Compositions and methods for inhalable therapeutic agents

Abstract

Described herein are therapeutic inhalation antibodies and methods of delivering these therapeutic antibodies that can maintain the concentration of therapeutic inhalation antibodies in the upper and lower respiratory tracts (URTs) and in the blood even after a single dose. The compositions and methods described herein can provide therapeutically related levels of inhaled antibodies delivered by inhalation at a single dose delivered once per day or less frequency. These methods can result in a concentration in both URT and LRT greater than a minimum threshold concentration with clinical relevance.

Description

Priority claim

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 345,019, filed on May 23, 2022, entitled “COMPOSITIONS AND METHODS FOR INHALABLE THERAPEUTICS,” and U.S. Patent Application No. 17 / 889,141, filed on August 16, 2022, which claims the benefit of U.S. Provisional Patent Application No. 63 / 233,661, filed on August 16, 2021, entitled “METHODS AND APPARATUSES FOR DELIVERY OF AN AGENT TO THELUNGS AND NASAL PASSAGES,” all of which are incorporated herein by reference in their entireties. Incorporated 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. background

[0003] It is generally acknowledged that antibodies (including Fc-conjugated antibodies) delivered to the lungs by inhalation are rapidly cleared from the lungs. For example, Fc-conjugated proteins given by inhalation typically have a Tmax (i.e., time to reach Cmax) in the range of 10-20 hours in serum, and therefore have much faster clearance (on the order of hours or minutes) in the lungs. Bitonti and Durmont, "Pulmonary administration of therapeutic proteins using animmunoglobulin transport pathway," Advanced Drug Delivery Reviews, Vol. 58, No. 9-10, 31 October 2006, pp. 1106-1118. In fact, it has long been believed that the therapeutic efficacy of inhaled drugs is limited by their rapid clearance in the lungs. Small solutes delivered to the lungs diffuse rapidly through the lung epithelium and penetrate the bloodstream within a few minutes. Peptides are also rapidly transported to the systemic circulation, but are significantly metabolized locally. As summarized by Loira-Pastoriza et al. (“Delivery strategies for sustained drug release in the lungs,” Advanced Drug Delivery Reviews, vol. 75, 30 August 2014, pp. 81-91): “Although large molecules can be absorbed into the systemic circulation within a few hours, they can be rapidly taken up by alveolar macrophages, they can be removed by the mucociliary escalator, and they can also be metabolized locally. For example, recombinant human deoxyribonuclease I is a 37 kDa glycoprotein that cleaves DNA in respiratory secretions of patients with cystic fibrosis and thereby reduces their viscosity. This glycoprotein is the most widely used mucolytic agent for the symptomatic treatment of cystic fibrosis. However, this glycoprotein is rapidly cleared from the human lung: when a daily dose of 2.5 mg is inhaled, a concentration of 3 μg / ml is measured in sputum immediately after inhalation, and the concentration decreases to 0.6 after 2 h. μg / ml. Therefore, one to two administrations per day provide limited therapeutic coverage for patients. "Unfortunately, more frequent dosing is also required because of the short residence time of the drug in the lungs, and this is thought to compromise patient compliance. For example, inhaled corticosteroids are recommended at least twice a day and short-acting β2-agonists up to 4 times a day.

[0004] Therefore, it would be beneficial to provide compositions, and particularly mAb compositions, that can 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. Summary of the Disclosure

[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 in the 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 with 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 in both the URT and the LRT greater than the minimum threshold concentration with clinical relevance.

[0006] The persistence of therapeutic mAbs in the URT and LRT appears to be the result of interactions with the core Fc region of the IgG backbone common to the therapeutic antibodies described herein (including, for example, regdanvimab), and is independent of the target specificity (variable region) of the individual mAbs. This may be because the Fc region interacts with mucus and other components that drive mAb clearance 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 glycosylated with G0 glycosylation, for example, a bi-branched core polysaccharide structure comprising Manα1-6 (Manα1-5) Manβ1-4GlcNAcβ1-4GlcNAcβ1, with a terminal N-acetylglucosamine on 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 condition comprising administering to the subject by inhalation a formulation comprising a therapeutic antibody that binds a respiratory virus in a dosing regimen comprising once daily or twice daily dosing cycles.

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

[0009] In some examples, a method of treating a subject having or at risk of having a respiratory condition can include administering to the subject by inhalation a dose of a therapeutic human IgG monoclonal antibody (mAb) that binds respiratory viruses greater than 20 ng / ml in the subject's upper respiratory tract (URT) and greater than 100 ng / ml in the subject's lower respiratory tract (LRT) for more than 12 hours after administration, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice a day.

[0010] In any of these examples, administration can include administering the dose no more than once per day.

[0011] In some examples, the therapeutic antibody can comprise at least 45% G0 glycosylation pattern (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.).

[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 can be regdanvimab. The dosing regimen can include a dosing cycle of twice a day over a period of two to seven days. The dosing regimen can include a dosing cycle of every other day, every two days, or every three days. The dosing regimen can include administering a therapeutic mAb at a dose of at least 10 mg. The dosing regimen can include administering a therapeutic mAb at a dose between about 10 mg and 100 mg. In some instances, administration includes maintaining the release of the therapeutic mAb from the LRT into the blood over multiple days. Administration can include maintaining the release of the mAb into the lungs and blood over at least two days.

[0014] The formulation may further comprise a pharmaceutically acceptable diluent, excipient and / or carrier. In some examples, the formulation further comprises one or more of the following: citrate, arginine, mannitol, sorbitol, trehalose.

