JP2025518050A - Compositions and methods for inhalable therapeutic agents - Google Patents

Abstract

Described herein are therapeutic inhaled antibodies and methods of delivering these therapeutic antibodies that may sustain concentrations of the therapeutic inhaled antibodies in the upper respiratory tract (URT) and lower respiratory tract (LRT) and blood even after a single dose. The compositions and methods described herein can provide therapeutically relevant levels of inhaled antibodies delivered by inhalation in a single dose delivered no more frequently than once a day. These methods can result in concentrations in both the URT and LRT that are higher than the minimum threshold concentration that has clinical relevance.

Description

Claiming priority
[0001] This application is a joint application of U.S. Provisional Patent Application No. 63/345,019, entitled "COMPOSITIONS AND METHODS FOR INHALABLE THERAPEUTICS," filed May 23, 2022, and entitled "METHODS AND APPARATUSES FOR DELIVERY OF AN AGENTS TO THE LUNGS AND NASAL AIR ... This application claims priority to U.S. Patent Application No. 17/889,141, filed August 16, 2022, which claims the benefit of U.S. Provisional Patent Application No. 63/233,661, entitled "METHOD FOR USE IN HYDROXY-INDUCED HYDROXY-PROPYLENE PHARMACEUTICAL SYSTEMS AND METHOD FOR USE IN HYDROXY-INDUCED HYDROXY-PROPYLENE PHARMACEUTICAL SYSTEMS," all of which are incorporated by reference in their entirety herein.
Incorporation by Reference
[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0003] It is believed to be accepted that antibodies delivered to the lung by inhalation, including Fc-conjugated antibodies, are rapidly cleared from the lung. For example, Fc-conjugated proteins given by inhalation typically have a serum Tmax (i.e., time to reach Cmax) in the range of 10-20 hours, and therefore have a fairly rapid clearance in the lung (on the order of hours or minutes). Bitonti and Durmont, "Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway," Advanced Drug Delivery Reviews, Volume 58, Issues 9-10, 31 October 2006, pp. 1106-1118. Indeed, the therapeutic efficacy of inhaled drugs has long been thought to be limited by their rapid clearance in the lung. Small solutes delivered to the lung diffuse rapidly into the pulmonary epithelium and penetrate into the bloodstream within minutes. Peptides are similarly rapidly transported into the systemic circulation, but are extensively metabolized locally. Loira-Pastoriza et al., (“Delivery strategies for sustained drug release in the lungs,” Advanced Drug Delivery Reviews, Volume 75, 30 August As summarized by Friedrich Schmidt, 2014, pp. 81-91, "Macromolecules may be absorbed into the systemic circulation over several hours, but they may be rapidly taken up by alveolar macrophages, cleared by the mucociliary escalator, or metabolized locally. For example, recombinant human deoxyribonuclease I is a 37 kDa glycoprotein that cleaves DNA in the respiratory secretions of cystic fibrosis patients, thus reducing their viscosity. This glycoprotein is the most widely used mucolytic drug in the symptomatic treatment of cystic fibrosis. However, it is rapidly cleared from the human lung when a daily dose of 2.5 mg is inhaled, with concentrations of 3 μg/ml measured in sputum immediately after inhalation, reduced to 0.6 μg/ml after 2 hours. Thus, one to two daily administrations provide limited therapeutic coverage for patients." Unfortunately, the short residence time of the drug in the lungs also requires more frequent dosing, which is thought to compromise patient compliance. For example, inhalation of a corticosteroid at least twice daily and a short-acting beta-2 agonist up to four times daily is recommended.

[0004] It would therefore be beneficial to provide compositions, particularly mAb compositions, that may remain in the lungs at clinically significant levels for extended periods of time without being cleared. Such compositions and methods may provide numerous clinical and compliance benefits.

[0005] The present invention relates to therapeutic inhaled antibodies and methods of delivering these therapeutic antibodies to maintain concentrations in the upper respiratory tract (URT) and lower respiratory tract (LRT) and blood even after a single dose. Surprisingly, the compositions and methods described herein can provide therapeutically relevant levels of inhaled IgG antibodies delivered by inhalation in a single dose delivered once a day or less frequently (e.g., between once a day and once every five days). These methods can result in concentrations that are greater than the minimum threshold concentrations that have clinical relevance in both the URT and LRT.

[0006] The persistence of therapeutic mAbs in URT and LRT is likely a result of interactions of the core Fc region of the IgG backbone common to the therapeutic antibodies described herein (including, for example, regdanvimab), regardless of the target-specific portion (variable region) of the individual mAb. This may be because it is the Fc region that interacts with mucus and other components that drive clearance of the mAb from the lung. The effects described herein are particularly relevant to compositions of mAbs in which the IgG Fc region is glycosylated in a manner that modulates mucin interactions. For example, these compositions may include an Fc region that is glycosylated with G0 glycosylation, including a biantennary core glycan structure of Manα1-6 (Manα1-5)Manβ1-4GlcNAcβ1-4GlcNAcβ1, with a terminal N-acetylglucosamine at each branch that enhances the capture efficacy of the recombinant antibody in mucus.

[0007] For example, described herein are methods of treating a subject having or at risk of having a respiratory disorder, comprising administering to the subject by inhalation a formulation comprising a therapeutic antibody that binds to a respiratory virus in a dosing regimen that includes a once-daily or twice-daily dosing cycle.

[0008] Thus, described herein is a method of treating a subject having or at risk of having a respiratory disorder, comprising administering to the subject by inhalation a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein the administering comprises administering at a dose of 0.02 μmol or more of the therapeutic human mAb no more than twice daily to achieve a concentration of greater than 20 ng/mL in the upper respiratory tract (URT) and greater than 100 ng/mL in the lower respiratory tract (LRT) for 12 hours or longer after dosing.

[0009] In some examples, a method of treating a subject having or at risk of having a respiratory disorder may include maintaining a concentration of therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in the upper respiratory tract (URT) of the subject greater than 20 ng/ml and in the lower respiratory tract (LRT) of the subject greater than 100 ng/ml for greater than 12 hours after the dose by inhalation to the subject of a dose of a therapeutic human IgG monoclonal antibody (mAb) that includes a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern that includes a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein administering the dose includes administering 0.02 μmol or more of the therapeutic human mAb no more than twice daily.

[0010] In any of these examples, the administering step can include administering the dose no more than once per day.
[0011] In some examples, a therapeutic antibody may comprise at least 45% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, etc.) of a G0 glycosylation pattern.

[0012] In some examples, the therapeutic antibody comprises an Fc sequence that is at least X% (e.g., 80%, 85%, 90%, 95%) homologous to the sequence of SEQ ID NO:1 (e.g., human IgG1). For example, the therapeutic antibody comprises an Fc sequence that is at least 85% homologous to the sequence of SEQ ID NO:1, including conservative peptide substitutions.

[0013] The therapeutic antibody may be regdanvimab. The dosing regimen may include twice-daily dosing cycles over a period of 2 to 7 days. The dosing regimen may include dosing cycles every 2, 3 or 4 days. The dosing regimen may include administering a dose of at least 10 mg of the therapeutic mAb. The dosing regimen may include administering a dose of between about 10 mg and 100 mg of the therapeutic mAb. In some examples, the administering step includes sustaining release of the therapeutic mAb from the LRT into the blood for multiple days. The administering step may include sustaining release of the mAb into the lungs and blood for at least 2 days.

[0014] The formulation may also include a pharma- ceutically acceptable diluent, excipient, and/or carrier. In some examples, the formulation further includes one or more of citric acid, arginine, mannitol, sorbitol, and trehalose.

[0015] The therapeutic antibody formulation may be administered to the subject via a nebulizer, e.g., a vibrating mesh nebulizer. In some examples, the therapeutic antibody formulation is administered via inhalation or via direct instillation into the upper airway. The therapeutic antibody formulation may be self-administered by the subject.

[0016] The respiratory disorder may include a lower respiratory tract disorder. The respiratory disorder may include an upper respiratory tract disorder. In some examples, the respiratory disorder includes an inflammatory disorder. The respiratory virus may include a coronavirus. The respiratory virus may include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The respiratory virus may include respiratory syncytial virus (RSV). The respiratory virus may include one or more of influenza, metapneumovirus, parainfluenza, (certain coronaviruses). In some examples, the respiratory virus includes a paramyxovirus.

[0017] The formulation may include a second or more therapeutic agents in addition to the therapeutic antibody. The formulation may include a therapeutic mAb and a second therapeutic antibody, where the first therapeutic antibody and the second therapeutic antibody bind to the same virus but do not compete for binding to the virus. In some cases, the formulation includes a second therapeutic antibody in addition to the first therapeutic antibody, and further, the first antibody and the second antibody bind to different viruses. The formulation includes a biologic in addition to the therapeutic mAb.

[0018] For example, a method of treating a subject having or at risk of having a respiratory disorder may include administering to the subject by inhalation a dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus, thereby maintaining a concentration of the therapeutic human IgG monoclonal antibody (mAb) that binds to the respiratory virus greater than 25 ng/ml in the subject's upper respiratory tract (URT) and greater than 25 ng/ml in the subject's lower respiratory tract (LRT) for greater than 12 hours after the dose, where the administering step includes administering 0.02 μmol or more of the therapeutic human mAb no more than twice daily.

[0019] Also described herein is a method of treating a subject having or at risk of having a respiratory disorder, comprising administering to the subject by inhalation a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus, the administering step comprising administering a dose of 0.02 μmol or more of the therapeutic human mAb no more than once per day to achieve a concentration of the therapeutic human mAb in the upper respiratory tract (URT) greater than 25 ng/ml and in the lower respiratory tract (LRT) greater than 25 ng/ml for greater than 24 hours after the dose.

[0020] Also described herein is a method of treating a subject having or at risk of having a respiratory disorder, the method comprising administering to the subject by inhalation a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that is glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, the administering step comprising administering at a dose of 0.02 μmol or more of the therapeutic human mAb no more than once daily to achieve a concentration of greater than 20 ng/mL in the upper respiratory tract (URT) and greater than 100 ng/mL in the lower respiratory tract (LRT) for 24 hours or longer after dosing.

[0021] For example, a method of treating a subject having or at risk of having a respiratory disorder may include administering to the subject by inhalation a dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus, thereby maintaining a concentration of the therapeutic human IgG monoclonal antibody (mAb) that binds to the respiratory virus in the upper respiratory tract (URT) of the subject greater than 25 ng/ml and in the lower respiratory tract (LRT) of the subject greater than 25 ng/ml for more than 24 hours after the dose, wherein the administering step includes administering 0.02 μmol or more of the therapeutic human mAb no more than once per day.

[0022] In some examples, a method of treating a subject having or at risk of having a respiratory disorder may include administering to the subject by inhalation a dose of a therapeutic human IgG monoclonal antibody (mAb) that is glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, thereby maintaining a concentration of the therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in the upper respiratory tract (URT) of the subject greater than 20 ng/ml and in the lower respiratory tract (LRT) of the subject greater than 100 ng/ml for greater than 24 hours after the dose, wherein administering the dose includes administering 0.02 μmol or more of the therapeutic human mAb no more than once per day.

[0023] In any of the methods described herein, the therapeutic antibody can be a therapeutic human IgG monoclonal antibody (mAb). In any of the methods described herein, the therapeutic human IgG monoclonal antibody (mAb) is a human IgG1 mAb. In any of the methods described herein, the therapeutic antibody comprises an Fc sequence that is at least X% (e.g., 80%, 85%, 90%, 95%) homologous to the sequence of SEQ ID NO:1 (e.g., human IgG G1). For example, the therapeutic antibody can comprise regdanvimab. Alternatively, in any of these methods and compositions, the Fc sequence can be at least X% homologous to one or more of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and/or SEQ ID NO:4.

