; and by minipump or other implanted extended release device or formulation. According to some embodiments, systemic administration is carried out by a route selected from the group consisting of intraperitoneal, intravenous, subcutaneous and intranasal administration, and combinations thereof.

[0072] The terms "subject", "patient" and "individual" used interchangeably herein, refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, (e.g. human) with a coronavirus infection or a coagulopathy.

[0073] As used herein, the terms "treatment", "treating", and the like, refer to obtaining a desired pharmacologic and/or physiologic effect in a subject in need of treatment, that is, a subject who has a disease associated with a coronavirus infection or a subject with an inflammation-induced hypercoagulopathy. By "treatment" is meant ameliorating or preventing one or more symptoms of the disease associated with a coronavirus infection or the inflammation-induced hypercoagulopathy. Reference to "treatment", "treat" or "treating" does not necessarily mean to reverse or prevent any or all symptoms. For example, the subject may ultimately suffer one or more symptoms, but the number and/or severity of the symptoms is reduced and/or the quality of life is improved compared to prior to treatment.

[0074] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise. 2. CD14 antagonist antibodies

[0075] The present disclosure provides methods, uses and compositions that include a CD14 antagonist antibody for treating a disease associated with a coronavirus infection. The present disclosure also provides methods, uses and compositions that include a CD14 antagonist antibody for treating a disease associated with a coagulopathy, such as an inflammation-induced hypercoagulopathy.

[0076] The present disclosure contemplates any CD14 antagonist antibody that binds to CD14 ( e.g . mCD14 or sCD14) and blocks the binding of a DAMP or PAMP to CD14 and/or that binds to CD14 and inhibits or decreases a CD14 agonist-mediated response resulting in the production of pro-inflammatory mediators, including the production of pro-inflammatory cytokines. In some embodiments, a CD14 antagonist antibody of the present invention inhibits binding of a CD14 agonist, suitably a DAMP or PAMP, to CD14 thus inhibiting or decreasing the production of pro-inflammatory cytokines. In illustrative examples of this type, the CD14 antagonist antibody is selected from the 3C10 antibody that binds an epitope comprised in at least a portion of the region from amino acid 7 to amino acid 14 of human CD14 (van Voohris et al., 1983. J. Exp. Med. 158: 126-145; Juan et al., 1995. J. Biol. Chem. 270(29): 17237-17242), the MEM-18 antibody that binds an epitope comprised in at least a portion of the region from amino acid 57 to amino acid 64 of CD14 (Bazil et al., 1986. Eur. J. Immunol.

16(12): 1583-1589; Juan et al., 1995. J. Biol. Chem. 270(10): 5219-5224), the 4C1 antibody (Adachi et al., 1999. J. Endotoxin Res. 5: 139-146; Tasaka et al., 2003. Am. J. Respir. Cell. Mol. Biol.) 2003. 29(2): 252-258), as well as the 28C5 and 23G4 antibodies that inhibit binding of LPS and suppress production of pro-inflammatory cytokines, and the 18E12 antibody that partly inhibits binding of LPS and suppresses production of pro- inflammatory cytokines (U.S. Patent Nos. 5,820,858, 6,444,206 and 7,326,569 to Leturcq et al.). In some embodiments, a CD14 antagonist antibody of the present disclosure inhibits binding of CD14 to a TLR such as TLR4, thereby blocking CD14-agonist mediated response, illustrative examples of which include the F1024 antibody disclosed in International Publication WO2002/42333. Each of the above references relating to CD14 antagonist antibodies is incorporated herein by reference in its entirety. The CD14 antagonist antibody may be a full-length immunoglobulin antibody or an antigen-binding fragment of an intact antibody, representative examples of which include a Fab fragment, a F(ab')2 fragment, an Fd fragment consisting of the VH and CH1 domains, an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, a single domain antibody (dAb) fragment (Ward et al., 1989. Nature 341:544-546), which consists of a VH domain; and an isolated CDR. Suitably, the CD14 antagonist antibody is a chimeric, humanized or human antibody.

[0077] In some embodiments, the CD14 antagonist antibody is selected from the antibodies disclosed in U.S. Pat. No. 5,820,858:

[0078] (1) an antibody comprising: a VL domain comprising, consisting or consisting essentially of the sequence:

[SEQ ID NO: 1]

(3C10 VL); and a VH domain comprising, consisting or consisting essentially of the sequence:

[SEQ ID NO: 2]

(3C10 VH);

[0079] (2) an antibody comprising: a VL domain comprising, consisting or consisting essentially of the sequence:

[SEQ ID NO: 3] (28C5 VL); and a VH domain comprising, consisting or consisting essentially of the sequence:

[SEQ ID NO: 4] (28C5 VH); and

[0080] (3) an antibody comprising: a VL domain comprising, consisting or consisting essentially of the sequence:

[SEQ ID NO: 5] (18E12 VL); and a VH domain comprising, consisting or consisting essentially of the sequence:

[SEQ ID NO: 6] (18E12 VH);

[0081] Also contemplated are antibodies that comprise the VL and VH CDR sequences of the above antibodies and related antibodies, representative embodiments of which include: (1) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 7] (3C10 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 11] (3C10 H-CDR2); and H- CDR3 comprises the sequence

[SEQ ID NO: 12] (3C10 H-CDR3);

(2) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 13] (28C5 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (28C5 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (28C5 H-CDR2); and H- CDR3 comprises the sequence

[SEQ ID NO: 18] (28C5 H-CDR3);

(3) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 13] (IC14 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (IC14 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (IC14 H-CDR2); and H- CDR3 comprises the sequence

[SEQ ID NO: 18] (IC14 H-CDR3);and

(4) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising an L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 19] (18E12 L-CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 20] (18E12 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 24] (18E12 H-CDR3).