[0015] The therapeutic antibody formulation can be administered to the subject via a nebulizer (such as a vibrating mesh nebulizer). In some instances, the therapeutic antibody formulation is administered via inhalation or via direct instillation into the upper airway. The therapeutic antibody formulation can be self-administered by the subject.

[0016] Respiratory conditions may include lower airway conditions. Respiratory conditions may include upper airway conditions. In some instances, respiratory conditions include inflammatory conditions. Respiratory viruses may include coronaviruses. Respiratory viruses may include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Respiratory viruses may include respiratory syncytial virus (RSV). Respiratory viruses may include one or more of the following: influenza virus, metapneumovirus, parainfluenza virus, (specific coronavirus). In some instances, respiratory viruses include paramyxovirus.

[0017] In addition to the therapeutic antibody, the preparation may also include a second therapeutic agent or more therapeutic agents. The preparation may include a therapeutic mAb and a second therapeutic antibody, wherein 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 instances, in addition to the first therapeutic antibody, the preparation also includes a second therapeutic antibody, and in addition, the first antibody and the second antibody bind to different viruses. In addition to the therapeutic mAb, the preparation also includes a biologic.

[0018] For example, a method of treating a subject having or at risk of having a respiratory condition may comprise administering to the subject by inhalation a dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds a respiratory virus that maintains a concentration of 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 more than 12 hours following administration, wherein administration comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice a day.

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

[0020] Also described herein are methods 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) glycosylated with a G0 glycosylation pattern comprising a bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein administration comprises administering the therapeutic human mAb no more than once a day at a dose of 0.02 μmol or more to achieve a concentration of the therapeutic human mAb greater than 20 ng / mL in the upper respiratory tract (URT) and greater than 100 ng / mL in the lower respiratory tract (LRT) for more than 24 hours after administration.

[0021] For example, a method of treating a subject having or at risk of having a respiratory condition can comprise administering to the subject by inhalation a dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds a respiratory virus that maintains a concentration of greater than 25 ng / ml in the upper respiratory tract (URT) of the subject and greater than 25 ng / ml in the lower respiratory tract (LRT) of the subject for more than 24 hours following administration, wherein administration comprises administering 0.02 μmol or more of the therapeutic human mAb no more than once a day.

[0022] In some examples, a method of treating a subject having or at risk of having a respiratory condition can include administering to the subject by inhalation a dose of a therapeutic human IgG monoclonal antibody (mAb) that binds respiratory viruses greater than 20 ng / ml in the subject's upper respiratory tract (URT) and greater than 100 ng / ml in the subject's lower respiratory tract (LRT) for more than 24 hours after administration, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than once a day.

[0023] In any method described herein, therapeutic antibodies can be therapeutic human IgG monoclonal antibodies (mAb). In any method described herein, therapeutic human IgG monoclonal antibodies (mAb) are human IgG1 mAbs. In any method described herein, therapeutic antibodies include Fc sequences at least X% (e.g., 80%, 85%, 90%, 95%) homologous to SEQ ID NO: 1 sequence (e.g., human IgG G1). For example, therapeutic antibodies can include regdanvimab. Alternatively, in any of these methods and compositions, Fc sequences 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] Typically, the subject can be any subject in need of treatment. 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 12 years of age and older.

[0025] In any of the methods described herein, the therapeutic antibody may comprise an oligosaccharide that enhances the capture efficiency of the recombinant antibody in mucus. For example, the therapeutic antibody may comprise a mAb population, wherein at least 40% of the mAb population comprises an oligosaccharide having a G0 glycosylation pattern, wherein the G0 glycosylation pattern comprises a bi-branched core polysaccharide structure of Manα1-6 (Manα1-5) Manβ1-4GlcNAcβ1-4GlcNAcβ1, with a terminal N-acetylglucosamine on each branch that enhances the capture efficiency of the recombinant antibody in mucus.

[0026] In any of the methods described herein, the dosing regimen may include a dosing cycle of once a day over a period of two to seven days. The dosing regimen may include a dosing cycle of every other day, every two days, or every three days. The dosing regimen may include administering a total of two, three, or four doses. The dosing regimen may include administering only a single dose. The dosing regimen may include administering a therapeutic mAb at a dose of at least 30 mg. The dosing regimen may include administering a therapeutic mAb at a dose between about 30 mg and 90 mg.

[0027] In any of the methods described herein, administration can include maintaining release of the therapeutic mAb from the LRT into the blood over multiple days. Administration can include maintaining release of the mAb into the lungs and blood over at least two days.

[0028] In any method described herein, the preparation also includes a pharmaceutically acceptable diluent, excipient and / or carrier. For example, the preparation may also include one or more of the following: citrate, arginine, mannitol, sorbitol, trehalose. The therapeutic antibody preparation can be administered to the subject via a nebulizer. The therapeutic antibody preparation can be administered to the subject via a vibrating mesh nebulizer. The therapeutic antibody preparation can be administered to the subject via a nebulizer. The therapeutic antibody preparation can be administered via inhalation or via direct instillation into the upper airway. The therapeutic antibody preparation can be self-administered by the subject.

[0029] Respiratory conditions include lower airway conditions. Respiratory conditions may include upper airway conditions. Respiratory conditions may include inflammatory conditions. Respiratory viruses may include coronaviruses. Respiratory viruses may include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Respiratory viruses may include respiratory syncytial virus (RSV). Respiratory viruses may include one or more of the following: influenza virus, metapneumovirus, parainfluenza virus, (specific coronavirus). Respiratory viruses may include paramyxovirus.