[0024] Generally, the subject can be any subject in need of therapy. In particular, the subject can be an adult subject and a young adult subject. As used herein, a young adult subject can refer to any individual aged 12 years or older.

[0025] In any of the methods described herein, the therapeutic antibody may comprise oligosaccharides that enhance the capture efficacy of the recombinant antibody in mucus. For example, the therapeutic antibody may comprise a population of mAbs in which at least 40% comprise oligosaccharides having a G0 glycosylation pattern that includes a biantennary core glycan structure of Manα1-6 (Manα1-5)Manβ1-4GlcNAcβ1-4GlcNAcβ1 with a terminal N-acetylglucosamine at each branch that enhances the capture efficacy of the recombinant antibody in mucus.

[0026] In any of the methods described herein, the dosing regimen may include a dosing cycle once a day for a period of 2 to 7 days. The dosing regimen may include a dosing cycle every 2 days, every 3 days, or every 4 days. The dosing regimen may include administering a total of 2, 3, or 4 doses. The dosing regimen may include administering only a single dose. The dosing regimen may include administering a dose of at least 30 mg of the therapeutic mAb. The dosing regimen may include administering a dose of between about 30 mg and 90 mg of the therapeutic mAb.

[0027] In any of the methods described herein, the administering step may include sustaining release of the therapeutic mAb from the LRT into the blood for multiple days. The administering step may include sustaining release of the mAb into the lungs and blood for at least two days.

[0028] In any of the methods described herein, the formulation further comprises a pharma- ceutically acceptable diluent, excipient, and/or carrier. For example, the formulation further comprises one or more of citric acid, arginine, mannitol, sorbitol, trehalose. The therapeutic antibody formulation may be administered to the subject via a nebulizer. The therapeutic antibody formulation may be administered to the subject via a vibrating mesh nebulizer. The therapeutic antibody formulation may be administered to the subject via a nebulizer. The therapeutic antibody formulation may be administered via inhalation or via direct instillation into the upper airway. The therapeutic antibody formulation may be self-administered by the subject.

[0029] The respiratory disorder may include a lower respiratory tract disorder. The respiratory disorder may include an upper respiratory tract disorder. The respiratory disorder may include an inflammatory disorder. The respiratory virus may include a coronavirus. The respiratory virus may include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The respiratory virus may include respiratory syncytial virus (RSV). The respiratory virus may include one or more of influenza, metapneumovirus, parainfluenza, (certain coronaviruses). The respiratory virus may include a paramyxovirus.

[0030] In any of the methods described herein, the formulation may include a second or more therapeutic agents in addition to the therapeutic antibody. The formulation may include a therapeutic mAb and a second therapeutic antibody, where the first therapeutic antibody and the second therapeutic antibody bind to the same virus but do not compete for binding to the virus. The formulation may include a second therapeutic antibody in addition to the first therapeutic antibody, and further, where the first antibody and the second antibody bind to different viruses. The formulation may include a biologic in addition to the therapeutic mAb.

[0031] Also described herein are compositions for use in a method of treating any of the respiratory disorders described herein by carrying out any of the methods described (e.g., therapeutic human IgG monoclonal antibodies, particularly therapeutic human IgG monoclonal antibodies (mAbs) comprising a population of antibodies in which at least 40% are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1. For example, in a method of treating a respiratory disorder by administering a therapeutic human IgG monoclonal antibody (mAb) by inhalation. Described herein is a therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1 for use in a method comprising administering to a patient in need thereof, the administering step comprising administering no more than twice daily at a dose of 0.02 μmol or more of the therapeutic human mAb to achieve a concentration of greater than 20 ng/mL in the upper respiratory tract (URT) and greater than 100 ng/mL in the lower respiratory tract (LRT) for 12 hours or longer after dosing.

[0032] Also described herein is a therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1 for use in a method of treating a respiratory disorder by administering a dose of the therapeutic human IgG mAb by inhalation, maintaining a concentration of the therapeutic human IgG mAb in the upper respiratory tract (URT) of a subject greater than 20 ng/ml and in the lower respiratory tract (LRT) of a subject greater than 100 ng/ml for greater than 12 hours after dosing, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice daily.

[0033] These methods, and in particular the dosing regimens described herein, are surprising and effective: prior to this work, it was believed that the predicted clearance of the therapeutic agent (mAb) from the lungs of such compositions would be extremely rapid (e.g., less than 30 minutes) and therefore would require significantly larger and/or more frequent dosing.

[0034] All of the methods and apparatus described herein are contemplated and can be used, in any combination, to achieve the benefits as described herein.
[0035] A better understanding of the features and advantages of the methods and apparatus described herein can be obtained by reference to the following detailed description illustrating exemplary embodiments and the accompanying drawings, in which:

[0036] Figure 1 is Table 1 describing the demographics of patients enrolled in the study described in Example 1 and shows the persistence (as seen at serum levels) in the upper and lower respiratory tract of a therapeutic mAb with a human IgG Fc region that is glycosylated (e.g., such that greater than 40% of the mAb is glycosylated). [0037] Figure 2 is Table 2 summarizing adverse events from the study described in Example 1. Side effects marked with ( ^* ) occurred within 2 hours of completing the inhalation dose; (cough, decreased FEV1). Complications marked with ( ^** ) included contraceptive IUD use. [0038] Figure 3 (left) shows an example process flow for an example method of the procedure described in Example 1. Figure 3 (right) shows an example study overview and sample collection time points used in Example 1. [0039] Figures 4A-4C illustrate nasal fluid concentrations. Figure 4A shows concentrations in a single dose cohort. Figure 4B shows concentrations in a multiple daily dose cohort (e.g., 90 mg 7 days). The arrow on the x-axis indicates the 7 90 mg dose administrations in Figure 4B. Figure 4C shows a comparison of nasal concentrations between single and multiple dose cohorts. The mean LLOQ for all nasal fluid samples is shown as 450 ng/g, however, the LLOQ varied from sample to sample depending on the mass of nasal fluid collected in the swab, resulting in some detectable samples below the overall mean LLOQ. The fractions under each time point represent the number of samples below the LLOQ at that time. [0040] Figures 5A-5B show serum IN-006 concentrations in the single dose cohort (Figure 5A) and multiple dose cohort (Figure 5B, last dose administered at 144 hours). Symbols plotted below the dotted LLOQ of 25 ng/mL represent the number of samples in each group that were at BLQ at each time point. [0041] Figure 6 is a schematic diagram illustrating one example of a method as described herein.

[0042] Methods, compositions and apparatus (e.g., devices, systems, etc.) useful for treating a subject having or at risk of having a respiratory disorder are described herein. In some embodiments, methods are provided for administering a therapeutic antibody to treat a subject having or at risk of having a respiratory disorder affecting the upper respiratory tract (upper airway) or the lower respiratory tract (lower airway). The methods provided herein may be particularly useful for treating subjects who have or are at risk of having a respiratory disorder affecting both the upper respiratory tract (upper airway) or the lower respiratory tract (lower airway). Applicants have surprisingly and unexpectedly found the ability to achieve long-term coverage with therapeutic antibodies using the methods, compositions and devices described herein, allowing for infrequent or episodic dosing regimen frequencies (e.g., one-time delivery, once-daily delivery, at most twice-daily delivery).

[0043] The term "antibody" (Ab) refers to an immunoglobulin molecule that specifically binds to or immunologically reacts with a particular antigen. Basic antibodies have a Y-shape with a stem region and two arm regions and can be classified into different categories called isotypes based on features found in the antibody stem region. Basic antibodies are heterotetrameric glycoproteins composed of two identical light (L) chains and two identical heavy (H) chains. Each of the four chains has a variable (V) region at its amino terminus that contributes to the antigen binding site and a constant (C) region that determines the isotype. Experimentally, antibodies can be cleaved with the proteolytic enzyme papain, which breaks each of the heavy chains, resulting in three separate subunits. Two of the units are composed of a light chain and a fragment of the broken heavy chain of approximately the same mass as the light chain. Each of these two units can bind antigen separately and is called a Fab fragment (i.e., an "antigen-binding" fragment). According to some estimates, humans may be capable of producing as many as 10 ¹⁸ or 10 quintillion distinct antibodies, each with a unique Fab fragment. The third of the three units is composed of two identical segments of the heavy chain. This third unit is not usually involved in antigen binding, but is important in later processes in the body involved in clearing the antigen from the body. In contrast to the Fab fragment, the third unit from an antibody usually has only one of five physicochemical properties and is therefore called the Fc fragment (i.e., the "crystallizable" fragment). The types of human antibodies that contain one of the five types of Fc fragments are called IgA, IgD, IgE, IgG, and IgM isotypes. These isotypes also have several subclasses. For example, IgG antibodies can be further divided in humans into subclasses IgG1, IgG2, IgG3, and IgG4. IgG antibodies can be further subdivided into subclasses IgG1, IgG2a, IgG2b and IgG3 in mice. Antibody types and modified forms can be produced by methods known in the art and include polyclonal, monoclonal, genetically engineered, bifunctional, chimeric, humanized, heteroconjugate antibodies (e.g., bispecific antibodies, diabodies, triabodies and tetrabodies) and antigen-binding fragments of antibodies or single chain antibodies including, for example, Fab', F(ab') ₂ , Fab, Fv, rIgG and scFv fragments (e.g., single chain Fv) fragments comprising a VL domain linked to a VH domain by a linker.

[0044] A "blocking" antibody (also called an "antagonist" antibody) is an antibody that inhibits or reduces the biological activity of the antigen to which it binds. In some embodiments, a blocking or antagonist antibody substantially or completely inhibits the biological activity of the antigen.

[0045] A "carrier" is generally designed to interact with and enhance the properties of an active ingredient (API) (e.g., an antibody). The carrier is generally safe and non-toxic to the subject and cells exposed thereto at the dosages and concentrations used. One example of a physiologically acceptable carrier is an aqueous pH buffered solution, e.g., a saline solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; salt-forming counterions such as sodium and/or non-ionic surfactants such as TWEEN™, polyethylene glycol (PEG) and PLURONICS™.

[0046] The term "Cmax" refers to a standard pharmacokinetic measure used to determine drug dosing. Cmax is the peak (highest), maximum (or peak) concentration achieved by a drug in a specified compartment or test area of the body (e.g., blood, serum, nasal cavity, etc.) after the drug is administered and prior to administration of a subsequent (second) dose.

[0047] The term "effective amount" (or "therapeutically effective amount") is at least the minimum drug concentration required to cause a measurable improvement or prevention of a particular disorder. The effective amount herein may vary depending on factors such as the particular disorder (e.g., disease state), age, sex and weight of the subject, and the ability of the drug (e.g., antibody) to elicit a desired response in the individual. An effective amount is also one in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, the beneficial or desired results include eliminating or reducing the risk, reducing the severity of the disorder (disease), or delaying the onset of the disorder (disease), including the biochemical, histological and/or behavioral symptoms of the disorder (disease), its complications, and intermediate pathological phenotypes presented during the development of the disorder (disease). For therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms resulting from a disorder, enhancing the quality of life of a person suffering from a disorder, reducing the dose of other medications required to treat the disorder, enhancing the effect of another medication through targeting, delaying disease progression, etc., and/or prolonging survival. An effective amount may be administered in one or more administrations. For purposes herein, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment, either directly or indirectly. As will be understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administration of one or more therapeutic agents, or a single agent may be considered to be given in an effective amount, where a desired result may or is achieved in conjunction with one or more other agents.