[0082] In some embodiments, the CD14 antagonist antibody is humanized. In illustrative examples of this type, the humanized CD14 antagonist antibodies suitably comprise a donor CDR set corresponding to a CD14 antagonist antibody ( e.g ., one of the CD14 antagonist antibodies described above), and a human acceptor framework. The human acceptor framework may comprise at least one amino acid substitution relative to a human germline acceptor framework at a key residue selected from the group consisting of: a residue adjacent to a CDR; a glycosylation site residue; a rare residue; a canonical residue; a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and a residue in a region that overlaps between a Chothia-defined VH CDR1 and a Kabat-defined first heavy chain framework. Techniques for producing humanized mAbs are well known in the art (see, for example, Jones et al., 1986. Nature 321: 522-525; Riechmann et al. 1988. Nature 332:323-329; Verhoeyen et al., 1988. Science 239: 1534-1536; Carter et al., 1992. Proc. Natl. Acad. Sci. USA 89: 4285-4289; Sandhu, JS., 1992. Crit. Rev. Biotech. 12: 437-462, and Singer et al., 1993. J. Immunol. 150: 2844-2857). A chimeric or murine monoclonal antibody may be humanized by transferring the mouse CDRs from the heavy and light variable chains of the mouse immunoglobulin into the corresponding variable domains of a human antibody. The mouse framework regions (FR) in the chimeric monoclonal antibody are also replaced with human FR sequences. As simply transferring mouse CDRs into human FRs often results in a reduction or even loss of antibody affinity, additional modification might be required in order to restore the original affinity of the murine antibody. This can be accomplished by the replacement of one or more human residues in the FR regions with their murine counterparts to obtain an antibody that possesses good binding affinity to its epitope. See, for example, Tempest et al. (1991. Biotechnology 9:266-271) and Verhoeyen et al. (1988 supra). Generally, those human FR amino acid residues that differ from their murine counterparts and are located close to or touching one or more CDR amino acid residues would be candidates for substitution.

[0083] In a preferred embodiment, the CD14 antagonist antibody is the IC14 antibody (Axtelle et al., 2001. J. Endotoxin Res. 7: 310-314; and U.S. Pat. Pub. No. 2006/0121574, which are incorporated herein by reference in their entirety) or an antigen-binding fragment thereof. The IC14 antibody is a chimeric (murine/human) monoclonal antibody that specifically binds to human CD14. The murine parent of this antibody is 28C5 noted above (see, Patent Nos. 5,820,858, 6,444,206 and 7,326,569 to Leturcq et al., and Leturcq et al., 1996. J. Clin. Invest. 98: 1533-1538). The IC14 antibody comprises a VL domain and a VH domain, wherein: the VL domain comprises the VL domain within the amino acid sequence:

[SEQ ID NO: 30]; and the VH domain comprises the VH domain within amino acid sequence:

[SEQ ID NO: 31] (i.e. the VL domain comprises the amino acid sequence:

[SEQ ID NO: 25]; and the VH domain comprises the amino acid sequence:

[SEQ ID NO: 26] .

[0084] The light chain of IC14 comprises the light chain within the amino acid sequence set forth in SEQ ID NO: 30 (i.e. comprises the amino acid sequence:

[SEQ ID NO: 28]; and the heavy chain of IC14 comprises the heavy chain within the amino acid sequence set forth in SEQ ID NO: 31 (i.e. comprises the amino acid sequence:

[SEQ ID NO: 29]). [0085] The IC14 L-CDR1, L-CDR2 and L-CDR3 are those within the sequence set forth in SEQ ID NO:30 (i.e. wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 13]; L-CDR2 comprises the sequence RASNLQS [SEQ ID NO: 14]; and L-CDR3 comprises the sequence

[SEQ ID NO: 27]); and the IC14 H-CDR1, H-CDR2 and H-CDR3 are those within the sequence set forth in SEQ ID NO:31 (i.e. wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16]; H- CDR2 comprises the sequence

[SEQ ID NO: 17]; and H-CDR3 comprises the sequence

[SEQ ID NO: 18]).

[0086] Additional antagonist antibodies of CD14 suitable for use in the methods herein can be identified by methods well known to those skilled in the art. These methods generally comprise determining whether an antibody is capable of directly antagonizing CD14. For example, the methods may involve determining whether an antibody is capable of inhibiting or decreasing the amount or agonist activity of CD14, wherein the ability to inhibit or decrease the amount or agonist activity of CD14 indicates that the antibody may be suitable for use in treating a disease associated with a coronavirus infection or an inflammation-induced hypercoagulopathy as described herein. In some embodiments, the antibody is contacted with CD14, or a cell that expresses CD14 on its surface, or a nucleic acid sequence from which CD14 is expressed, suitably in the presence of a CD14 agonist such as a DAMP or PAMP, wherein a decrease in the amount or agonist activity of CD14 in the presence of the agonist, when compared to a control, indicates that the antibody binds to CD14 and directly antagonizes CD14. A decrease or inhibition of CD14 agonist activity, includes for example inhibiting, or decreasing activation of, downstream pathways such as TLR signaling pathways ( e.g ., TLR4 signaling pathway) and the TRIF pathway, or elicitation of a cellular response (e.g., production of pro-inflammatory mediators including pro-inflammatory cytokines).

[0087] These methods may be carried out in vivo, ex vivo or in vitro. In particular, the step of contacting an antibody with CD14 or with a cell that expresses CD14 on its surface (e.g., immune cells) may be carried out in vivo, ex vivo or in vitro. The methods may be carried out in a cell-based or a cell-free system. For example, the method may comprise a step of contacting a cell expressing CD14 on its surface with an antibody and determining whether the contacting of the cell with the antibody leads to a decrease in the amount or agonist activity of CD14. In such a cell-based assay, the CD14 and/or the antibody may be endogenous to the host cell, may be introduced into a host cell or tissue, may be introduced into the host cell or tissue by causing or allowing the expression of an expression construct or vector or may be introduced into the host cell by stimulating or activating expression from an endogenous gene in the cell. In such a cell-based method, the amount of activity of CD14 may be assessed in the presence or absence of an antibody in order to determine whether the agent is altering the amount of CD14 in the cell, such as through regulation of CD14 expression in the cell or through destabilization of CD14 protein within the cell, or altering the CD14 agonist activity of the cell. The presence of a lower CD14 agonist activity or a decreased amount of CD14 on the cell surface in the presence of the antibody indicates that the antibody may be a suitable antagonist of CD14 for use in accordance with the present disclosure.