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

[0031] Also described herein are compositions (e.g., therapeutic human IgG monoclonal antibodies, and in particular 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 bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, for use in a method of treating any respiratory disorder described herein by performing any of the methods described. For example, described herein are therapeutic human IgG monoclonal antibodies (mAbs) for use in a method of treating a respiratory condition by administering the therapeutic human IgG monoclonal antibodies (mAbs) by inhalation, the 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 bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein administering comprises administering the therapeutic human mAb no more than twice a day at a dose of 0.02 μmol or more to achieve a concentration of the therapeutic human mAb 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 more after administration.

[0032] Also described herein are therapeutic human IgG monoclonal antibodies (mAbs) for use in a method of treating a respiratory disorder, the 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 bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, the method administering by inhalation a dose of the therapeutic human IgG mAb that maintains a concentration of the therapeutic human IgG mAb greater than 20 ng / ml in the upper respiratory tract (URT) of the subject and greater than 100 ng / ml in the lower respiratory tract (LRT) of the subject for more than 12 hours after administration, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice a day.

[0033] These methods, and in particular the dosing regimens described herein, are both surprising and effective; prior to this work, it was thought that much larger and / or more frequent dosing would be required because the predicted clearance of the therapeutic agent (mAb) from the lungs was thought to be very rapid (e.g., less than 30 minutes) for such compositions.

[0034] All methods and apparatus described herein, in any combination, are contemplated herein and can be used to achieve the benefits as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] A better understanding of the features and advantages of the methods and apparatus described herein will be obtained by referring to the following detailed description, which sets forth illustrative embodiments, and the accompanying drawings, in which: Figure 1 Table 1, which describes the demographics of the patients enrolled in the study described in Example 1, shows the persistence (as observed in serum levels) of therapeutic mAbs with human IgG Fc regions that are glycosylated (e.g., such that greater than 40% of the mAb is glycosylated) in the upper and lower respiratory tracts.

[0036] Figure 2 Table 2 summarizes the adverse events from the study described in Example 1. * ) marked side effects occurred within 2 hours of completing nebulization; (cough, decreased FEV1). ** )Complications marked by this include the use of IUDs for contraception.

[0037] Figure 3 (Left) An example of a process flow for the exemplary treatment method described in Example 1 is shown. Figure 3(Right) An example of the study protocol and sample collection time points used in Example 1 is shown.

[0038] Figure 4A-4C Nasal fluid concentrations are shown. Figure 4A Concentrations in the single-dose cohort are shown. Figure 4B Concentrations in a multiple daily dose cohort (e.g., 90 mg for 7 days) are shown. The arrows on the x-axis indicate Figure 4B The 90 mg dose was administered 7 times. Figure 4C A comparison of nasal concentrations between the single-dose and multi-dose cohorts is shown. The average LLOQ for all nasal fluid samples is shown to be 450 ng / g, but the LLOQ varies from sample to sample, depending on the quality of the nasal fluid collected on the swab, resulting in some detectable samples being below the overall average LLOQ. The score below each time point indicates the number of samples below the LLOQ at that time.

[0039] Figure 5A-Figure 5B The single-dose cohort ( Figure 5A ) and multiple dose cohorts ( Figure 5B , last dose administered at 144 h). Symbols drawn below the 25 ng / mL LLOQ dashed line represent the number of samples in each group that were BLQ at each time point.

[0040] Figure 6 is a schematic diagram illustrating one example of a method as described herein. describe

[0041] Described herein are methods, compositions and devices (e.g., devices, systems, etc.) that can be used to treat subjects with respiratory conditions or at risk of respiratory conditions. In some embodiments, a method for administering therapeutic antibodies to treat subjects with respiratory conditions that affect the upper respiratory tract (upper airway) or the lower respiratory tract (lower airway) or the risk of respiratory conditions that affect the upper respiratory tract (upper airway) or the lower respiratory tract (lower airway) is provided. The methods provided herein can be particularly useful for treating subjects with respiratory conditions that affect both the upper respiratory tract (upper airway) and the lower respiratory tract (lower airway) or the risk of respiratory conditions that affect both the upper respiratory tract (upper airway) and the lower respiratory tract (lower airway). The applicant surprisingly and unexpectedly found that using the methods, compositions and devices described herein, it is possible to achieve extended coverage with therapeutic antibodies, which allow infrequent or sporadic dosing regimen frequencies (such as one-time delivery, delivery once a day, no more than twice a day).

[0042] The term "antibody" (Ab) refers to an immunoglobulin molecule that specifically binds to or immunoreacts with a specific antigen. Basic antibodies have a Y-shape containing a stem region and two arm regions, and can be divided into different categories, called isotypes, based on the features present in the antibody stem region. Basic antibodies are heterotetrameric glycoproteins that include 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 causes each of the heavy chains to break, producing three separate subunits. Two of the units include a light chain and a fragment of the broken heavy chain that is approximately equal in mass to the light chain. Each of these two units can bind to an antigen alone and is called a Fab fragment (i.e., an "antigen binding" fragment). According to some estimates, humans may be able to produce up to 10 18 The Fab fragment of the present invention is a kind of antibody of the present invention.There are 1 or 100 different antibodies, and each antibody will have a unique Fab fragment.The third of the three units includes two equal heavy chain segments.This third unit is not usually involved in antigen binding, but is important in the later process of eliminating the antigen body in vivo.Compared with the Fab fragment, the third unit from the antibody usually has only one of five physicochemical properties, and is therefore referred to as an Fc fragment (that is, a "crystallizable" fragment).The type of human antibodies containing one of the five types of Fc fragments is referred to as IgA, IgD, IgE, IgG and IgM isotypes.These isotypes can also have several subclasses.For example, the IgG antibody in humans can be further divided into subclasses IgG1, IgG2, IgG3 and IgG4.The IgG antibody in mice can be further subdivided into subclasses IgG1, IgG2a, IgG2b and IgG3. Types and modified forms of antibodies can be produced by methods known in the art, and include polyclonal, monoclonal, genetically engineered, bifunctional, chimeric antibodies, humanized antibodies, 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 connected to a VH domain by a linker.