[0048] The term "excipient" refers to a substance in a formulation other than the active ingredient(s) (e.g., an antibody). Examples of excipients include antioxidants, buffers, emulsifiers, penetration enhancers, preservatives, release control agents, and viscosity modifiers.

[0049] The term "humanized antibody" or "humanized" form of a non-human (e.g., murine) antibody refers to a chimeric antibody that contains minimal sequence derived from non-human immunoglobulin. In some embodiments, a humanized antibody is a human immunoglobulin (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 non-human primate having the desired specificity, affinity, and/or capacity. A humanized antibody may also comprise at least a portion of an Fc, which is usually of a human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art. In some examples, framework ("FR") residues of a human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody.

[0050] The term "ka" (M ^-1 sec ^-1 ) is intended to refer to the association rate constant of a particular antibody-antigen interaction. The term "K _A " (M), as used herein, is intended to refer to the association equilibrium constant of a particular antibody-antigen interaction.

[0051] The term "kd" (sec ^-1 ), as used herein, is intended to refer to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the off value. The term "K _D " (M ^-1 ), as used herein, is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction.

[0052] In certain embodiments, the antibodies of the present disclosure are monoclonal antibodies. The term "monoclonal antibody" as used herein includes, but is not limited to, antibodies produced by hybridoma technology. The term "monoclonal antibody" refers to an antibody derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced. Monoclonal antibodies useful with the present disclosure can be prepared using a wide variety of techniques or combinations thereof known in the art, including the use of hybridoma, recombinant, and phage display technologies. Antibodies of the present disclosure include chimeric, primatized, humanized, or human antibodies.

[0053] The term "nebulizer" refers to a device configured to convert a medicament (formulation) from a liquid into an aerosol or suspension of fine particles or droplets (also referred to herein as a mist) and deliver the aerosol to a subject for inhalation into the lungs. Nebulizer devices include jet nebulizers, mesh nebulizers, and ultrasonic nebulizers. Nebulizers can also be heated or refillable. Jet nebulizers (which use a compressor, nozzle, compressed air, or are sometimes referred to as venturi nebulizers) use compressed gas (e.g., air or oxygen) to form an aerosol. For example, a nebulizer reservoir can be filled with a medicament (formulation). The compressed gas can be applied to the inlet of the reservoir, travel at high velocity, and exit through a narrow opening, creating a region of low pressure at the outlet. The resulting pressure difference causes the fluid to be drawn up from the reservoir into and out of the reservoir. The fluid can then be broken up into droplets of various sizes by the walls or internal baffles of the nebulizer. Ultrasonic nebulizers use high frequency vibrations, such as 2-3 million times per second, from a piezoelectric vibrator. The vibrations are transferred to the medicament (formulation) through a tank of cooled water to form an aerosol. Mesh nebulizers use a very fine mesh to create a mist. The vibrating element pushes the medicament (formulation) through very fine holes in a membrane (e.g., mesh). This creates an aerosol of small droplets. The phrase "pharmaceutical acceptable" indicates that a substance or composition must be chemically and/or toxicologically compatible with other ingredients comprising the formulation and/or the mammal being treated with it.

[0054] The term "peak level" refers to the highest concentration of a therapeutic agent (eg, an antibody) in an individual's body.
[0055] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, acetate, bisulfate, bromide, chloride, citrate, iodide, nitrate, oleate, oxalate, pantothenate, sulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, tannate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium) and ammonium salts. Pharmaceutically acceptable salts may include those that contain another molecule, such as acetate, succinate or other counter ions. Counter ions may be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions. Thus, pharmaceutically acceptable salts may have one or more charged atoms and/or one or more counter ions.

[0056] The term "specific binding" of an antibody refers to antibody binding to a given antigen. Typically, an antibody binds with an affinity corresponding to a _KD of about ^10-8 M or less and binds to a given antigen with an affinity (as represented by a _KD) that is at least 10-fold, preferably at least 100-fold, lower than its affinity for binding to a nonspecific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein). Alternatively, an antibody can bind with an affinity corresponding to a KA of about ¹⁰⁶ M ^-1 or about ¹⁰⁷ M ^-1 or about ¹⁰⁸ M ^-1 or ¹⁰⁹ M ^-1 or higher and binds to a given antigen with an affinity (as represented by a KA) that is at least 10-fold higher, preferably at least 100-fold higher, than its affinity for binding to a nonspecific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein).

[0057] The term "treatment" refers to a clinical intervention designed to alter the natural course of an individual or cell being treated during a clinical pathology process or to prevent a clinical pathology process from occurring. Desirable effects of treatment include slowing the rate of disease progression, reversing or mitigating the disease state, and remission or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with respiratory disorders, such as pain, bronchitis, chills, confusion, cough, death, diarrhea, dyspnea, fatigue, fever, headache, inflammation, pale/gray/blue skin/lips/nail beds, pneumonia, rhinorrhea (nasal congestion), shortness of breath, sneezing, sore throat, vomiting, weakness, are ameliorated, reduced, eliminated, or prevented.

[0058] The term "trough level" refers to the lowest concentration in an individual's body of a therapeutic agent at which the therapeutic agent is in the therapeutic range or the concentration of the therapeutic agent before a further dose of the therapeutic agent is given.
[0059] The term "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains are sometimes referred to as "VH" and "VL", respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen-binding site. Therapeutic antibodies can be administered to the upper repiratory tract (also called the upper airway) and/or the lower repiratory tract (also called the lower airway). In some embodiments, the antibody is administered to both the upper and lower respiratory tract. The upper respiratory tract includes the nose and nasal cavities, the paranasal sinuses and the oral cavity and the pharynx and the part of the larynx above the vocal cords, while the lower respiratory tract is further divided into the conductive zone and the respiratory zone. The conductive zone is formed by the part of the larynx below the vocal cords, the trachea and the bronchi and bronchioles in the lungs. The respiratory zone is formed by the respiratory bronchioles, the alveolar ducts and the alveoli. The therapeutic antibody can be administered to the upper and/or lower respiratory tract by dry powder inhaler (DPI), injection, metered dose inhaler, nasal spray or nebulizer. A nebulizer is a drug delivery device that turns liquid medicine, such as the antibody composition described herein, into fine droplets (aerosol or mist) that are inhaled into the subject's lungs through a face mask or mouthpiece. Nebulizers include jet nebulizers, ultrasonic nebulizers and mesh nebulizers. Examples of nebulizers that can be used to administer therapeutic antibodies include Acorn and Acorn II® nebulizers (Vital Signs), AERx nebulizers (Aradigm), AeroDose nebulizers (AeroGen Inc., Mountain View, CA), Respimat nebulizers (Boehringer, Germany) and UltraVent™ nebulizers (Mallinckrodt). In some embodiments, the nebulizers used to carry out the methods herein are non-jet nebulizers and/or non-ultrasonic nebulizers. In some embodiments, the nebulizers used to carry out the methods herein are mesh nebulizers. Mesh nebulizers may be gentler and less disruptive to antibody structure. Antibody efficacy is highly dependent on its higher order structure or conformation. Antibodies are proteins that undergo multiple stages of complex protein folding during formation to generate their complex higher order structure. These stages are primary, secondary, tertiary and quaternary. The primary stage is a sequence of amino acids held together by peptide bonds. The secondary stage is a protein that has begun to fold (e.g., to form an alpha helix or a beta pleated sheet). Hydrogen bonds are formed between amino acids. The tertiary stage is the antibody tertiary structure when the protein folds into its 3D structure associated with its function. The quaternary structure is held together by various non-covalent interactions between side chains including ionic interactions, disulfide bridge formation, hydrophobic interactions, van der Waals forces and hydrogen bonds. The quaternary stage is when a single peptide binds to another peptide, e.g., when a heavy and light chain bind together. Antibodies may be sensitive to degradation by many types of physical and chemical stresses, such as freezing, heating, agitation, oxidation and pH changes. Any of the compositions herein may include a pharma- ceutically acceptable diluent, excipient or carrier.

[0060] The nebulizers described herein can be configured to generate a range of particle sizes. The particle size range can be within a predetermined range for deposition in both the lungs and the nasal cavity using the methods described herein. Particles outside the desired range may not be delivered to the nasal cavity in the desired distribution pattern or level. For example, in any of the methods described herein, operating the nebulizer to continuously form particles containing an agent can include forming particles with an average particle or droplet size (commonly defined as mass median aerodynamic diameter, MMAD) in the range of about 0.1 to about 200 microns (e.g., between about 1-10 microns, between about 2-7 microns, between about 2-20 microns, between about 10-40 microns, between about 20-60 microns, between about 30-70 microns, between about 40-80 microns, between about 50-90 microns, between about 60-100 microns, between about 70-110 microns, between about 80-120 microns, between about 90-130 microns, between about 100-150 microns, between about 125-200 microns, etc.). For example, operating the nebulizer to continuously form particles containing an agent can include forming particles with an average particle or droplet size in the range of about 2-7 microns. In some examples, the methods described herein can be used with two distributions of particle sizes, including smaller and larger particle sizes.

[0061] In some variations, inhaled respiratory medications can be administered using a device called a metered dose inhaler, or MDI. An MDI is a pressurized canister of medication in a plastic holder with a mouthpiece. When aerosolized, it can give a reliable, consistent dose of medication.

[0062] The present disclosure provides a therapeutic regimen that includes administering one or more therapeutic agents, including one or more antibodies, to a subject having or at risk of having a disorder (respiratory disorder). The dosing regimen for administration (e.g., therapeutic regimen) may vary depending on the age and size of the subject to be administered, the target disease, the antibody particles, the condition/health/disease state, and the route of administration. The dosing regimen can be more than once a day, but generally will be once or twice a day. In some variations, the dosing regimen may include more frequent administration of the therapeutic agent, e.g., three times a day, four times a day, etc. In some embodiments, the dosing regimen is administered once a day for only one day (i.e., only one dose). In some embodiments, the dosing regimen can continue for one day to an indeterminate period. In some embodiments, the dosing regimen continues for two, three, four, five, six, seven, etc. days or longer. In some embodiments, the dosing regimen may have regular dosing intervals, such as daily, every 2 days, every 3 days, weekly, every 2 weeks, monthly, etc., or between these dosing intervals. In some embodiments, the dosing regimen may be a non-variable dose regimen (e.g., each dose is the same amount) or a variable dose regimen (different doses are different amounts, e.g., more antibody in the first dose and less, e.g., half, a third, a quarter, etc., in subsequent doses). A once-daily delivery regimen may be convenient and promote successful compliance with the regimen. A delivery regimen more frequent than once-daily may be less convenient, but there may be advantages to more frequent delivery than once-daily. For example, for some therapeutics, e.g., expensive monoclonal antibodies, the total amount of therapeutic delivered in two doses may be less than the amount of therapeutic that would be delivered in a single once-daily dose, and a delivery regimen of two (or optionally more) doses per day may lead to lower costs. As illustrated in Example 4, either a single high dose once daily or a substantially lower dose twice daily can be administered to minimize trough levels becoming too low and losing efficacy. Each of these two doses can be sufficiently low to more than compensate for the inconvenience of administering the dose twice daily. Thus, providing once-daily versus twice-daily (e.g., three times) dosing can balance the convenience and efficient use of the antibody depending, for example, on antibody manufacturing costs, accessibility of delivery options (e.g., self-administration, availability of medical professionals to administer the therapeutic, use of medical facilities to administer the therapeutic, etc.).