[0088] In some examples, it is further determined whether the antibody lacks substantial or detectable binding to another cellular component, suitably a binding partner of CD14, such as a CD14 binding partner that is either secreted ( e.g ., MD2) or located on the cell membrane (e.g., TLR4), to thereby determine that the antibody is a specific antagonist of CD14. In a non-limiting example of this type, the antibody is contacted in the presence of a CD14 agonist such as a DAMP or PAMP (1) with a wild- type cell that expresses CD14 on its surface (e.g., an immune cell such a macrophage), and (2) with a CD14 negative cell (e.g., an immune cell that is the same as in (1) but has a loss of function in the CD14 gene). If the antibody inhibits a CD14 agonist activity of the wild-type cell but not of the CD14 negative cell, this indicates that the antibody is a CD14 specific antagonist. Cells of this type may be constructed using routine procedures or animals.

[0089] In other examples, potential CD14 antagonist antibodies are assessed in vivo, such as, for example, in an animal model. In such an in vivo model, the effects of the antibody may be assessed in the circulation (e.g., blood), lung, liver, kidney, or the brain. In particular examples, models of coronavirus infection are used, e.g. models using hamsters, ferrets, cats, and nonhuman primates (Lakdawala and Menachaerry, 2020, Science 368:942-943).

[0090] Exemplary antagonist antibodies of CD14 effect a decrease in CD14 activity or levels of at least 5%, at least 10%, at least 25%, at least 50%, at least 60%, at least 75%, or at least 85% or more compared to in the absence of the antibody, in some examples, the antibody may result in a decrease in CD14 agonist activity or levels such that the agonist activity or level of CD14 is no longer detectable in the presence of the antibody. Such a decrease may be seen in the sample being tested or, for example where the method is carried out in an animal model.

[0091] Preferably, the antibody is a specific antagonist of CD14 as described above. However, this does not mean that a specific antagonist of CD14 has a complete absence of off-target antagonistic activity. In this regard, the specific antagonist of CD14 may have negligible or a minor direct binding and effect on other cellular components, such that the antagonism of the activity, signaling or expression of a non-CD14 cellular component, is less than less than 15%, less than 10%, less than 5%, less than 1%, or less than 0.1% of the direct binding and effect of that agent on the activity, signaling or expression of CD14.

[0092] Levels or amounts of CD14 may be measured by assessing expression of the CD14 gene. Gene expression may be assessed by looking at mRNA production or levels or at protein production or levels. Expression products such as mRNA and proteins may be identified or quantified by methods known in the art. Such methods may utilize hybridization to specifically identify the mRNA of interest. For example such methods may involve PCR or real-time PCR approaches. Methods to identify or quantify a protein of interest may involve the use of antibodies that bind that protein. For example, such methods may involve western blotting. Regulation of CD14 gene expression may be compared in the presence and absence of an antibody. Thus, antibodies can be identified that decrease CD14 gene expression compared to the level seen in the absence of the antibody. Such antibodies may be suitable antagonists of CD14 in accordance with the present disclosure.

[0093] The methods for identifying suitable antagonist antibodies for use in accordance with the present disclosure may assess the agonist activity of CD14. For example, such a method may be carried out using peripheral blood mononuclear cells. Such cells will produce cytokines such as IL-1 α, IL-6, TNF-α, IFN-β, IL-1β, IL-17 and IL- 8 on response to stimulation with, for example, LPS. Methods may therefore comprise combining peripheral blood mononuclear cells with the antibody or a vehicle and adding LPS. The cells may then be incubated for an amount of time ( e.g ., 24 hours) to allow the production of pro-inflammatory mediators such as cytokines. The level of cytokines such as IL-1α, IL-6, TNF-α, IFN-β, IL-1β, IL-17 and IL-8 produced by the cells in that time period can then be assessed. If the antibody has anti-CD14 properties, then the production of such cytokines should be reduced compared to the vehicle-treated cells.

3. Ancillary agents and interventions

[0094] The CD14 antagonist antibody may administered alone or in combination with other active agents (also referred to as "ancillary agents") or other interventions, such as agents and interventions useful for the treatment of a disease associated with a coronavirus infection. [0095] In one example, the ancillary agent is an antiviral, such as remdesivir, lopinavir, ritonavir, emtricitabine, tenofovir, ivermectin, faviparavir, imatininb and baricitinib, and combinations thereof (e.g. lopinavir/ritonavir, or emtricitabine/tenofovir).

[0096] In other examples, the ancillary agent is an anti-malarial, such as chloroquine/hydroxychloroquine.

[0097] In further examples, the ancillary agent is an anti-inflammatory, such as an inhibitor or antagonist of IL-6 or IL-6 receptor, IL-1 receptor, IL-1β, TNF, GM-CSF, IFN-γ, JAK-STAT signaling, CCR2, CCR5, complement component C5,IRAK4 and M-CSF receptor. The antagonist or inhibitor may be, for example, an antibody antagonist or a small molecule inhibitor.

[0098] Other ancillary agents include, but are not limited to, vitamin D, azithromycin, vitamin C, angiotensin 2 receptor blocker (e.g. telmisartan), aspirin, statin, colchicine, , dexamethasone, BCG vaccine, steroids, IVIG, and oxygen.

[0099] In another example, administration of the antibody is in conjunction with an intervention, such as a ventilator.

[00100] When combination therapy is desired, the CD14 antagonist antibody is administered separately, simultaneously or sequentially with one or more ancillary agents or interventions. In some embodiments, this may be achieved by administering, such as systemically, a single composition or pharmacological formulation that includes both types of agent, or by administering two separate compositions or formulations at the same time, wherein one composition includes the CD14 antagonist antibody and the other the ancillary agent. In other embodiments, the treatment with the CD14 antagonist antibody may precede or follow the treatment with the ancillary agent by intervals ranging from minutes to hours or even days or weeks.