[0043] A "blocking" antibody (also called an "antagonist" antibody) is an antibody that inhibits or reduces the biological activity of an antigen to which it binds. In some embodiments, a blocking antibody or antagonist antibody substantially or completely inhibits the biological activity of an antigen.

[0044] "Carriers" are generally designed to interact with active pharmaceutical ingredients (API) (e.g., antibodies) and enhance their properties. At the doses and concentrations employed, carriers are generally safe and nontoxic to subjects and cells exposed thereto. Examples of physiologically acceptable carriers are pH-buffered aqueous solutions, such as saline solutions. Examples of physiologically acceptable carriers include buffers such as phosphates, citrates, 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 sugars including glucose, mannose, or dextrins; chelating agents such as EDTA; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0045] The term "Cmax" refers to a standard pharmacokinetic measurement used to determine drug administration. Cmax is the peak (highest) concentration / maximum (or peak) concentration of a drug achieved in a specified compartment or test area of ​​the body (e.g., blood, serum, nasal cavity, etc.) after administration of the drug and before administration of the subsequent (second) dose.

[0046] The term "effective amount" (or "therapeutically effective amount") is at least the minimum concentration of the agent required to cause a measurable improvement or prevention of a specific condition. The effective amount herein may vary according to factors such as the specific condition (e.g., disease state) of the subject, age, sex, and weight, and the ability of the agent (e.g., antibody) to elicit a desired response in an individual. An effective amount is also an amount in which any toxic or harmful effects of the treatment are exceeded by the beneficial effects of the treatment. For preventive use, beneficial or desired results include such results as eliminating the condition (disease) or reducing the risk of the condition (disease), reducing the severity of the condition (disease), or delaying the onset of the condition (disease), including the biochemical, histological, and / or behavioral symptoms of the condition (disease), its complications, and the intermediate pathological phenotype presented during the development of the condition (disease). For therapeutic use, beneficial or desired results include clinical results, such as reducing one or more symptoms caused by the condition (disease), improving the quality of life of people suffering from the condition (disease), reducing the dose of other drugs required for treating the condition (disease), enhancing the effect of another drug, such as via targeting, delaying the progression of the disease, and / or prolonging survival. The effective amount may be administered in one or more administrations. For purposes herein, the effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly complete a preventive or therapeutic treatment. As understood in a clinical context, the effective amount of a drug, compound or pharmaceutical composition can be obtained in combination with another drug, compound or pharmaceutical composition, or can be obtained without combination. Therefore, an "effective amount" can be considered in the context of using one or more therapeutic agents, and if combined with one or more other agents, the desired result can be or has been achieved, then a single agent can be considered to be given with an effective amount.

[0047] The term "excipient" refers to substances in a formulation other than one or more active pharmaceutical ingredients (eg, antibodies). Examples of excipients include antioxidants, buffers, emulsifiers, penetration enhancers, preservatives, release controlling agents, and viscosity modifiers.

[0048] The term "humanized antibody" or "humanized" form of non-human (e.g., mouse) antibodies refers to chimeric antibodies containing minimal sequences derived from non-human immunoglobulins. In some embodiments, humanized antibodies are human immunoglobulins (acceptor antibodies) in which residues from the hypervariable regions of the recipient are replaced by residues from the hypervariable regions of non-human species (donor antibodies) with desired specificity, affinity, and / or ability. Humanized antibodies may also include at least a portion of Fc, typically a portion of a human immunoglobulin consensus sequence. Methods for antibody humanization are known in the art. In some cases, the framework ("FR") residues of human immunoglobulins are replaced by corresponding non-human residues. In addition, humanized antibodies may include residues that are not present in recipient antibodies or donor antibodies.

[0049] The term "ka" (M -1 sec -1 ) is intended to refer to the association rate constant for a particular antibody-antigen interaction. As used herein, the term "K A "(M) is intended to refer to the association equilibrium constant for a particular antibody-antigen interaction.

[0050] As used herein, the term "kd" (sec -1 ) is intended to refer to the dissociation rate constant for a particular antibody-antigen interaction. This value is also referred to as the off value. As used herein, the term "K D ”(M -1 ) is intended to refer to the dissociation equilibrium constant for a specific antibody-antigen interaction.

[0051] In certain embodiments, the antibodies of the present disclosure are monoclonal antibodies. As used herein, the term "monoclonal antibody" 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, rather than the method by which it is produced. The monoclonal antibodies available in conjunction with the present disclosure can be prepared using a variety of techniques known in the art, including the use of hybridoma technology, recombinant technology and phage display technology or a combination thereof. The antibodies of the present disclosure include chimeric antibodies, primatized antibodies, humanized antibodies or human antibodies.