[0063] Specific Antibodies and Their EC50s A variety of drug agents can benefit from the nebulized delivery methods and devices described herein. In particular, these methods and devices can benefit from drug agents for treating respiratory disorders that affect at least one of the upper and lower airways, but typically benefit (treat) both the upper and lower airways. In some embodiments, the methods and devices can be useful for alleviating symptoms (e.g., from respiratory infections) in the upper airways, as well as for treating the lower airways, which are typically more associated with hospitalizations and other severe adverse outcomes. These methods and devices can be particularly effective in delivering drug agents that are configured as mucosal binding and/or sequestering agents. For example, the methods and devices as described herein may be particularly useful and/or effective when the drug agent is a recombinant antibody comprising oligosaccharides having a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, with a terminal N-acetylglucosamine on each branch that enhances the capture efficacy of the recombinant antibody in mucus. In some examples, the drug agent includes a recombinant antibody comprising a human or humanized Fc region, the recombinant antibody comprising a population of antibodies in which at least 20% (e.g., 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, etc.) of the antibodies comprise oligosaccharides having a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1 with a terminal N-acetylglucosamine on each branch that enhances the capture efficacy of the recombinant antibody in mucus.

[0064] The methods and devices described herein can be used to treat subjects with or at risk of having a respiratory disorder by administering one or more therapeutic antibodies. Examples of antibodies that can be used with the methods and devices herein include anti-cluster of differentiation 39 (CD39) antibodies, such as those described in US20210388105A1, that have an antibody or antigen-binding fragment thereof that can specifically bind to human cluster of differentiation 39 (CD39). The antibody or antigen-binding fragment thereof can specifically bind to human CD39 with a half maximal effective concentration (EC50) of ≧10 ⁻⁸ M as measured by a fluorescence-activated cell sorting (FACS) assay. CD39 has been implicated in the pathogenesis of cigarette smoke-induced lung inflammation in patients and preclinical mouse models.

[0065] Another antibody that can be used with the methods and devices herein is an anti-influenza B antibody as disclosed in US20210171612A1 (Regeneron Pharmaceuticals Inc., Tarrytown, NY). The anti-influenza B antibody can be an IgG1 or IgG4 antibody that confers increased protection from influenza B virus in animals (e.g., mammals) when administered either subcutaneously or intravenously and/or before or after infection with influenza B virus, and can reduce headache, fever, pain, rhinorrhea (nasal congestion), chills, fatigue, weakness, sore throat, cough, shortness of breath, vomiting, diarrhea, pneumonia, bronchitis symptoms, and/or death. The anti-influenza B antibody binds to influenza B HA and has an EC50 of less than about ^10-9 M.

[0066] Another antibody that can be used with the methods and devices herein is an anti-PCRV antibody as disclosed in US20200392210A1 (Regeneron Pharmaceuticals Inc. Tarrytown, NY). The anti-PCRV antibody can bind to the V-tip protein (PcrV) of P. aeruginosa and inhibit or neutralize the activity of the bacterial type 3 secretion system (T3SS) in P. aeruginosa. The antibody is believed to be useful for blocking the transfer of toxins from bacteria to host cells and/or preventing the death of host cells. The anti-PCRV antibody can function by blocking pore-mediated membrane permeability in host cells. The anti-PCRV antibody can bind to full-length PcrV and has an EC50 of less than about ^10-8 M. As disclosed in US20200392210A1, patients at greater risk of P. aeruginosa infection may be those who have cystic fibrosis, have diabetes, are on a ventilator, are undergoing surgery, have tuberculosis, have HIV, have a compromised immune system, have neutropenia, have an indwelling catheter, after physical trauma, have burns, are in an intensive care unit, are bedridden, have a malignancy, have chronic obstructive pulmonary disease, are in a long-term care facility, or are intravenous drug users.

[0067] Another antibody that can be used with the methods and devices herein is an anti-PD1 antibody (Apollomics Inc., Foster City, Calif.) as disclosed in US10981994B2. The anti-PD-1 antibody can be a humanized antibody having a PD-1 binding EC50 of about 200 ng/ml or less, or about 150 ng/ml or less, or about 100 ng/ml or less, or about 80 ng/ml or less, or about 60 ng/ml or less as measured by ELISA or FACS. The provided anti-PD-1 antibodies and fragments thereof bind to PD-1 on T cells and disrupt the PD-1/PD-L1 interaction, resulting in increased T cell activation. US10981994B2 discloses that IgG1 and IgG4 versions of the humanized 7A4 and 13F1 antibodies have been produced. Anti-PD-1 antibodies may be useful for treating infectious diseases including respiratory diseases, such as candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal conditions, gram-negative sepsis, tuberculosis, mononucleosis, influenza, respiratory disease caused by respiratory syncytial virus, malaria, schistosomiasis, and trypanosomiasis. Another antibody that can be used with the methods and devices herein is bamlanivimab/etesevimab (created by Eli Lilly). Eli Lilly's monoclonal antibody, bamlanivimab (LY-CoV555, also known as LY3819253), was originally derived from the blood of one of the first U.S. patients to recover from COVID-19. It is a recombinant neutralizing monoclonal antibody against the SARS-CoV-2 spike protein. Eli Lilly's Etesevimab (LY-CoV016, aka JS016, aka LY3832479) is a monoclonal antibody against the receptor binding domain of the SARS-CoV-2 surface spike protein. Another antibody that can be used with the methods and devices herein is Bebtelovimab. The monoclonal antibody Bebtelovimab (Eli Lilly, Indianapolis, IN) is used for the treatment of mild to moderate COVID-19. Bebtelovimab binds to the SARS-CoV-2 spike protein. Bebtelovimab was administered as a single 175 mg intravenous injection over at least 30 seconds. Bebuterobimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody with two identical light chain polypeptides, each composed of 215 amino acids, and two identical heavy chain polypeptides composed of 449 amino acids. It is produced by Chinese Hamster Ovary (CHO) stable bulk cultures or cell lines and has a molecular weight of 144 kDa. Bebuterobimab is a recombinant neutralizing human IgG1 lambda monoclonal antibody (mAb) against the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bebuterobimab binds to the spike protein with a dissociation constant KD=0.046-0.075 nM and blocks spike protein binding to the human ACE2 receptor with a reported IC50 value of 0.39 nM (0.056 mcg/mL). Another antibody that can be used with the methods and devices herein is casirivimab/imdevimab (made by Regeneron, under the trade name REGEN-COV). Regeneron's REGEN-COV (previously also known as REGN-CoV2 or REGEN-CoV2) are two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain: casirivimab (REGN10933) and imdevimab (REGN10987). Another antibody that can be used with the methods and devices herein is regudanvimab or CT-P59 (Celltrion). Regudanvimab is a recombinant human monoclonal antibody targeted against the receptor binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a recombinant monoclonal antibody expressed in CHO-K1 cells. Dose-dependent binding of the CT-P59 clinical batch to the RBD was found, as shown by the half maximal effective concentration (EC50) of CT-P59 against the SARS-CoV-2 RBD protein of 4.4 ng/ml.

[0068] Another antibody that can be used with the methods and devices herein is sotrovimab (produced by Vir Biotechnology/GSK). Sotrovimab (formerly VIR-7831) is reported to bind to a highly conserved epitope in the receptor binding domain of the SARS-CoV-2 viral spike protein. Other antibodies that can be used with the methods and devices herein are tixagevimab/cilgavimab (AZD7442, trade name Evusheld™, produced by AstraZeneca). Evusheld™ has been granted emergency approval as pre-exposure prophylaxis against COVID-19 in immunocompromised individuals or those unable to vaccinate or mount an immune response after vaccination. AZD7442 contains two monoclonal antibodies, tixagevimab (AZD8895) and silgavimab (AZD1061), that target the receptor-binding domain of the SARS-CoV-2 spike protein.

[0069] The methods and devices described herein may be particularly useful for the treatment of respiratory disorders. In some embodiments, the disclosure provides a method of treating (ameliorating, alleviating or reducing) the severity, duration or frequency of occurrence of at least one symptom of a disorder, or preventing the disorder altogether. Symptoms that the methods of the disclosure can treat or prevent may be one or more of headache, fever, pain, rhinorrhea (nasal congestion), chills, fatigue, weakness, sore throat, cough, shortness of breath, vomiting, diarrhea, pneumonia, bronchitis, inflammation and death. The inflammation and other symptoms may be acute or chronic. The causative agent of the disorder may include one or more of disease, environmental factors, genetic factors, illness, infection, pathogens, toxins and or trauma. Pathogens may include archaea, eubacteria, fungi, protozoa and/or viruses. In some embodiments, the pathogen is a respiratory pathogen, and may be a bacteria (Haemophilus (such as Haemophilus influenzae, Haemophilus influenzae type B), Morazella (Morazella catarrhalis), Pseudomonas (Pseudomonas aeruginosa), Staphylococcus (Staphylococcus aureus), Streptococcus (Streptococcus pneumoniae), Streptococcus pyogenes, or a combination of both. The pathogenic bacteria may be a fungus (e.g., Aspergillus, Blastomyces, Candida, Cryptococcus, Histoplasma, mold, yeast, zygomycete) or a virus (such as adenovirus, coronavirus, influenza virus, metapneumovirus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), parainfluenza virus, respiratory syncytial virus, severe acute respiratory syndrome coronavirus (SARS-CoV), rhinovirus, SARS-CoV-2). Other respiratory disorders that can be treated using the methods and devices herein include asthma, rhinitis, pulmonary fibrosis, cystic fibrosis, and chronic obstructive pulmonary disease.

[0070] For the treatment of respiratory disorders, one (or more than one) additional therapeutic agent can be optionally used in combination with the antibodies described herein. The additional therapeutic agent can be a short-acting beta-agonist, e.g., a catecholamine or a non-catecholamine agent. Examples include, but are not limited to, albuterol (ProAir HFA, Proventil HFA, Ventolin HFA), bitolterol, carbuterol, clenbuterol, epinephrine (Asthmanefrin, Primatene Mist), levalbuterol (Xopenex HFA), metaproterenol (Alupent), pirbuterol (Maxair), procatenol, terbutaline (Brethine) or other bronchodilators. The additional therapeutic agent may be an anticholinergic, such as ipratropium (Atrovent) or other mucus reducing agent. The additional therapeutic agent may be a corticosteroid, such as methylprednisolone and prednisone or other swelling reducing agent. Anti-inflammatory drugs can be optionally used in combination with the antibodies of the present disclosure for the treatment of respiratory disorders. Anti-inflammatory drugs include, but are not limited to, acetaminophen, aspirin, dexamethasone, diphenhydramine, meperidine, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac, and indomethacin and ibuprofen.

[0071] In an example shown by the schematic diagram in FIG. 3, the method 100 may include instructing and/or guiding the patient to administer an inhaled dose by first (optionally) sitting upright 101. The patient may then activate the nebulizer to continuously provide atomized medication 103. For example, the method may include guiding the patient to press an on/off button on the nebulizer to begin treatment (e.g., in some examples, the button turns green and a mist begins to appear at the mouthpiece and/or backside of the nebulizer). The method may then guide the patient to hold the mouthpiece of the nebulizer between the lips, including holding the mouthpiece with the teeth and/or lips and closing the lips around the mouthpiece 105.