[00101] In some situations, the antibody and ancillary agent are administered within about 1-12 hours of each other or within about 2-6 hours of each other. In other situations, it may be desirable to extend the time period for treatment significantly, however, where one or more days (e.g. 1, 2, 3, 4, 5, 6, 7 or 8 days) lapse between the respective administrations. In embodiments where the ancillary agent is administered separately to the CD14 antagonist antibody, it will be understood that the ancillary agent can be administered by a method which is different to that of the administration method used for the CD14 antagonist antibody, e.g. the ancillary agent may be administered systemically or directly to the CNS. [00102] Where two or more agents are administered to a subject "in conjunction" or "concurrently" they may be administered in a single composition at the same time, or in separate compositions at the same time, or in separate compositions separated in time.

4. Compositions

[00103] As described herein, the use of a CD14 antagonist antibody, whether alone or in combination with ancillary agents, can treat a disease associated with a coronavirus infection or treat an inflammation-induced hypercoagulopathy. The CD14 antagonist antibody and optionally the ancillary agent can be administered either by themselves or with a pharmaceutically acceptable carrier. Thus, also provided herein are compositions comprising a CD14 antagonist antibody for use in treating a disease associated with a coronavirus infection or an inflammation-induced hypercoagulopathy.

[00104] The CD14 antagonist antibodies may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, stabilizers or excipients (vehicles) to form a pharmaceutical composition as is known in the art, in particular with respect to protein active agents. Carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient ( e.g . patient) thereof. Suitable carriers typically include physiological saline or ethanol polyols such as glycerol or propylene glycol.

[00105] The antibody may be formulated as neutral or salt forms. Pharmaceutically acceptable salts include the acid addition salts (formed with free amino groups) and which are formed with inorganic acids such as hydrochloric or phosphoric acids, or such organic acids such as acetic, oxalic, tartaric and maleic. Salts formed with the free carboxyl groups may also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxides, and organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine and procaine.

[00106] The compositions may be suitably formulated for systemic administration, including intravenous, intramuscular, subcutaneous, or intraperitoneal administration and conveniently comprise sterile aqueous solutions of the antibody, which are preferably isotonic with the blood of the recipient. Such formulations are typically prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering said solution sterile. These may be prepared in unit or multi-dose containers, for example, sealed ampoules or vials. [00107] The compositions may incorporate a stabilizer, such as for example polyethylene glycol, proteins, saccharides (for example trehalose), amino acids, inorganic acids and admixtures thereof. Stabilizers are used in aqueous solutions at the appropriate concentration and pH. The pH of the aqueous solution is adjusted to be within the range of 5.0-9.0, preferably within the range of 6-8. In formulating the antibody, anti-adsorption agent may be used. Other suitable excipients may typically include an antioxidant such as ascorbic acid. The compositions may be formulated as controlled release preparations which may be achieved through the use of polymer to complex or absorb the proteins. Appropriate polymers for controlled release formulations include for example polyester, polyamino acids, polyvinyl, pyrrolidone, ethylenevinylacetate, and methylcellulose. Another possible method for controlled release is to incorporate the antibody into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers. Alternatively, instead of incorporating these agents into polymeric particles, it is possible to entrap these materials in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacylate) microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.

[00108] A CD14 antagonist antibody and optionally an ancillary agent may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the inhibitors of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[00109] One of skill in the art will recognize that formulations are routinely designed according to their intended use, i.e. route of administration.

5. Methods of Treatment

[00110] The present disclosure provides for therapeutic methods of treating a subject with a disease associated with a coronavirus infection. In particular examples, the disease associated with a coronavirus infection (i.e. the disease that infection with a coronavirus causes) is characterized by systemic inflammatory response syndrome or sepsis (i.e. one aspect or symptom of the disease may be systemic inflammatory response syndrome or sepsis). In some examples, the disease associated with a coronavirus infection is characterized by hypercoagulopathy, multi-organ failure, pneumonia, ARDS, and/or a pediatric multisystem inflammatory syndrome (i.e. one aspect or symptom of the disease may be hypercoagulopathy, multi-organ failure, pneumonia, ARDS, and/or a pediatric multisystem inflammatory syndrome). In particular examples, the coronavirus is severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) and the disease is COVID-19. In other examples, the coronavirus is SARS-CoV or MERS-CoV, and the disease is SARS or MERS, respectively.

[00111] Thus, in some embodiments, the methods of the present disclosure may include an assessment of whether the subject has a coronavirus infection (e.g. by RT- PCR), and therapy proceeds on the basis that they do have a coronavirus infection. In other examples, the methods of the present disclosure may include an assessment of whether the subject has a coronavirus infection and is at risk of developing one of systemic inflammatory response syndrome, sepsis, hypercoagulopathy, multi-organ failure, pneumonia, ARDS, a pediatric multisystem inflammatory syndrome, and therapy proceeds on the basis that they do. In further examples, the methods of the present disclosure may include an assessment of whether the subject has a coronavirus infection and has one of systemic inflammatory response syndrome, sepsis, hypercoagulopathy, multi-organ failure, pneumonia, ARDS, a pediatric multisystem inflammatory syndrome, and therapy proceeds on the basis that they do.

[00112] The present disclosure also provides for therapeutic methods of treating a subject with an inflammation-induced hypercoagulopathy. Thus, in some embodiments, the methods of the present disclosure may include an assessment of whether the subject has inflammation-induced hypercoagulopathy, and therapy proceeds on the basis that they do.