[0052] The term "nebulizer" refers to a device configured to change a drug (preparation) from a liquid to an aerosol or suspension (also referred to herein as mist) of particles or droplets and deliver the aerosol to a subject to breathe the aerosol into the lungs. Nebulizer devices include jet nebulizers, mesh nebulizers, and ultrasonic nebulizers. Nebulizers can also be heated or refillable. Jet nebulizers (sometimes also referred to as compressors, nozzles, pneumatic nebulizers, or Ventori nebulizers) use compressed gas (such as air or oxygen) to form an aerosol. For example, a nebulizer reservoir can be filled with a drug (preparation). Compressed gas can be applied to the inlet of the reservoir and travel at high speed, discharged through a narrow orifice, and a low-pressure area is generated at the outlet. The resulting pressure difference causes the fluid from the reservoir to be sucked and discharged from the reservoir. The fluid can then be crushed into droplets of various sizes by the nebulizer wall or internal baffle. Ultrasonic nebulizers use high frequency vibrations such as 2 million to 3 million per second from a piezoelectric vibrator. The vibrations can be transmitted to the drug (preparation) through a cooling water tank to form an aerosol. A mesh nebulizer uses a very fine mesh to form a mist. The vibrating element pushes the drug (preparation) through the micropores in the membrane (e.g., mesh). This produces an aerosol of small droplets. The wording "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and / or toxicologically with the other ingredients constituting the preparation and / or the mammal treated therewith.

[0053] The term "peak level" refers to the highest concentration of a therapeutic agent (eg, antibody) in a subject.

[0054] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the 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 (methanesulfonate "mesylate"), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may include another molecule, such as an acetate ion, a succinate ion, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Cases where more than one charged atom is part of a pharmaceutically acceptable salt may have more than one counterion. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0055] The term "specific binding" of an antibody refers to the binding of an antibody to a predetermined antigen. -8 M or smaller K D The binding affinity of the antigen is at least 10 times smaller, and preferably at least 100 times smaller, than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen (e.g., as determined by K D Alternatively, the antibody may be expressed as a protein corresponding to about 10 6 M -1 , or about 10 7 M -1 , or about 10 8 M -1 , or 10 9 M -1 or higher, and binds to the predetermined antigen with an affinity (e.g., represented by KA) that is at least 10 times higher, and preferably at least 100 times higher, than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen.

[0056] The term "treatment" refers to a clinical intervention designed to change the natural course of the individual or cell being treated or to prevent the occurrence of a clinical pathological process during the clinical pathological process. The desired therapeutic effect includes reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. For example, 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 improved, reduced, eliminated or prevented, the individual is successfully "treated".

[0057] The term "trough level" refers to the lowest concentration of a therapeutic agent in a subject when the therapeutic agent is in the therapeutic range or the concentration of the therapeutic agent before a further dose of the therapeutic agent is administered.

[0058] The term "variable region" or "variable domain" of an antibody refers to the amino terminal domain of the heavy or light chain of an antibody. The variable domains of the heavy and light chains may be referred to as "VH" and "VL", respectively. These domains are typically the most variable parts of an antibody (relative to other antibodies of the same type) and contain antigen binding sites. Therapeutic antibodies may be administered to the upper respiratory tract (also referred to as the upper airway) and / or the lower respiratory tract (also referred to as the lower airway). In some embodiments, the antibody is administered to both the upper and lower respiratory tracts. The upper airway includes the nose and nasal passages, paranasal sinuses, oral cavity, pharynx, and the part of the larynx above the vocal cords, while the lower airway is further divided into a conduction zone and a respiratory zone. The conduction zone is formed by the part of the larynx below the vocal cords, the trachea and lungs, the bronchi and bronchioles. The respiratory zone is formed by respiratory bronchioles, alveolar ducts, and alveoli. Therapeutic antibodies may be administered to the upper and / or lower airways by dry powder inhaler (DPI), injection, metered dose inhaler, nasal spray, or nebulizer. Nebulizer is a drug delivery device that converts liquid medicine (such as antibody composition described herein) into fine droplets (aerosol or mist) such as being inhaled into the lungs of a subject through a mask or mouthpiece.Nebulizer includes jet nebulizer, ultrasonic nebulizer and mesh nebulizer.The example of the nebulizer that can be used to administer therapeutic antibodies includes Acorn and Acorn II® nebulizer (VitalSigns), AERx nebulizer (Aradigm), AeroDose nebulizer (AeroGen Inc., Mountain View, CA), Respimat nebulizer (Boehringer, Germany) and UltraVent™ nebulizer (Mallinckrodt).In some embodiments, the nebulizer for practicing the method herein is a non-jet nebulizer and / or a non-ultrasonic nebulizer.In some embodiments, the nebulizer for practicing the method herein is a mesh nebulizer.The mesh nebulizer can be gentler and less damaging to the antibody structure.Antibody efficacy is highly dependent on its higher structure or conformation. Antibodies are proteins that undergo multiple complex protein folding stages during formation to produce their complex higher-order structures. These stages are primary, secondary, tertiary and quaternary. The primary stage is the amino acid sequence held together by peptide bonds. The secondary stage is when the protein begins to fold (forming, for example, 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 related to its function. The tertiary structure is held together by various non-covalent interactions between side groups, 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 other peptides, such as when a heavy chain and a light chain are linked together. Antibodies can be sensitive to degradation due to many types of physical and chemical stresses, such as freezing, heating, stirring, oxidation and pH changes.Any of the compositions herein may comprise a pharmaceutically acceptable diluent, excipient or carrier.