[0072] The method may then include activating (e.g., triggering) a first indicator to coach or guide the patient in inhaling the atomized medication through the mouth 107. The first indicator may be, for example, a light (LED(s)), sound, message, countdown, etc., that remains on while the patient inhales to guide the patient to inhale more deeply and draw in the atomized medication through the mouth. The indicator may count (e.g., count up or down). The indicator may be automatically initiated, including with or without input from the patient by the controller. In some examples, the patient may manually trigger the initiation (activation) of the first indicator. Alternatively, in some examples, the first indicator may be triggered upon sensing (e.g., in the nebulizer and/or in the dose guide device) that the patient has begun inhaling through the mouth. The first indicator may remain on, for example, for an inhalation period of 4 seconds or more (e.g., 4 seconds, 4.5 seconds, 5 seconds, 6 seconds, 7 seconds, etc.). The inhalation period may be fixed or set (e.g., by a user, e.g., a doctor, nurse, pharmacist, and/or patient), or may be variable. In some examples, the inhalation period may change to indicate that a minimum inhalation period (e.g., 4 seconds, 4.5 seconds, 5 seconds, etc.) has been reached, but indicates that continued inhalation is recommended. For example, a first indicator may be on for the 4 second minimum inhalation period using a first sound, color, etc., and may remain on for another 2-3 seconds, but change to a first optional/continuation indicator using a second sound, color, etc. For example, the nebulizer and/or dose guide device may change from red to yellow, or some other change, to indicate that inhalation may optionally continue.

[0073] The first indication (and/or the first optional/continuation indicator) can, for example, be automatically turned off after the patient has finished inhaling and/or begun exhaling through the nebulizer. The methods and devices can include sensing inhalation and/or exhalation. For example, the nebulizer and/or dose guide device can include one or more sensors to detect or estimate the start/stop of inhalation and/or exhalation. For example, the nebulizer can include one or more sensors to detect flow or pressure at the mouthpiece. The flow sensor can be used to determine the start and/or stop of inhalation through the mouthpiece. Any of these methods and devices can include a controller (including one or more processors) capable of implementing these methods, including activating the first indicator, the second indicator, etc. The controller can analyze sensor data to activate the first and/or second indicator.

[0074] In general, the methods described herein may include instructing or guiding the patient to breathe in breaths such that each breath is slow and long, and until the patient's lungs are as full as possible (e.g., breathing as deeply as possible). Each internal breath should last at least four seconds or more as described109.

[0075] The second indicator to guide the patient for a rapid (e.g., 3 seconds or less) exhalation may be automatically initiated as described above (e.g., at the cessation of inhalation) or based on a preset and/or configurable timer. In general, the method may include turning off the first indicator and/or activating the second indicator to guide exhalation 111. Because the exhalation phase is intended to be rapid and brief, the second indicator may include a "stop" indicator to warn the user to stop after a second (exhalation) period of 3 seconds or less (e.g., 2 seconds). For example, in some cases, the second indicator may include the first phase from the start of exhalation to the end of the exhalation phase (2-3 seconds) 113, after which the second indicator may change to highlight that exhalation must be completed, for example, by changing volume, sound, intensity, color, continuity, etc. (e.g., flashing). The second indicator may then be turned off or otherwise stopped 115.

[0076] Thus, during inhalation, the patient may be instructed and/or guided to exhale through the nose and attempt to complete exhalation within about 3 seconds (within about 2 seconds, within about 2-3 seconds, etc.). As discussed herein, this allows the atomized drug agent (e.g., mist) to be directed in a desired distribution from the patient's lungs into the nose where it can be captured and treatment can be provided to this area.

[0077] After completing the long inhale/rapid exhale, the patient may be instructed to rest, e.g., breathe normally without the nebulizer for one or more breaths, or perform another cycle of long inhale/rapid exhale 117. For example, the patient may need to rest or may have a cough or urge to cough. The patient may press the on/off button to stop the nebulizer. Treatment can be continued by pressing the on/off button on the nebulizer and/or dose guide device again to begin inhaling through the mouthpiece and exhaling through the nose (repeated steps 107-117 in FIG. 6). The patient may rest for as long as necessary.

[0078] Treatment can continue until the desired (e.g., preset, user-set, etc.) dose is delivered. In some examples, treatment can continue including multiple cycles of long inhale/rapid exhale until the nebulizer and/or dose guide device indicates that the full treatment dose has been delivered. For example, treatment can continue until the nebulizer issues an alarm (e.g., beep and/or flash of light) indicating treatment is complete. The device can automatically turn off. Any of the methods (including user interfaces) described herein can be implemented as software, hardware or firmware and may be described as a non-transitory computer-readable storage medium (e.g., computer, tablet, smartphone, etc.) that stores a set of instructions executable by a processor that, when executed by the processor, causes the processor to control to perform any of the steps including, but not limited to, displaying, communicating with the user, analyzing, modifying parameters (including timing, frequency, intensity, etc.), determining, alerting, etc.

[0079] As described above, the device may be configured to perform any of the methods described herein. For example, the device may be configured as a nebulizer integrated with (or forming) a dose guide device. The nebulizer may be configured to emit a first indicator, such as a sound (e.g., a beep, etc.) or illumination of one or more LEDs (e.g., a countdown of LEDs), and a second indicator, such as a second sound or illumination of a different color or set of LEDs, etc. As described above, the nebulizer includes one or more sensors for detecting and triggering the start of inhalation and/or exhalation, allowing the device to count down and guide the user in inhalation and exhalation as described herein.

[0080] In some examples, a separate dose guidance device can be used with the nebulizer. For example, the dose guidance device can be software. In some examples, the software can run on a processor in a wearable or handheld computing device, e.g., a smartphone.

[0081] These methods and devices can be used with any type of nebulizer. For example, these devices can be used with jet nebulizers, which use compressed gas to create an aerosol, ultrasonic nebulizers, which form an aerosol by high frequency vibrations, and/or mesh nebulizers, in which a liquid is passed through a very fine mesh to form an aerosol. In particular, these methods can be used with continuous nebulizers, which when turned on, form particles continuously. Alternatively, these methods can be used with on-demand nebulizers.

[0082] In general, the methods and devices described herein can accommodate aerosol particles of a specified or predetermined size or size distribution. For example, particles of drug agent (MMAD) can be in the range of about 0.1 to about 200 microns (e.g., between about 1-10 microns, between about 2-7 microns, between about 2-20 microns, between about 10-40 microns, between about 20-60 microns, between about 30-70 microns, between about 40-80 microns, between about 50-90 microns, between about 60-100 microns, between about 70-110 microns, between about 80-120 microns, between about 90-130 microns, between about 100-150 microns, between about 125-200 microns, etc.). For example, drug-containing particles can have a particle or droplet size in the range of about 2-7 microns. In some examples, the methods described herein can be used with two particle size distributions including smaller and larger particle sizes.

[0083] Any suitable drug agents may be used, including, but not limited to, drug agents that are mucosally trapped drug agents and/or immunotherapeutic agents. Generally, these drug agents may be drug agents for treating respiratory disorders/diseases, including respiratory transmitted disorders/diseases.

[0084] In particular, the drug agents described herein may be any of the methods and compositions described in, for example, U.S. Pat. Nos. 10,829,543, 10,100,102, 10,793,623, U.S. Patent Application No. 16/982,682 (entitled "COMPOSITIONS AND METHODS FOR INHIBITING PATHOGEN INFECTION" and filed on March 20, 2019), U.S. Patent Application No. 17/063,122 (entitled "OPTIMIZED CROSSLINKERS FOR TRAPPING A TARGET ON A TARGET OF A TARGET OF A TARGET OF A TARGET of ... No. 17/278,217 (entitled "SYNTHETIC BINDING AGENTS FOR LIMITING PERMEATION THROUGH MUCUS" and filed on September 23, 2019), each of which is incorporated herein by reference in its entirety.

[0085] For example, the methods described herein may be particularly useful for delivering a dose of a drug agent configured to have enhanced capture efficacy in mucus, including, but not limited to, a protein (e.g., an antibody) that includes one or more glycosylation patterns that enhance capture in mucus. In some examples, the drug agent may be a recombinant antibody that includes oligosaccharides having a G0 glycosylation pattern that includes a biantennary core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1 with a terminal N-acetylglucosamine at each branch that enhances the capture efficacy of the recombinant antibody in mucus. For example, the drug agent can be a recombinant antibody comprising a human or humanized Fc region, the recombinant antibody comprising a population of antibodies comprising oligosaccharides having a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, at least 40% of which have a terminal N-acetylglucosamine at each branch that enhances the capture efficacy of the recombinant antibody in mucus.

[0086] The techniques and procedures described or referenced herein may be modified, for example, from Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Current Protocols in Molecular Biology (F. M. Ausubel et al. (eds.), (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor (eds.) (1995)), Harlow and Lane (ed.) (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R. I. Freshney (ed.) (1987)); Oligonucleotide Synthesis (M. J. Gait et al. (ed.) 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis (ed.) 1998) Academic Press; Animal Cell Culture (RI. Freshney) (ed., 1987); Current Protocols in Immunology (J.E. Coligan et al. (eds.), 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty (ed.), IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean (Ed.), Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor) Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra (eds.), Harwood Academic Methods and techniques for identifying amino acid sequences in constant and variable regions are well known in the art and can be used to identify CDRs within the specific HCVR and/or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, 1995. See, J. MoI. Health, Bethesda, Md., (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies. For example, software packages and databases for determining antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites and sequence alignments are available (e.g., GenBank, Vector NTI® suite (Informax, Inc, Bethesda, Md.); GCG Wisconsin package (Accelrys, Inc., San Diego, CA). Diego, Calif.); DeCypher® (TimeLogic Corp., Crystal Bay, Nev.); Menne et al. (2000) Bioinformatics 16:741-742; Menne et al. (2000) Bioinformatics Applications Note 16:741-742; Wren et al. (2002) Comput. Methods Programs Biomed, 68:177-181; von Heijne (1983) Eur. J. Biochem. 133:17-21; von See Heijne (1986) Nucleic Acids Res. 14:4683-4690).

[0087] Using a variety of mAbs with different variable regions, but with the same common Fc region (e.g., SEQ ID NO:1), we surprisingly demonstrated that despite the widely held belief that such proteins in the lungs would be rapidly cleared (within hours if not minutes), such mAb proteins, especially those that were glycosylated to increase mucus capture, instead persisted at therapeutically appreciable levels for days when inhaled in safe and reasonable amounts during monotherapy as described herein.

[0088] The results described herein are not limited to mAbs against pathogens. For example, the same Fc region can be used with mAbs that are anti-inflammatory and therefore will generally show the same clearance profile as described herein. Anti-pathogen and anti-inflammatory mAbs can be administered together to treat hospitalized patients, and the methods and compositions described herein can be used for indications where anti-inflammatory mAbs are used alone.

[0089] As shown in the Examples below, the results described herein are particularly surprising given that increased mucoadhesion, e.g., from having a mAb with a "mucus-capturing" Fc domain by enriching for G0 glycosylation, has long been thought to lead to faster clearance by mucosa, and surprisingly, the methods and compositions described herein may persist long enough to sustain meaningful concentrations after 24 hours in both the URT and LRT.

Example 1
Human IgG G1 Fc region
[0090] Human IgG G1 Fc region (IN-006, a reformulation of regdanvimab), with an Fc region homologous to SEQ ID NO:1, was investigated as part of a study conducted in Australia. Study staff and participants were blinded to treatment assignment, except for the pharmacy staff preparing the study drug. Primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetic assessment of IN-006 in nasal fluid and serum.

[0091] Twenty-three participants were enrolled and randomized across two single-dose and one multiple-dose cohorts. There were no serious adverse events (SAEs). All enrolled participants completed the study without treatment interruptions or discontinuations. All treatment-emergent adverse events were transient, graded as mild to moderate in severity, and not dose-related. Inhalation administration was well tolerated and completed in a mean of 6 minutes for the high-dose group. Mean nasal fluid concentrations of IN-006 in the multiple-dose cohort were 921 μg/mL at 30 minutes and 5.4 μg/mL at 22 hours. Mean serum levels in the multiple-dose cohort peaked at 0.55 μg/mL 3 days after the final dose.