[00113] Contemplated herein are therefore methods for treating a disease associated with a coronavirus infection in a subject by administering to the subject a CD14 antagonist antibody, and optionally an ancillary agent. The CD14 antagonist antibody, and optionally the ancillary agent (collectively referred to herein as "therapeutic agents"), will be administered in an "effective amount(s)", to achieve an intended purpose in a subject, such as the reduction or prevention of one or more symptoms of the disease associated with a coronavirus infection. The dose of therapeutic agents(s) administered to a patient should be sufficient to achieve a beneficial response in the subject, such as a reduction in at least one symptom. Symptoms may include, but are not limited to, fever, tachycardia (at least 90 beats per minute); tachypnea (at least 20 breaths per minute or PaCC >2 less than 4.3 kPa (32.0 mm Hg) or the need for mechanical ventilation); and an altered white blood cell (WBC) count of 12 x 10⁶ cells/mL or more, or an altered WBC count of 4 x 10⁶ cells /mL or less, or the presence of more than 10% band forms (immature neutrophils), coagulopathy (as measured by elevated D-dimer or fibrinogen levels, or prolonged prothrombin time), liver dysfunction (e.g. as measured by elevated levels of alanine aminotransferase and aspartate aminotransferase (AST), and kidney dysfunction (e.g. as measured by an elevated urine albumin-to- creatinine ratio (AURC)). In some examples, treatment is sufficient to result in improved or increased lung function (e.g. as measured by reduced tachypnea), improved or increased liver function (e.g. as measured by a reduction or normalization of alanine aminotransferase and aspartate aminotransferase (AST), improved or increased kidney function (e.g. as measured by an a reduction or normalization of AURC), reduced or normalized levels of D-dimers or fibrinogen, or reduced or normalized prothrombin time.

[00114] Also contemplated herein are therefore methods for treating an inflammation-induced hypercoagulopathy by administering to the subject a CD14 antagonist antibody, and optionally an ancillary agent. The CD14 antagonist antibody, and optionally the ancillary agent (collectively referred to herein as "therapeutic agents"), will be administered in an "effective amount(s)", to achieve an intended purpose in a subject, such as the reduction or prevention of one or more symptoms of the inflammation-induced hypercoagulopathy. The dose of therapeutic agents(s) administered to a patient should be sufficient to achieve a beneficial response in the subject, such as a reduction in at least one symptom. In some examples, treatment is sufficient to result in reduced or normalized levels of D-dimers or fibrinogen, or reduced or normalized prolonged prothrombin time.

[00115] The quantity or dose frequency of the therapeutic agent(s) to be administered may depend on the subject to be treated, inclusive of their diagnosis (i.e. the severity or disease or the symptoms they present with), age, sex, weight and general health condition thereof. In this regard, precise amounts of the therapeutic agent(s) for administration will depend on the judgment of the practitioner. One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic amount of a CD14 antagonist antibody, and optionally an ancillary agent described herein, for administration to a subject. In particular examples, the amount of CD14 antagonist antibody administered to a subject is between 0.1 mg/kg and 50 mg/kg, between 0.5 mg/kg and 40 mg/kg, between 2 mg/kg and 20 mg/kg or between 5 mg/kg and 10 mg/kg. In particular examples, the amount of CD14 antagonist antibody administered to a subject is (or is about) 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg/kg. [00116] The CD14 antagonist antibody may be administered to the subject as a single dose or multiple doses, as determined by a skilled practitioner to provide the optimal therapy. In particular embodiments, the CD14 antagonist antibody is administered as a multiple doses, such as daily, twice-daily; every 2, 3, 4, 5, 6, 7, 8 or more days; or every 2, 3, 4 or more weeks; and over a period of days, weeks or months.

[00117] In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting example.

EXAMPLES

EXAMPLE 1

PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFECT OF ANTI-CD14 TREATMENT IN PATIENTS WITH SARS-COV-2 (COVID-19)

Summary of the trial

[00119] The primary objective of this trial is to test the efficacy and safety of an antibody to the CD14 pattern-recognition receptor in reducing the severity of respiratory disease in patients hospitalized with the SARS-CoV-2 virus, which causes the clinical illness known as COVID-19. The efficacy and safety of IC14, an anti-CD14 chimeric antibody, in patients hospitalized with respiratory disease due to SARS-CoV-2, is determined, in terms of increasing the number of days alive and free of any episodes of acute respiratory failure through Day 22. Whether the treatment with the IC14 antibody improves time to improvement in clinical status is determined using an eight-point ordinal scale.

[00120] Patients are randomized to IC14 (n = 150) or placebo (n = 150). Study drug is administered daily on Days 1-4. Study participation continues for 60 days after enrolment. Enrolment is stratified by baseline COVID-19 antiviral therapy.

Study Objectives

Primary Endpoint

[00121] The primary endpoint is days alive and free of any episodes of acute respiratory failure through Day 22 defined by need for the following oxygen delivery resource that requires intensive care unit (ICU) admission: a. High-flow nasal cannula (flow rates ≥30L/min with Fi02 ≥0.4); b. Noninvasive positive-pressure ventilation; c. Endotracheal intubation and mechanical ventilation; d. Extracorporeal membrane oxygenation

Secondary Endpoints

[00122] The secondary endpoints are as follows:

1. Time to clinical improvement, defined as time to the first day that a subject is in categories 6, 7, or 8 on the Eight-Point Ordinal Scale. The Eight-Point Ordinal Scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non- invasive ventilation or high-flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen— requiring ongoing medical care (COVID-19-related or otherwise); 6) Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.

2. Proportion of patients alive and free of any episode of acute respiratory failure through Days, 8, 15, 22, and 29.

3. Proportion of patients alive and free of invasive mechanical ventilation through Days 8, 15, 22, and 29.

4. Days alive and free of acute respiratory failure through Days 15 and 29.

5. Days alive and free of invasive mechanical ventilation through Days 15, 22, and 29.

6. Days alive and hospitalized through Day 29.

7. Change in Sequential Organ Failure Assessment (SOFA) score from baseline to Day 8, Day 15, Day 22, and Day 29.

8. Worst SOFA score from baseline to Day 29.

9. Proportion of patients alive and discharged from the hospital at Days 15 and 29.

10. All-cause mortality on Days 29 and 60.

11. Mean change in the ordinal scale through Day 29.

12. Time to improvement in one category from baseline using an ordinal scale through Day 29.

13. Time to improvement in two categories from baseline using an ordinal scale through Day 29.

14. Time to recovery through Day 29. Day of recovery is defined as the first day on which the subject satisfies one of categories 6-8 from the ordinal scale.