[0059] Atomizer described herein can be configured to produce a particle size with a predetermined range. The particle size range can be within a preferred range for being deposited in the lungs and nasal passages using the method described herein. Particles outside the desired range may not be delivered in the nasal passages with a desired distribution pattern or level. For example, in any method described herein, operating the atomizer to continuously form particles containing agents may include particles with an average particle or droplet size (generally defined as a median mass aerodynamic diameter, MMAD) in the following range: about 0.1 to about 200 microns (such as between about 1 to 10 microns, between about 2 to 7 microns, between about 2 to 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 atomizer to continuously form particles containing the agent includes forming particles having an average particle or droplet size in the range of about 2 to 7 microns. In some examples, the methods described herein can be used with two particle size distributions, including smaller and larger particle sizes.

[0060] In some variations, inhaled respiratory medications can be administered using a device called a metered dose inhaler, or MDI. An MDI is a mouthpiece-loaded pressurized can of medication in a plastic holder. When sprayed, an MDI can provide a reliable, consistent dose of medication.

[0061] The present disclosure provides a treatment regimen, which involves administering one or more therapeutic agents (including one or more than one antibody) to a subject suffering from a disease (respiratory disease) or being at risk of suffering from a disease (respiratory disease). The dosage regimen (e.g., treatment regimen) for administration can vary according to the age and size of the subject to be administered, the target disease, the antibody details, the condition / health / disease condition, and the route of administration. The dosage regimen can be more than once a day, but will generally be once a day or twice a day. In some variations, the dosage regimen can include more frequent administration of therapeutic agents, such as three times a day, four times a day, etc. In some embodiments, the dosage regimen is administered once a day for only one day (i.e., only one dose). In some embodiments, the dosage regimen can last from one day to indefinitely. In some embodiments, the dosage regimen lasts for two days, three days, four days, five days, six days, seven days, etc. or longer. In some embodiments, the dosage regimen can have a regular administration interval, such as every day, every other day, every two days, every week, every two weeks, every month, etc. or between these administration intervals. In some embodiments, the dosing regimen can be a non-variable dosage regimen (for example, each dosage is the same amount) or a variable dosage regimen (different dosages are different amounts, such as a larger amount of antibody in the first dose and a smaller amount in the subsequent dose, such as half, one-third, one-quarter, etc. in the subsequent dose). A once-a-day delivery regimen can be convenient and contribute to successful adherence to the regimen. Although a more frequent delivery regimen than once a day may be less convenient, there may be advantages in more frequent delivery than once a day. For example, for some therapeutic agents, such as expensive monoclonal antibodies, the total amount of the therapeutic agent delivered with two doses can be less than the amount of the therapeutic agent delivered with a single once-a-day dose, and the delivery regimen of two (or optionally more) doses per day can result in lower costs. As shown in Example 4, in order to minimize the trough level that becomes too low and therefore loses efficacy, a single high dose once a day or a significantly lower dose twice a day can be applied. Each of these two doses can be much lower, thereby being enough to compensate for the inconvenience of twice-daily administration of the dose. Thus, providing once-daily versus twice-daily (three-times, etc.) dosing can balance convenience and effective use of the antibody, such as, for example, depending on the cost of antibody production, the accessibility of delivery options (e.g., self-administration, availability of medical professionals for therapeutic administration, access to medical facilities for therapeutic administration, etc.).

[0062] Specific antibodies and EC50 multiple agents thereof can benefit from the aerosol delivery methods and devices described herein. In particular, these methods and devices can benefit agents for treating respiratory diseases affecting at least one of the upper respiratory tract and the lower respiratory tract, although both the upper respiratory tract and the lower respiratory tract can generally benefit (treatment). In some embodiments, the methods and devices can be used to alleviate symptoms in the upper respiratory tract (e.g., from respiratory tract infections) and treat the lower respiratory tract, which is generally more relevant to hospitalization and other serious adverse outcomes. These methods and devices can be particularly effective in delivering agents configured as mucosal binding agents and / or capture agents. For example, when the agent is a recombinant antibody comprising an oligosaccharide with a G0 glycosylation pattern, the methods and devices described herein can be particularly useful and / or effective, and the G0 glycosylation pattern comprises a bi-branched core polysaccharide structure of Manα1-6 (Manα1-5) 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 agent comprises a recombinant antibody comprising a human Fc region or a humanized Fc region, wherein the recombinant antibody includes an antibody population of which at least 20% (e.g., 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, etc.) comprises oligosaccharides having a G0 glycosylation pattern, wherein the G0 glycosylation pattern comprises a bi-branched core glycan structure of Manα1-6(Manα1-5)Manβ1-4GlcNAcβ1-4GlcNAcβ1 with a terminal N-acetylglucosamine on each branch that enhances the capture efficacy of the recombinant antibody in mucus.

[0063] The methods and devices described herein can be used to treat a subject having a respiratory condition or at risk of having a respiratory condition by administering one or more therapeutic antibodies. Examples of antibodies that can be used with the methods and devices herein include anti-differentiation cluster 39 (CD39) antibodies having antibodies or antigen-binding fragments thereof that can specifically bind to human differentiation cluster 39 (CD39), and as described in US20210388105A1. As measured by fluorescence activated cell sorting (FACS) assay, the antibody or antigen-binding fragment thereof is capable of ≯10 -8 The half-maximal effective concentration (EC50) of M specifically binds to human CD39. CD39 has been implicated in the pathogenesis of cigarette smoke-induced lung inflammation in patients and preclinical mouse models.