[0092] IN-006 was well tolerated and achieved airway concentrations several orders of magnitude above its inhibitory concentrations. These data support further clinical development of IN-006.
[0093] SARS-CoV-2, like many viruses that cause acute respiratory infections (ARI), infects cells almost exclusively through the apical (luminal) side of the airway epithelium and buds off from infected cells primarily through the apical surface. As infection spreads from the upper respiratory tract (URT) to the lower respiratory tract (LRT) and into the deep lung, progeny virus must travel through airway mucus to reach uninfected epithelial cells. Thus, neutralizing monoclonal antibodies (mAbs) must reach the airway lumen in sufficient quantities to effectively neutralize the virus and stop infection.

[0094]mAbs distribute very poorly and slowly from blood to the airways, with concentrations in the airways orders of magnitude lower than those in serum after intravenous (IV) or intramuscular (IM) administration. Despite these limitations, clinical experience to date indicates that mAbs that neutralize SARS-CoV-2 can be effective in treating infected individuals at high risk for severe COVID if administered IV early in the course of infection. Nevertheless, high doses of mAbs are generally required to do so, reducing the available drug supply. Delayed distribution to the lungs also limits the treatment window for preventing severe COVID.

[0095] Inhalation administration has been used to deliver protein therapeutics (e.g., Pulmozyme) directly to the lungs, allowing dosing within minutes. Importantly, direct inhalation delivery can achieve significantly higher concentrations of drug in the lungs than can be achieved by IV or IM administration, and does so within minutes. Because the pattern of deposition along the airways is determined in large part by the aerosol droplet size, it is possible to use nebulizers that generate a wide aerosol size distribution to deliver drug throughout the airways, from the nasal turbinates in the URT, through the conducting airways in the LRT, to the deep lung. Thus, nebulized delivery is likely the fastest way to achieve high inhibitory concentrations of mAbs in airway fluids. Inhalation administration also allows for convenient home self-dosing, reducing the burden on patients and on the medical infrastructure associated with systemic delivery.

[0096] IN-006 is a reformulation of regdanvimab configured as described herein specifically for nebulized delivery as an inhalation treatment for COVID-19. Regdanvimab, an IV-administered human IgG1 mAb against the SARS-COV-2 spike protein receptor binding domain (RBD), is approved in the European Union for adults with COVID-19 who do not require supplemental oxygen and are not at increased risk for progression to severe COVID-19.

[0097] A double-blind, placebo-controlled, first-in-human, ascending-dose pharmacokinetic and safety study was conducted in a Phase 1 unit in Melbourne, Australia. The study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines, in compliance with local regulatory requirements, and was approved by The Alfred Hospital Office of Ethics and Research Government, Melbourne, Victoria, Australia. Informed consent was obtained prior to all study-related procedures. Eligible participants were enrolled sequentially into three cohorts: a single low-dose cohort (30 mg), a single high-dose cohort (90 mg), and a multiple high-dose cohort (seven daily 90 mg doses). For each single-dose cohort, a sentinel pair (with one active and one placebo recipient) was dosed first, followed by a 2-day safety monitoring period before dosing of the remainder of the cohort. Transition to subsequent cohorts occurred after review of safety parameters 7 days after dosing of the preceding cohort. Figure 3 shows a diagram of the study structure and time of pharmacokinetic assessments.

[0098] Eligibility criteria required participants to be adult 18-55 years of age, in good health as judged by medical history, physical examination, clinical chemistry and hematology evaluation, electrocardiogram, forced expiratory volume in 1 second (FEV ₁ ) ≥ 90% predicted, and negative serology for HBsAg, HCV and HIV antibodies, with a body mass index of 18-32 kg/m ^2. Participants were required to be non-smokers or light smokers. The FEV ₁ threshold was changed to ≥ 80% predicted after enrollment of the first 7 participants. Participants were excluded for known or suspected symptomatic viral infection or signs of pulmonary infection or pulmonary inflammatory conditions within 14 days of starting dosing, airway hyperresponsiveness, angioedema, history of anaphylaxis, or a positive alcohol breathalyzer and/or urine drug screen for drug abuse. Upon recruitment of seven participants including the first single dose cohort, participants receiving a COVID-19 vaccine were excluded, however, due to the rapid increase in local vaccine availability and uptake, this criterion was modified to exclude only those who had been vaccinated within 2 weeks of their first dose or planned to be vaccinated within 2 weeks of completing dosing.

[0099] The primary endpoint of the trial was the safety and tolerability of IN-006. This was assessed by monitoring treatment-emergent adverse events, pre- and post-dose vital signs, ECG, FEV ₁ , SpO ₂ , hematological and chemical safety blood tests, and physical examinations. Follow-up lasted for 28 days and was assessed on the days indicated in Figure 3. Exploratory outcomes were drug levels in nasal fluid and serum at pre- and post-dose intervals. The randomization schedule was prepared using software (SAS) that was validated by a statistical team member not responsible for monitoring and data management of the study, with one active and one saline placebo assignment for each sentinel pair, with an overall ratio of active to placebo assignment of each cohort of 3:1. The randomization codes were held by unblinded pharmacy staff, who prepared the doses in matching syringes with identical appearance for loading into the nebulizers by the clinical staff.

[0100] IN-006 was manufactured under Good Manufacturing Practices (GMP) and supplied by the manufacturer as a liquid formulation in glass vials. IN-006 was provided in a syringe to be loaded into an InnoSpire Go vibrating mesh nebulizer (Koninklijke Philips N.V.). Placebo participants received an identical syringe containing saline instead of IN-006. Participants were instructed to breathe slowly through the nebulizer mouthpiece and exhale through their nose. Nasal fluid was obtained by rotating a flocked swab (Copans catalog number 56380CS01) at mid-turbinate depth (4-5 cm) for 10-15 seconds. Sampling alternated between the right and left nostrils during subsequent sampling time points. The amount of nasal fluid sample collected by each individual swab was determined by comparing pre- and post-weights. This was accomplished by weighing the sample-containing swabs and sample tubes before and after being incubated in buffer for extraction, rinsed, and oven-dried. Nasal fluid and serum sampling times are shown in Figure 3. Vital signs and FEV ₁ were measured before, 15 and 30 minutes after completion of inhalation administration. IN-006 concentrations were measured in human serum and nasal fluid. Sample size was selected according to convention for phase I in human studies. No formal sample size and power calculations were performed. Continuous variables were summarized using descriptive statistics including number of non-missing observations, mean, SD, median, minimum and maximum. Categorical variables were summarized using frequency counts and percentages. Placebo recipients from different cohorts were pooled. Safety analyses included all randomized participants who received any dose of study drug. The pharmacokinetic population included all participants who received any dose of IN-006. No inferential statistical tests were performed. Serum PK parameters of IN-006 were determined using Phoenix WinNonlin version 8.3.

[0101] Of the 102 screened adults, 23 participants were assigned sequentially to one of three cohorts. The first participant was randomized on September 22, 2021, and the last participant visit was December 29, 2021. Of these participants, 17 were randomly assigned to receive IN-006 and 6 were randomly assigned to receive placebo. All 23 participants received their assigned treatment as intended and completed their last study visit on study day 29. They completed the study on December 29, 2021. Participant flow is diagrammed in Figure 3 and participant demographics are listed in Table 1 (Figure 1).

[0102] Treatment-emergent adverse events (TEAEs) are listed in Table 2 (Figure 2). Inhaled administration of IN-006 was well tolerated and was completed in an average of 6 minutes for the 90 mg dose (range 4-9 minutes). Eight of 15 participants (53.3%) included in the single ascending dose cohort experienced at least one TEAE (6 receiving IN-006 and 2 receiving placebo). The most frequently reported TEAEs were headache (4/15; 26.7%) and oropharyngeal pain (2/15; 13.3%). All but one TEAE was mild. One participant receiving the low dose (30 mg) of IN-006 experienced a moderate event (increased transaminases on day 29) that was considered unrelated to study drug by the investigator. Three (3/15; 20.0%) participants experienced at least one TEAE that was considered by the investigator to be related to the study drug. These events included headache, cough, and oropharyngeal pain. All three related TEAEs were mild and resolved. There was no evidence of a dose-related effect.

[0103] In the multiple dose cohort, no TEAEs were reported in participants receiving placebo. Among the six participants receiving IN-006, four (66.7%) participants experienced at least one TEAE. The most frequently reported TEAE was dizziness (2/6; 33.3%). All but one TEAE was mild. One single dose participant receiving IN-006 experienced a moderate event (extreme pain). The event was considered unlikely to be related to the study drug by the investigator. Two (33.3%) participants experienced at least one TEAE considered to be related to the study drug by the investigator. These drug-related TEAEs were dizziness and a decline in FEV ₁ , the latter of which was noticed 15 minutes after inhalation administration, was not accompanied by symptoms or abnormal vital signs, resolved within 15 minutes, and did not recur with subsequent doses. Both events were mild in severity.

[0104] No serious TEAEs, SAEs, or TEAEs leading to discontinuation were reported in any of the single-dose or multiple-dose cohorts. There were no unexpected safety signals.
[0105] For the single dose cohort, the mean nasal concentrations measured 3 hours after dosing were 261 μg/g and 710 μg/g for the 30 mg and 90 mg doses, respectively; these values are consistent with a three-fold increase in the dose administered. In the multiple dose cohort, repeated dosing provided additional opportunities for more nasal concentration measurements over more time points. Nasal concentrations measured 30 minutes after dosing on days 1, 2, and 3 averaged 773 μg/g, which is higher than the concentration measured 3 hours after dosing (405 μg/g). This indicates that peak exposure occurred immediately after dosing, with nasal concentrations appreciably declining by 3 hours after dosing. There was minimal intranasal accumulation, as the concentration of IN-006 measured 22 hours after dosing was <2% of the concentration immediately after dosing (Figures 4A-4C). The difference in nasal concentrations between 30 minutes and 22 hours post-dose suggests an interval spanning approximately 6-7 half-lives, while the difference between 30 minutes and 3 hours post-dose was approximately half that, both consistent with an intranasal half-life of approximately 3-4 hours and significantly longer than the timescale of mucociliary clearance transit time estimates of approximately 5-15 minutes obtained from saccharin transit time studies.

[0106] As shown in Figures 5A-5B, serum concentrations of IN-006 were detectable by 12 hours after inhaled administration for the 90 mg dose and continued to rise by 120 hours after a single dose (Cohorts 1 and 2) or 216 hours after the first dose for those receiving multiple doses (Cohort 3). The elimination half-life of IN-006 in serum was estimated to be approximately 253, 292, and 402 hours in the 30 mg single dose, 90 mg single dose, and seven daily 90 mg dose cohorts, which is comparable to the previously estimated elimination half-life of regdanvimab from serum after intravenous administration (288 hours). Although the serum concentrations of IN-006 were significantly lower than those in the nasal fluid (serum C _max of 0.52 μg/mL compared to 990 μg/mL in the nasal fluid), they were still significantly higher than the IC ₅₀ of IN-006 (approximately 0.01 μg/mL).