15. Change in pro-inflammatory cytokines and other biomarkers in blood on Days 4 and 8 compared to baseline.

16. Safety of IC14 as measured by change from baseline in liver (alanine transaminase, aspartate transaminase, total bilirubin), renal (creatinine), hematological (hemoglobin, white blood cell count with differential), and coagulation function (platelets, prothrombin time). 17. Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events.

18. Cumulative incidence of serious adverse events.

Safety Objectives

[00123] The safety and tolerability of IC14 is determined by examining the toxicities and adverse events that are attributable to treatment. The safety parameters include an evaluation of the clinical signs and symptoms from the history and physical exam, vital signs, adverse events, and safety laboratory findings (chemistries, complete blood count, platelet count). New infections are recorded as adverse events and should include the site of infection and source of culture. Ocular slit lamp examinations will be conducted when the patient is clinically stable, free of COVID-19 symptoms and able to comply with the exam.

Prognostic Biomarkers

[00124] Baseline serum prognostic biomarkers to be measured include presepsin (fragment of sCD14), sCD14, D-dimer, ferritin, C-reactive protein (CRP), and lactate dehydrogenase (LDH).

Inflammatory Biomarkers

[00125] In addition, a biomarker bank of serum and/or plasma samples is established and stored frozen. It may be used to measure additional biomarkers, for example, but not necessarily including, procalcitonin, IL-1, IL-2, IL-6, IL-7, IL-8, G-CSF, GM-CSF, C-reactive protein, interferon-gamma inducible protein 10 (CXCL10), monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, TNF-α, soluble CD163, fibrinogen, triglycerides, or others.

Pharmacokinetic/Pharmacodvnamic Markers

[00126] Pharmacokinetic measurements are made of serum IC14 before infusion on Days 2-4 and on Days 8 and 15. Pharmacodynamic markers consist of urinary sCD14 at baseline, Day 2, Day 4, Day 8, Day 15, and Day 22.

Investigational Plan

Overall study design

[00127] This protocol describes a randomized, double-blind, placebo-controlled study of IC14. Patients hospitalized with pulmonary complications of SARS-CoV-2 infection are randomized to IC14 at a dosage of 4 mg/kg on Day 1, then 2 mg/kg once daily on Days 2-4 or identical-appearing placebo. Study participation is for a total of 60 days.

[00128] Screening/baseline assessments and initiation of the first study drug administration occurs within 48 hours after meeting inclusion criteria. Study Days are defined as consecutive calendar days beginning from the start time of the first study drug administration (Day 1). Study drug is administered at approximately 24-hr intervals beginning from the start time of the first study drug administration (Day 1).

Treatment Assignment

[00129] Following receipt of signed informed consent from the patient or legally authorized representative, completion of baseline assessments at screening and meeting study inclusion and exclusion criteria, the patient is evaluated by the site PI for enrolment eligibility. Study randomization is in blocks of 4 and stratified by baseline use of anti-viral therapy for COVID-19 (remdesivir or another antiviral).

Safety Criteria for Stopping Dosing

[00130] A Data Safety Monitoring Board is assigned to review the safety of this study.

[00131] If a patient develops anaphylaxis/hypersensitivity fulfilling the following criteria, the study drug infusion must be discontinued and the patient must be discontinued from further study treatment: Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least one of the following: a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow (PEF), hypoxemia); or b. Reduced BP or associated symptoms of end- organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence).

[00132] These criteria do not include respiratory compromise, reduced BP, or symptoms of end-organ dysfunction determined by the PI to be related to the underlying SARS-CoV-2 infection.

[00133] If a patient develops eye symptoms such as decreased visual acuity, significant redness, pain, or light sensitivity, they should be discontinued from study drug and scheduled for ocular slit-lamp examination.

Early Study Termination

[00134] Patients who must discontinue treatment for any reason should continue to be monitored by the Study Team through final study time point (Day 60). Study population

[00135] Patients are required to meet all inclusion criteria to enroll in this study. If any exclusion criteria are met, enrolment is declined.

Inclusion criteria

[00136] Patients are included in the study only if they meet all of the following criteria:

1. Signed informed consent form and able to give informed consent

2. Age >18 years

3. Presence of SARS-CoV-2 infection documented by positive RT-PCR testing or history of positive RT-PCR test for SARS-CoV-2 within 7 days

4. Radiologic findings compatible with diagnosis of SARS-CoV-2 pulmonary infection with no alternative explanation for the radiologic findings

5. Hypoxemia as defined by any of the following: a. S_PC>2 <94% on room air, or b. Requirement for ≥2L/m 02 per standard nasal cannula, but not requiring high- flow nasal cannula (defined as ≥30 L/m)

6. Women of childbearing potential must have a negative pregnancy test

Exclusion Criteria

[00137] An individual fulfilling any of the following criteria is excluded from enrolment in the study:

1. Intubation

2. Receiving non-invasive positive-pressure ventilation

3. Receiving invasive mechanical ventilation

4. Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care other than attempts at resuscitation from cardiac arrest)

5. Anticipated survival <48 hours

6. Underlying malignancy or other condition with estimated life expectancy of less than one month

7. Significant pre-existing organ dysfunction: a. Lung: Currently receiving home oxygen therapy as documented in medical record; b. Heart: Pre-existing congestive heart failure defined as an ejection fraction <20% as documented in the medical record; c. Renal: End-stage renal disease requiring renal replacement therapy d. Liver: Severe chronic liver disease defined as Child-Pugh Class C

8. Presence of coexisting infection, including, but not limited to: a. HIV infection not virally suppressed with CD4 county < 500 cell/mm3); b. Active tuberculosis or a history of inadequately treated tuberculosis c. Active hepatitis B or hepatitis C viral infection

9. Ongoing immunosuppression: a. Solid organ transplant recipient; b. High- dose corticosteroids (equivalent to >20 mg/prednisone/day) within the past 14 days; c. Oncolytic drug therapy within the past 14 day