[0064] 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 against influenza B virus in animals (e.g., mammals) when administered subcutaneously or intravenously and / or when administered before or after infection with influenza B virus, and can reduce symptoms of headache, fever, pain, rhinorrhea (nasal congestion), chills, fatigue, weakness, sore throat, cough, shortness of breath, vomiting, diarrhea, pneumonia, bronchitis, and / or death. The anti-influenza B antibody is administered at a dose of less than about 10 -9 EC50 of M for binding to influenza B HA.

[0065] 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). Anti-PCRV antibodies can bind to the V-tip protein (PcrV) of Pseudomonas aeruginosa (P. aeruginosa) and inhibit or neutralize the activity of the bacterial type 3 secretion system (T3SS) in P. aeruginosa. It is believed that the antibodies can be used to block the translocation of toxins from bacteria to host cells and / or to prevent host cell death. Anti-PCRV antibodies can act by blocking pore-mediated membrane permeability in host cells. Anti-PCRV antibodies can be used at a concentration of less than about 10 -8 EC50 of M binds to full-length PcrV. As disclosed in US20200392210A1, patients at greater risk of infection with Pseudomonas aeruginosa may be patients with cystic fibrosis, diabetes, mechanical ventilator use, undergoing surgery, tuberculosis, HIV, compromised immune system, neutropenia, indwelling catheters, after physical trauma, burns, in intensive care units, bedridden, malignant tumors, chronic obstructive pulmonary disease, in long-term care health facilities, or intravenous drug users.

[0066] Another antibody that can be used with the methods and devices herein is an anti-PD1 antibody (Apollomics Inc., Foster City, CA), as disclosed in US10981994B2. The anti-PD-1 antibody can be a humanized antibody, wherein the anti-PD-1 antibody has 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, disrupting PD-1 / PD-L1 interactions and leading to an increase in T cell activation. US10981994B2 discloses the production of IgG1 and IgG4 forms of humanized 7A4 and 13F1 antibodies. Anti-PD-1 antibodies can be used to treat infectious diseases, including respiratory diseases, such as candidiasis, candidemia, aspergillosis, streptococcal pneumonia, streptococcal skin and oropharyngeal conditions, Gram-negative sepsis, tuberculosis, mononucleosis, influenza, respiratory diseases 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 (also known as LY-CoV555, also known as LY3819253) was originally derived from the blood of one of the first COVID-19 recovered patients in the United States. It is a recombinant neutralizing monoclonal antibody against the SARS-CoV-2 spike protein. Eli Lilly's Etesilmab (LY-CoV016, also known as JS016, also known as 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) has been used to treat mild to moderate COVID-19. Bebtelovimab binds to the SARS-CoV-2 spike protein. Bebtelovimab is administered as a single 175 mg intravenous injection for at least 30 seconds. Bebtelovimab is a human immunoglobulin G-1 (IgG1 variant) monoclonal antibody with 2 identical light chain polypeptides each comprising 215 amino acids and 2 identical heavy chain polypeptides comprising 449 amino acids. Bebtelovimab has been produced by Chinese Hamster Ovary (CHO) stable batch culture or cell line with a molecular weight of 144 kDa.Bebtelovimab is a recombinant neutralizing human IgG1λ monoclonal antibody (mAb) against the spike protein of SARS-CoV-2, and the Fc region is not modified. Bebtelovimab reportedly binds to the spike protein with a dissociation constant KD = 0.046 to 0.075nM, and blocks the attachment of the spike protein to the human ACE2 receptor with an 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 (created by Regeneron, trade name REGEN-COV). Regeneron's REGEN-COV (formerly known as REGN-CoV2 or REGEN-CoV2) is 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 regdanvimab or CT-P59 (Celltrion). Regdanvimab is a recombinant human monoclonal antibody that targets the receptor binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Regdanvimab is a recombinant monoclonal antibody expressed in CHO-K1 cells. CT-P59 clinical batches were found to bind to the RBD in a dose-dependent manner, as shown by a half-maximal effective concentration (EC50) of 4.4 ng / ml for CT-P59 to the SARS-CoV-2 RBD protein.

[0067] Another antibody that can be used with the methods and devices herein is sotrovimab (created by VirBiotechnology / GSK). Sotrovimab (formerly VIR-7831) is reported to bind to a highly conserved epitope of 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 (created by AstraZeneca, AZD7442, trade name Evusheld™). Evusheld™ is urgently authorized as pre-exposure prophylaxis against COVID-19 in immunocompromised individuals or individuals who cannot be vaccinated or cannot establish an immune response after vaccination. AZD7442 contains two monoclonal antibodies, tixagevimab (AZD8895) and cilgavimab (AZD1061), which target the receptor binding domain of the SARS-CoV-2 spike protein.

[0068] The methods and devices described herein can be particularly useful for treating respiratory diseases. In some embodiments, the present disclosure provides a method for treating (improving, alleviating or reducing) the severity, duration or frequency of at least one symptom of a disease or completely preventing a disease. The symptoms that the methods of the present disclosure can treat or prevent can be one or more of the following: headache, fever, pain, rhinorrhea (nasal congestion), chills, fatigue, weakness, sore throat, cough, shortness of breath, vomiting, diarrhea, pneumonia, bronchitis, inflammation and death. Inflammation and other symptoms can be acute, or can be chronic. The important causes of disease (causative agents) can include one or more of disease, environmental factors, genetic factors, illness, infection, pathogens, toxins and / or trauma. Pathogens can include archaea, true bacteria, fungi, protozoa and / or viruses. In some embodiments, the pathogen is a respiratory pathogen and can be a bacterium (such as Haemophilus (Haemophilus influenzae, Haemophilus influenzae (type B)), Moraxella (Moraxella catarrhalis), Pseudomonas (Pseudomonas aeruginosa), Staphylococcus (Staphylococcus aureus), Streptococcus (Staphylococcus pneumoniae); Streptococcus pyogenes (Streptococcus pyogenes); pyogenes), fungi (such as Aspergillis, Blastomyces, Candida, Cryptococcus, Histoplasma, molds, yeasts, zygomycetes), or viruses (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 conditions that can be treated using the methods and devices herein include asthma, rhinitis, pulmonary fibrosis, cystic fibrosis, and chronic obstructive pulmonary disease.