[0107] The long-standing theory is that it is very difficult to nebulize mAbs stably (e.g., Respaud, R et al., Nebulization as a delivery method for mAbs in respiratory diseases. Expert Opin Drug Deliv, 2015.12(6):1027-39; Mayor, A et al., Inhaled antibodies: formulations require specific development to overcome instability due to nebulization. Drug Deliv Transl Res, 2021.11(4):1625-1633; Bodier-Montagutelli, E et al., Protein stability during nebulization: Mind the collection step! Eur J Pharm Biopharm, 2020.152:23-34; and Bodier-Montagutelli, E et al., Designing inhaled protein therapeutics for topical lung delivery: what are the next steps? Expert Opin Drug Deliv. 2018.15(8):729-736), and it has been suggested that biological drugs would be rapidly cleared from the airways either by systemic absorption, physical mucociliary clearance, or degradation by alveolar macrophages, making it difficult to sustain therapeutic concentrations. See, e.g., Loira-Pastoriza, C., J. Todoroff, and R. Vanbever, Delivery strategies for sustained drug release in the lungs. See Adv Drug Deliv Rev, 2014.75:81-91 and Suri, R. The use of human deoxyribonucleotide (rhDNase) in the management of cystic fibrosis. BioDrugs, 2005.19(3):135-44.

[0108] Surprisingly, IN-006, a reformulation of regdanvimab for nebulized delivery, as described herein, was safe and well tolerated in healthy adults with minimal side effects, with high drug concentrations recovered from nasal and serum samples, and sustained therapeutic concentrations. This may be due in part to glycosylation of the therapeutic antibody as described herein in combination with the administration technique. Treatment was easily self-administered by all participants and completed within minutes. Encouragingly, concentrations of IN-006 measured in nasal secretions were well above its _IC50 even 22-24 hours after dosing. In the multiple-dose cohort receiving seven daily 90 mg doses, a mean nasal fluid IN-006 concentration of 920 μg/mL was observed 30 minutes after the first dose, and maintained a mean concentration of 5.4 μg/mL 22 hours later, prior to receiving the second dose. The ability to maintain mAb concentrations that were in the range of 3-7 orders of magnitude higher than the _IC50 of regdanvimab and other COVID mAbs against susceptible variants (~4-20 ng/mL) strongly supports our proposed once-daily dosing regimen. Because SARS-CoV-2 infection and replication begins in the upper respiratory tract, we suggest that our efficient delivery of IN-006 to the nasal cavity may provide a more highly effective treatment of early COVID-19, allowing for earlier resolution of infection and reduced risk of progression to severe COVID.

[0109] Although mAbs have proven to be effective therapeutics for COVID-19, the need for administration by IV, IM or SC routes has limited the scope of their use in clinical practice. The need for infusion centers and post-dosing observation for intravenous administration severely limited the number of treated patients and significantly increased costs. IM injections shorten administration time but are limited by the volume that can be administered per injection (approximately 5 mL), which in turn limits the dose of mAb that can be administered per injection and can be painful if the maximum injection volume is used. In contrast, nebulized delivery using handheld nebulizers allows the convenience of dosing at home and takes only a few minutes to complete. Furthermore, IV, IM and SC routes deliver mAbs to the airway lining fluid only after a delay of one or more days, but even then achieve airway concentrations that are only a fraction of the concentration in plasma. For example, in a recent clinical trial of the anti-influenza mAb CR6261 given as a single 50 mg/kg dose IV, peak nasal concentrations were not achieved until 2 days after infusion, and despite a significantly lower total dose of IN-006 versus CR6261 (90 mg IN-006 vs. approx. 2,000-4,000 mg CR6261), the peak nasal concentration of 0.597 μg/mL was approximately 10-fold lower than that observed for IN-006 at the trough of our daily dosing (approx. 5.4 μg/mL). Due to increased convenience, more efficient pulmonary delivery, and superior pharmacokinetics, inhalation may become a more preferred route of mAb delivery for treating acute respiratory infections.

[0110] COVID-19 is primarily a respiratory tract infection, but currently available treatments are administered by systemic dosing. Described herein are methods and compositions of mAbs constructed using human IgG that bind to the spike protein of SARS-CoV-2. The methods and compositions described herein may provide for inhaled delivery of mucosally-trapping monoclonal antibodies (containing Fc regions with G0 glycosylation), which may provide a more convenient and effective treatment of COVID-19. Results described in Example 1 show the safety, tolerability, and pharmacokinetics of one example of a human IgG G1 Fc region (IN-006, a reformulation of regdanvimab, an approved intravenous treatment for COVID-19) that can be used for nebulized delivery by a handheld nebulizer.

[0111] Severe disease due to SARS-Cov-2 involves viral transmission from the initial upper respiratory tract infection site to the deep lung. Unfortunately, the exact timing of such transmission is likely to be highly variable between individuals. Indeed, there is evidence suggesting that the virus may already reach the LRT during early stages of disease, even around the time of symptom onset. Similarly, rapid transmission of infection to the LRT is likely to be frequent for other viruses, such as influenza. Thus, dosing both in the URT and LRT, rather than focusing exclusively on the URT (e.g., by nasal spray), may be important to widen the treatment window and reduce the risk of COVID-induced pneumonia and hospitalization. Although IN-006 levels in the LRT are not directly measured in this study, both the discernible serum concentrations and the delayed serum Tmax strongly suggest that IN-006 is efficiently delivered into the LRT and deep lung. Indeed, in a multiple dose inhalation study of the toxicokinetics of IN-006 in rats, the IN-006 concentration in airway fluids exceeded serum concentrations by approximately 100-fold. Efficient delivery to the LRT is a direct result of our design requirements for the vibrating mesh nebulizer. The droplet sizes generated by the nebulizer (fine particle fraction, i.e., <5 μm droplets, and especially <2.5 μm) were purposefully selected to deliver mAb into the LRT and deep lung. Furthermore, the fact that a slow and steady rise in serum concentrations was observed over approximately 4 days in the single dose cohort and peak serum concentrations in the multiple dose cohort at approximately 9 days (or 2 days after the last dose) implies that high levels of IN-006 are sustained in the deep lung for at least that period, i.e., multiple days. Assuming a similar ratio of 100:1 airway fluid to serum concentrations in humans as observed in rats, the mean human serum concentrations of 200 ng/mL 2 days after the first dose and 550 ng/mL on day 9 must translate to lung concentrations of around 50 μg/mL, which is >3 orders of magnitude above the IC ₅₀ and comparable to serum concentrations achieved with some IV/IM administered mAbs. The extremely high mAb levels sustained relative to the intrinsic activity (IC ₅₀ ) of the mAb may continue to provide effective treatment against variants even in the presence of appreciable genetic drift, potentially reducing the risks of including viral escape. It also suggests that shorter durations of therapy, perhaps as short as a single dose, may confer appreciable protection against hospitalization.

[0112] Despite significant extrapulmonary manifestations of severe COVID-19 and frequent detection of SARS-CoV-2 RNA in blood, infectious SARS-CoV-2 was only rarely detected in the blood of affected patients, suggesting that extrapulmonary injury may be caused by indirect factors such as inflammatory responses rather than extrapulmonary viral infection. Nevertheless, it is encouraging to observe that serum levels of IN-006 achieved after nebulized delivery exceeded the _IC50 by at least one order of magnitude.

[0113] Regdanvimab (administered IV) has been shown to be highly effective for preventing severe COVID-19 in a global Phase 3 study, leading to its formal approval in South Korea and the European Union (EMEA/H/C/005854) for preventing severe disease in patients with mild to moderate COVID-19, as well as Emergency Use Authorization (EUA) or Conditional Manufacturing Authorization in several additional countries around the world. IN-006 can be combined with a second potently neutralizing mAb to create a mAb cocktail with potent binding activity against any variant tested to date. The surprisingly long airway retention of IN-006 observed here can be used virtually for mAbs that contain an Fc region (e.g., SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4). IN-006, a reformulation of regdanvimab for inhaled delivery, was found to be safe and well tolerated in healthy participants at single doses of 30 mg and 90 mg and seven consecutive daily doses of 90 mg. Inhaled administration resulted in IN-006 levels in nasal fluid and possibly the lungs that exceeded inhibitory concentrations of susceptible SARS-CoV-2 variants by orders of magnitude within 30 minutes and continued to elevate serum concentrations for several days after dosing, implying substantially sustained IN-006 levels in the lungs.

Example 2
[0114] The methods described herein can be used to provide sufficient levels of antibodies in both the upper and lower respiratory pathways.

[0115] Subjects receive a first dose of IN-006 or placebo via nebulizer on dosing day 1. Placebo is 0.9% saline and is administered via nebulizer in the same manner as IN-006. Subjects receive a second dose of IN-006 or placebo via nebulizer on at least one of dosing days 3 through 8. Placebo is 0.9% saline and is administered via nebulizer in the same manner as IN-006. Antibody measurements are performed using bronchoalveolar lavage (BAL) before and 2 weeks after treatment using bronchoscopy. Bronchoalveolar lavage is performed by injecting warmed sterile PBS into the segmental middle lobe bronchus using a bronchoscope. Fluid is withdrawn by gentle suction and collected in a sterile container. Filtered through a sterile 100 μm mesh to remove mucus and cellular debris and analyzed using the methods described herein.

Example 3
[0116] The methods described herein can be used to provide sufficient levels of at least two therapeutic agents in both the upper and lower respiratory pathways. Subjects can receive a first dose of IN-006 and a second therapeutic agent (e.g., a non-mAb) or placebo via nebulizer on dosing day 1. The placebo is 0.9% saline and is administered via nebulizer in the same manner as IN-006. Nasal swabs are taken on at least one of dosing days 3 through 8 to measure levels of antibodies. Subjects receive a second dose of IN-006 or placebo via nasal spray on at least one of dosing days 3 through 8. The placebo is 0.9% saline and is administered via nebulizer in the same manner as IN-006.

Example 4
[0117] Using the methods described herein, a 1X (single dose) or 2X (twice dose) per day dose can be used to provide sufficient levels of antibody in at least one or both of the upper and lower respiratory tract.

[0118] Subjects receive a first dose of antibody (e.g., IN-006 or other) or placebo via nebulizer at time 0 on dosing day 1. The antibody can be an antibody glycosylated with a G0 glycosylation pattern. The placebo is 0.9% saline and is administered via nebulizer in the same manner as the antibody (e.g., IN-006 or other). A first cohort of subjects receives a second dose of antibody (e.g., IN-006 or other) or placebo via nebulizer 12 hours after the first dose. The placebo is 0.9% saline and is administered via nebulizer in the same manner as the antibody (e.g., IN-006 or other). Antibody measurements are performed using bronchoscopy on bronchoalveolar lavage (BAL) fluid prior to dosing, immediately after dosing, 12 hours (before the second dose), and 24 hours. Bronchoalveolar lavage is performed by injecting warmed sterile PBS into the segmental middle lobe bronchus using a bronchoscope. Fluid is withdrawn by gentle suction and collected in a sterile container. It is filtered through a sterile 100 μm mesh to remove mucus and cellular debris and analyzed using the methods described herein.

[0119]

[0120] The methods and compositions described herein allow for the delivery of inhaled therapeutic mAbs, including those with a G0 glycosylation pattern, that would otherwise be predicted to be cleared within minutes based on published studies, to achieve sustained high concentrations for 24 hours or more, thereby allowing once-daily or twice-daily dosing using relatively low (and therefore available) concentrations. Thus, doses can be delivered such that sufficient levels (i.e., trough concentrations) of therapeutic mAb are maintained until the next dose.

[0121] As described herein, the peak concentration achieved in the upper airways scales with the amount of mAb inhaled (e.g., going from 30 mg to 90 mg inhalation resulted in an approximately 3x increase). The rate of clearance was then surprisingly dose-independent, with comparable clearance rates for single doses of 30 mg and 90 mg, as well as comparable clearance between a single 90 mg dose versus repeated 90 mg doses on different days. "Mucus-trapping" mAbs (those with a G0 glycosylation pattern) are not cleared within minutes (e.g., faster than 30 minutes) as previously suggested for the turnover rate of nasal secretions in the nasal turbinates of the nasal cavity, but rather have half-lives in the range of 3.5-4 hours.