10. Current treatment, or treatment within 30 days or five half-lives (whichever is longer) with etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab (Cimzia®), golimumab (Simponi®), anakinra (Kineret®), rilonacept (Arcalyst®), tocilizumab (Actrema®), sarilumab (Kevzara®), siltuximab (Sylvant®), or other potent immunosuppressant or immunomodulatory drugs or treatments

11. Current enrolment in a pharmacologic interventional trial of host response modifiers.

12. Concomitant COVID-19 antiviral therapy is allowed.

13. History of hypersensitivity or idiosyncratic reaction to IC14

Description of Treatment

Compound

[00138] The study drug, IC14, is supplied by Implicit Bioscience Ltd. IC14 is a recombinant chimeric (murine/human) monoclonal antibody against human CD14. IC14 is secreted from Chinese hamster ovary cells as an L2H2y4 immunoglobulin. IC14 is manufactured by AGC Biologies, Inc. under Good Manufacturing Practice guidelines. Drug product is manufactured by Althea Technologies, Inc. (now Ajinomoto Bio-Pharma Services) under Good Manufacturing Practice guidelines.

Dosing Regimen

[00139] Patients receive a dose of 4 mg/kg in a solution of 250 mL 0.9% w/v NaCI over 2 hours on Study Day 1, followed by 2 mg/kg in a solution of 250 mL 0.9% w/v NaCI over 2 hours once daily on Study Days 2-4. Study drug is administered as a single dose daily for four consecutive days at approximately 24-hr intervals. The dose of study drug is calculated based on body weight of the patient. The maximum dose administered is that for a 125-kg patient (i.e., if a patient weighs >125 kg, the dose of study drug is calculated based on a weight of 125 kg). Preparation of the infusion bag may occur up to 12 hours before administration. Once prepared, the infusion bag is kept refrigerated at 2-8°C until the time of administration.

[00140] Placebo consists of an identical-appearing infusion of 250 mL 0.9% w/v NaCI over 2 hours once daily on Study Days 1-4.

[00141] The Pharmacy labels study drug for infusion using institutional standard operating procedures. All study personnel other than the study pharmacist is blinded to study drug assignment.

Dosage Form

[00142] The investigational drug product is supplied by Implicit Bioscience Ltd. as a sterile solution at a concentration of 5 mg/mL for parenteral administration totaling 125 mg in a volume of 25 mL in a 30-mL single-use glass vial. More than one vial may be required to prepare each dose.

Timing of Doses

[00143] Daily doses are administered approximately 24 hours apart. The study drug administration start and stop times are recorded in the patient's chart.

Route of Administration

[00144] The study drug is administered via a volumetric infusion pump utilizing standard tubing.

[00145] Infusion is via a dedicated IV line or lumen of a multiple lumen catheter, preferably with no other medications, and flushed before and after with 10 mL normal saline. It is infused over 2 hours at a rate of approximately 2 mL/min. Study drug start and stop times are recorded.

Concomitant Therapy

[00146] All patients are administered remdesivir intravenously as a 200-mg loading dose on Day 1, followed by a 100-mg maintenance dose administered daily on Days 2 through 5, or until hospital discharge or death.

[00147] No immunosuppressant therapy is allowed including, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab (Cimzia®), golimumab (Simponi®), anakinra (Kineret®), rilonacept (Arcalyst®), tocilizumab (Actrema®), sarilumab (Kevzara®), siltuximab (Sylvant®), stem cell therapy, lymphocyte infusions, glucocorticoids, inhaled budesonide, or other potent immunosuppressant or immunomodulatory drugs. [00148] Off-label use of other drugs, devices, or interventions that might be used to manage COVID-19, e.g., anticoagulants, are addressed as additional information, such as from randomized controlled clinical trials, emerges and the standard of care changes. Schedule of Evaluations

[00149] The following table provides a schedule of evaluations.

[00150] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[00151] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application. [00152] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a disease associated with a coronavirus infection in a human subject, comprising, consisting or consisting essentially of administering an effective amount of a CD14 antagonist antibody to the subject.

2. The method of claim 1, wherein the disease is characterized by systemic inflammatory response syndrome or sepsis.

3. The method of claim 1 or claim 2, wherein the disease is characterized by hypercoagulopathy, multi-organ failure, pneumonia, adult respiratory distress syndrome (ARDS), a pediatric multisystem inflammatory syndrome.

4. The method of any one of claims 1-3, wherein the coronavirus is SARS- CoV-2 and the disease is COVID-19.

5. The method of any one of claims 1-4, wherein administration of the CD14 antagonist antibody increases lung function, increases liver function, increases kidney function, reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time.

6. A method for treating an inflammation-induced hypercoagulopathy in a human subject, comprising, consisting or consisting essentially of administering an effective amount of a CD14 antagonist antibody to the subject.

7. The method of claim 6, wherein administration of the CD14 antagonist antibody reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time.

8. The method of any one of claims 1-7, wherein the CD14 antibody is administered systemically.

9. The method of any one of claims 1-8, wherein the CD14 antagonist antibody is selected from:

(i) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L- CDR1 comprises the sequence

[SEQ ID NO: 7] (3C10 L- CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 8] (3C10 L-CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 9] (3C10 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H- CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SYAMS [SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 12] (3C10 H-CDR3);

(ii) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L- CDR1 comprises the sequence

[SEQ ID NO: 13] (28C5 L- CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (28C5 L- CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 18] (28C5 H-CDR3);

(iii) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L- CDR1 comprises the sequence

[SEQ ID NO: 13] (IC14 L- CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (IC14 L- CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 18] (IC14 H-CDR3); and

(iv) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L- CDR1 comprises the sequence

[SEQ ID NO: 19] (18E12 L-CDR1); L- CDR2 comprises the sequence

[SEQ ID NO: 20] (18E12 L-CDR2); and L- CDR3 comprises the sequence

[SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H- CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence

[SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 24] (18E12 H-CDR3).

10. The method of any one of claims 1-9, wherein the CD14 antagonist antibody is selected from:

[SEQ ID NO: 1] (3C10 VL); and a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 2] (3C10 VH);

[SEQ ID NO: 3] (28C5 VL); and a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 4]

(28C5 VH);

(iii) an antibody comprising : a VL domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 26]

( IC 14 VH); and

(iv) an antibody comprising: a VL domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 5] (18E12 VL); and a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 6] (18E12 VH).

11. The method according to any one of claims 1-10, wherein the CD14 antagonist antibody is humanized or chimeric.

12. The method of any one of claims 1-11, wherein the CD14 antagonist antibody comprises a light chain and a heavy chain, wherein: the light chain comprises the amino acid sequence:

[SEQ ID NO: 28]; and

the heavy chain comprises the amino acid sequence:

[SEQ ID NO: 29].

13. The method of any one of claims 1-12, wherein the CD14 antagonist antibody is administered in a single dose.

14. The method of any one of claims 1-13, wherein the CD14 antagonist antibody is administered in multiple doses.

15. The method of claim 14, wherein the CD14 antagonist antibody is administered every 1, 2, 3, 4, 5, 6, 7 or 8 days.

16. The method of claim 14, wherein the CD14 antagonist antibody is administered every 2, 3, 4, or 5 weeks.

17. The method of any one of claim 1-16, wherein the CD14 antagonist antibody is administered in combination with an ancillary agent.

18. The method of claim 17, wherein the CD14 antagonist antibody and the ancilliary agent are administered simultaneously or sequentially.

19. The method of claim 17 or 18, wherein the ancillary agent is an antiviral, an anti-inflammatory, or an anti-malarial.

20. Use of a CD14 antagonist antibody for the preparation of a medicament for treating a disease associated with a coronavirus infection in a human subject.

21. The use of claim 20, wherein the disease is characterized by systemic inflammatory response syndrome or sepsis.

22. The use of claim 20 or claim 21, wherein the disease is characterized by hypercoagulopathy, multi-organ failure, pneumonia, adult respiratory distress syndrome (ARDS), a pediatric multisystem inflammatory syndrome.

23. The use of any one of claims 20-22, wherein the coronavirus is SARS- CoV-2 and the disease is COVID-19.

24. The use of any one of claims 20-23, wherein the medicament increases lung function, increases liver function, increases kidney function, reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time in the subject.

25. Use of a CD14 antagonist antibody for the preparation of a medicament for treating an inflammation-induced hypercoagulopathy in a human subject

26. The use claim 25, wherein the medicament reduces levels of D-dimers, reduces levels of fibrinogen, and/or reduces prothrombin time in the subject.

27. The use of any one of claims 20-26, wherein the CD14 antagonist antibody is administered systemically.

28. The use of any one of claims 20-27, wherein the antibody is selected from:

(i) an antibody that comprises: a) an antibody VL domain, or antigen binding fragment thereof, comprising L-CDR1, L-CDR2 and L-CDR3, wherein: L-CDR1 comprises the sequence

[SEQ ID NO: 7] (3C10 L-CDR1); L- CDR2 comprises the sequence

[SEQ ID NO: 8] (3C10 L-CDR2); and L- CDR3 comprises the sequence

[SEQ ID NO: 10] (3C10 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 11] (3C10 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 12] (3C10 H-CDR3);

[SEQ ID NO: 13] (28C5 L- CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (28C5 L- CDR2); and L-CDR3 comprises the sequence [SEQ ID NO: 15] (28C5

L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H-CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence SDSAWN [SEQ ID NO: 16] (28C5 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (28C5 H-CDR2); and H-CDR3 comprises the sequence GLRFAY [SEQ ID NO: 18] (28C5 H-CDR3);

[SEQ ID NO: 13] (IC14 L- CDR1); L-CDR2 comprises the sequence

[SEQ ID NO: 14] (IC14 L- CDR2); and L-CDR3 comprises the sequence

[SEQ ID NO: 16] (IC14 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 17] (IC14 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 18] (IC14 H-CDR3); and

[SEQ ID NO: 19] (18E12 L-CDR1); L- CDR2 comprises the sequence

[SEQ ID NO: 20] (18E12 L-CDR2); and L- CDR3 comprises the sequence

[SEQ ID NO: 21] (18E12 L-CDR3); and b) an antibody VH domain, or antigen binding fragment thereof, comprising H- CDR1, H-CDR2 and H-CDR3, wherein: H-CDR1 comprises the sequence NYDIS [SEQ ID NO: 22] (18E12 H-CDR1); H-CDR2 comprises the sequence

[SEQ ID NO: 23] (18E12 H-CDR2); and H-CDR3 comprises the sequence

[SEQ ID NO: 24] (18E12 H-CDR3).

29. The use of any one of claims 20-28, wherein the CD14 antagonist antibody is selected from:

[SEQ ID NO: 1] (3C10

VL); and a VH domain that comprises, consists or consists essentially of the sequence:

[SEQ ID NO: 2] (3C10 VH);

[SEQ ID NO: 4] (28C5 VH); and

[SEQ ID NO: 26] (IC14 VH); and

[SEQ ID NO: 6] (18E12 VH).

30. The use of to any one of claims 20-29, wherein the CD14 antagonist antibody is humanized or chimeric.

31. The use of any one of claims 20-30, wherein the CD14 antagonist antibody comprises a light chain and a heavy chain, wherein: the light chain comprises the amino acid sequence:

[SEQ ID NO: 28]; and the heavy chain comprises the amino acid sequence:

[SEQ ID NO: 29].

32. The use of any one of claims 20-31, wherein the medicament antibody is administered in a single dose.

33. The use of any one of claims 20-31, wherein the medicament administered in multiple doses.

34. The use of any one of claims 20-33, wherein the medicament is administered in combination with an ancillary agent.

35. The use of claim 34, wherein the CD14 antagonist antibody and the ancillary agent are administered simultaneously or sequentially.

36. The use of claim 34 or 35, wherein the ancillary agent is an antiviral, an anti-inflammatory, or an anti-malarial.