[0122] This allows for a dosing regimen that not only achieves a mAb dose well in excess of the IC50 immediately after dosing, but also allows sufficient mAb to be maintained at the trough just prior to the next dose. Thus, doses of different mAbs can be selected depending on their characteristics to achieve a concentration well in excess of their inherent efficacy (e.g., maintaining 10-100x above the IC50 of a mAb with an IC50 of about 100 ng/mL). For example, the methods and compositions described herein show that a dose of 15 mg twice daily at each time provides a sufficient dose.

[0123] It will be appreciated that all combinations of the above concepts and additional concepts discussed in more detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter discussed herein and may be used to achieve the benefits described herein.

[0124] The process parameters and sequences of steps described and/or illustrated herein are provided by way of example only and may vary as desired. For example, although the steps illustrated and/or described herein may be shown or discussed in a particular order, the steps need not necessarily be performed in the order illustrated or discussed. Various example methods described and/or illustrated herein may also omit one or more of the steps described or illustrated herein or may include additional steps in addition to those disclosed.

[0125] When a feature or element is referred to herein as being "on" another feature or element, it may be directly on the other feature or element, or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements. Also, when a feature or element is referred to as being "connected," "attached," or "coupled" to another feature or element, it is understood that it may be directly connected, attached, or coupled to the other feature or element, or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected," "directly attached," or "directly coupled" to another feature or element, there are no intervening features or elements. Although described or illustrated with respect to one embodiment, features and elements so described or illustrated may apply to other embodiments. It will also be understood by those skilled in the art that a reference to a structure or feature that is located "adjacent" to another feature may have an overlapping or underlying portion of the adjacent feature.

[0126] The technical terms used herein are merely for the purpose of describing particular embodiments and are not intended to be limitations of the present invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the content clearly indicates otherwise. It will be further understood that the terms "comprises" and/or "comprising" as used herein specify the presence of stated features, steps, operations, elements and/or components, but do not preclude the presence or addition of one or more of other features, steps, operations, elements, components and/or groups thereof. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as "/".

[0127] Although the terms "first" and "second" may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms unless otherwise specified. These terms may be used to distinguish one feature/element from another. Thus, a first feature/element discussed below may be referred to as a second feature/element, and similarly, a second feature/element discussed below may be referred to as a first feature/element without departing from the teachings of the present invention.

[0128] Throughout this specification and the claims that follow, unless the content requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" mean that various components can be used together in methods and articles (e.g., apparatus and methods, including compositions and devices). For example, the term "comprising" is understood to mean the inclusion of any recited elements or steps, but not the exclusion of any other elements or steps.

[0129] Generally, any of the devices and methods described herein should be understood to be inclusive, although all or a subset of the components and/or steps may alternatively be exclusive and may be expressed as "consisting of" or alternatively "consisting essentially of" various components, steps, subcomponents, or substeps.

[0130] Unless otherwise specified, all numbers herein, in the specification, in the claims, and in the examples, can be read as if preceded by the word "about" or "approximately," even if this term does not explicitly appear. The phrase "about" or "approximately" can be used when describing a magnitude and/or location to indicate that the stated value and/or location is within a reasonably expected range of values and/or locations. For example, a numerical value can have a value that is +/-0.1% of the stated value (or range of values), +/-1% of the stated value (or range of values), +/-2% of the stated value (or range of values), +/-5% of the stated value (or range of values), +/-10% of the stated value (or range of values), and the like. Any numerical value given herein should also be understood to include about or approximately that value, unless otherwise specified. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all subranges incorporated herein. It is also understood that when a value is disclosed, "less than or equal to" the value, "more than or equal to" the value, and possible ranges between the values are also disclosed, as would be well understood by one of ordinary skill in the art. For example, if a value "X" is disclosed, "less than or equal to X" as well as "more than or equal to X" (e.g., where X is a numeric value) are also disclosed. It is also understood that throughout this application, data is provided in several different formats, and that this data represents endpoints and starting points and ranges for any combination of the data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, it is understood that greater than, greater than, less than, less than, and equal to 10 and 15, as well as between 10 and 15, are contemplated and disclosed. It is also understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0131] Although various exemplary embodiments have been described above, any of several variations can be made to the various embodiments without departing from the scope of the invention as set forth in the claims. For example, in alternative embodiments, the order in which the various described method steps are performed can often be changed, and in other alternative embodiments, one or more method steps can be skipped altogether. Optional features of the various device and system embodiments may be included in some embodiments and not in others. Thus, the foregoing description is provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as set forth in the claims. The examples and illustrations contained herein indicate specific embodiments in which the subject matter may be practiced, by way of example, and not limitation. As stated above, other embodiments can be utilized and derived therefrom, such that structural and logical substitutions and modifications can be made without departing from the scope of the present disclosure. Such embodiments of the inventive subject matter may be referred to herein, individually or collectively, simply by the term "invention," for convenience, and when more than one is actually disclosed, without any intention of spontaneously limiting the scope of this application to any single invention or inventive concept. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. The present disclosure is intended to cover any and all adaptations or modifications of the various embodiments. Combinations of the above embodiments and other embodiments not specifically described herein will be apparent to those of skill in the art upon reviewing the above description.
Sequence Listing SEQ ID NO:1
Human IgG G1 Fc Region (CH2 and CH3 Domains)
Organism: Homo sapiens (Human) (CH2 is residues 1-113, CH3 is residues 114-219)
PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:2
Human IgG G2 Fc Region (CH2 and CH3 Domains)
Organism: Homo sapiens (Human) (CH2 is residues 1-109, CH3 is residues 110-216)
APPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKT KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:3
Human IgG G3 Fc Region (CH2 and CH3 Domains)
Organism: Homo sapiens (Human) (CH2 is residues 1-110, CH3 is residues 111-216)
APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK TKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPG
SEQ ID NO:4
Human IgG G4 Fc Region (CH2 and CH3 Domains)
Organism: Homo sapiens (Human) (CH2 is residues 1-110, CH3 is residues 111-217)
APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

Claims (34)

A method of treating a subject having or at risk of having a respiratory disorder, comprising administering to the subject by inhalation a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein the administering step comprises administering at a dose of 0.02 μmol or more of the therapeutic human mAb no more than twice daily to achieve a concentration of greater than 20 ng/mL in the upper respiratory tract (URT) and greater than 100 ng/mL in the lower respiratory tract (LRT) for 12 hours or longer after dosing. A method of treating a subject having or at risk of having a respiratory disorder, comprising administering by inhalation to the subject a dose of a therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, thereby maintaining a concentration of the therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in the upper respiratory tract (URT) of the subject greater than 20 ng/ml and in the lower respiratory tract (LRT) of the subject greater than 100 ng/ml for greater than 12 hours after dosing, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice daily. The method of claim 1 or claim 2, wherein the administering step comprises administering a dose no more than once a day. The method of claim 1, wherein the therapeutic antibody comprises at least 50% G0 glycosylation pattern. The method of any one of claims 1 to 4, wherein the therapeutic antibody comprises an Fc sequence that is at least X% (e.g., 80%, 85%, 90%, 95%) homologous to the sequence of SEQ ID NO:1 (e.g., human IgG1). The method according to any one of claims 1 to 5, wherein the subject is an adult. The method of any one of claims 1 to 4, wherein the therapeutic antibody comprises regdanvimab. The method of any one of claims 1 to 7, wherein the dosing regimen comprises a twice-daily dosing cycle for a period of 2 to 7 days. The method of any one of claims 1 to 7, wherein the dosing regimen includes a dosing cycle every 2 days, every 3 days, or every 4 days. The method of any one of claims 1 to 9, wherein the dosage regimen comprises administering a dose of at least 10 mg of the therapeutic mAb. The method of any one of claims 1 to 11, wherein the dosage regimen comprises administering a dose of the therapeutic mAb of between about 10 mg and 100 mg. The method of any one of claims 1 to 11, wherein the administering step includes sustaining release of the therapeutic mAb from the LRT into the blood over multiple days. 12. The method of claim 1, wherein the administering step comprises sustaining release of the mAb into the lungs and blood for at least 2 days. The method of any one of claims 1 to 13, wherein the formulation further comprises a pharma- ceutically acceptable diluent, excipient and/or carrier. The method of any one of claims 1 to 14, wherein the formulation further comprises one or more of citric acid, arginine, mannitol, sorbitol, and trehalose. The method according to any one of claims 1 to 15, wherein the therapeutic antibody formulation is administered to the subject via a nebulizer. The method of any one of claims 1 to 15, wherein the therapeutic antibody formulation is administered to the subject via a vibrating mesh nebulizer. The method of any one of claims 1 to 15, wherein the therapeutic antibody formulation is administered via inhalation or via direct instillation into the upper respiratory tract. The method of any one of claims 1 to 15, wherein the therapeutic antibody formulation is self-administered by the subject. 20. The method of claim 1, wherein the respiratory disorder comprises a lower airway disorder. 20. The method of claim 1, wherein the respiratory disorder comprises an upper airway disorder. 20. The method of claim 1, wherein the respiratory disorder comprises an inflammatory disorder. The method of any one of claims 1 to 19, wherein the respiratory virus comprises a coronavirus. 20. The method of any one of claims 1 to 19, wherein the respiratory virus comprises severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 20. The method of claim 1, wherein the respiratory virus comprises respiratory syncytial virus (RSV). 20. The method of any one of claims 1 to 19, wherein the respiratory virus comprises one or more of influenza, metapneumovirus, parainfluenza, (certain coronaviruses). The method of any one of claims 1 to 19, wherein the respiratory virus comprises a paramyxovirus. 28. The method of any one of claims 1 to 27, wherein the formulation comprises a second or more therapeutic agents in addition to the therapeutic antibody. 28. The method of any one of claims 1 to 27, wherein the formulation comprises a therapeutic mAb and a second therapeutic antibody, the first therapeutic antibody and the second therapeutic antibody bind to the same virus but do not compete for binding to the virus. 28. The method of any one of claims 1 to 27, wherein the formulation comprises a second therapeutic antibody in addition to the first therapeutic antibody, and further wherein the first antibody and the second antibody bind to different viruses. The method of any one of claims 1 to 30, wherein the formulation comprises a biologic in addition to the therapeutic mAb. A method of treating a subject having or at risk of having a respiratory disorder, comprising administering to the subject by inhalation a dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus, thereby maintaining a concentration of the therapeutic human IgG monoclonal antibody (mAb) that binds to the respiratory virus in the upper respiratory tract (URT) of the subject greater than 25 ng/ml and in the lower respiratory tract (LRT) of the subject greater than 25 ng/ml for greater than 12 hours after the dose, wherein the administering comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice daily. A therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, for use in a method of treating a respiratory disorder by administering the therapeutic human IgG monoclonal antibody (mAb) by inhalation, the administering step comprising administering no more than twice daily at a dose of 0.02 μmol or more of the therapeutic human mAb to achieve a concentration of greater than 20 ng/mL in the upper respiratory tract (URT) and greater than 100 ng/mL in the lower respiratory tract (LRT) for 12 hours or longer after the dose. 1. A therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies, at least 40% of which are glycosylated with a G0 glycosylation pattern comprising a biantennary core glycan structure of Manα1-6 (Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, for use in a method of treatment of a respiratory disorder by administering a dose of the therapeutic human IgG mAb by inhalation, maintaining a concentration of the therapeutic human IgG mAb in the upper respiratory tract (URT) of a subject greater than 20 ng/ml and in the lower respiratory tract (LRT) of a subject greater than 100 ng/ml for greater than 12 hours post-dosing, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human IgG mAb no more than twice daily.