[0069] For the treatment of respiratory diseases, one (or more than one) other therapeutic agent can be appropriately used in combination with the antibody described herein. Other therapeutic agents can be short-acting beta-agonists, such as catecholamines or non-catecholamine agents. Examples include but are not limited to salbutamol (ProAir HFA, Proventil HFA, Ventolin HFA), bitolterol, carbuterol, clenbuterol, epinephrine (Asthmanefrin, Primatene Mist), salbutamol (Xopenex HFA), metaproterenol (metaproterenol) (Alupent), pirbuterol (Maxair), procaterol, terbutaline (Brethine) or other bronchodilators. Other therapeutic agents can be anticholinergics, such as ipratropium (Atrovent) or other mucus-lessening agents (mucus-lessening agents). Other therapeutic agents can be corticosteroids such as methylprednisolone and prednisone or other detumescent agents. For the treatment of respiratory diseases, anti-inflammatory agents can be used in combination with the antibodies of the present disclosure as appropriate. Anti-inflammatory agents include, but are not limited to, acetaminophen, aspirin, dexamethasone, diphenhydramine, pethidine, mesalazine, asacol, codeine phosphate, benolate, fenbufen, naproxen (naprosyn), diclofenac, etodolac and indomethacin and ibuprofen.

[0070] In one example, if Figure 3 As shown in the schematic diagram in , the method 100 may include instructing and / or guiding the patient to apply the aerosolized dose by first (optionally) sitting in an upright position 101. The patient can then activate the nebulizer to continuously provide the aerosolized medicament 103. For example, the method may include instructing the patient to press an on / off button on the nebulizer to start treatment (e.g., in some instances, the button will turn green and mist will appear at the mouthpiece and / or rear of the nebulizer). The method may then instruct the patient to hold the mouthpiece of the nebulizer between the lips 105, including holding the mouthpiece with teeth and / or lips, and closing the lips around the mouthpiece.

[0071] Then, the method may include activating (e.g., triggering) a first indication signal to guide or instruct the patient to inhale the aerosolized medicament 107 through the mouth. The first indication signal may be, for example, a light (one LED or multiple LEDs), a tone, a message, a countdown, etc., which is kept on when the patient inhales to instruct them to inhale deeply to inhale the aerosol through the mouth. The indication signal may be a count (e.g., count up or down). The indication signal may be triggered automatically, including being triggered by a controller with or without input from the patient. In some instances, the patient may manually trigger the start (activation) of the first indication signal. Alternatively, in some instances, the first indication signal may be triggered when (e.g., in a nebulizer and / or in a dosage guidance device) it is sensed that the patient has begun to inhale through their mouth. The first indication signal may remain on for, for example, 4 seconds or longer (e.g., 4 seconds, 4.5 seconds, 5 seconds, 6 seconds, 7 seconds, etc.) for an inhalation duration. The inhalation duration may be fixed or set (e.g., by a user, such as a physician, nurse, pharmacist, and / or patient), or the inhalation duration may be variable. In some examples, the inhalation duration can be changed to indicate that a minimum inhalation duration (e.g., 4 seconds, 4.5 seconds, 5 seconds, etc.) has been reached, but it is recommended to continue inhalation. For example, a first indicator signal can be effective for a minimum inhalation duration of 4 seconds, using a first tone, color, etc., and can remain on for an additional 2-3 seconds, but can be changed to a first optional / continue indicator signal using a second tone, color, etc. For example, the nebulizer and / or dosage guidance device can change from red to yellow or some other change to indicate that inhalation can optionally continue.

[0072] The first indication (and / or the first optional / continue indication signal) can be automatically turned off, for example, after the patient has completed inhalation through the nebulizer and / or started exhalation. The methods and devices may include sensing inhalation and / or exhalation. For example, the nebulizer and / or the dosage guidance device may include one or more sensors for detecting or inferring the start / stop of inhalation and / or exhalation. For example, the nebulizer may include one or more sensors for detecting the 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 may include a controller (including one or more processors) that can perform these methods, including triggering a first indication signal, a second indication signal, etc. The controller can analyze sensor data to trigger the first indication signal and / or the second indication signal.

[0073] Typically, the methods described herein may include instructing or guiding the patient to inhale so that each breath is slow and long, inhaling until their lungs are as full as possible (e.g., inhaling as deeply as possible). As described at 109, each inhalation should last at least 4 seconds or more.

[0074] The second indicator signal to instruct the patient to exhale quickly (e.g., 3 seconds or less) can be triggered automatically as described above (e.g., when inhalation stops) or based on a preset and / or settable timer. Generally, the method can include turning off the first indicator signal and / or activating the second indicator signal to guide the exhalation 111. Because the exhalation phase is intended to be rapid and short, the second indicator signal can include a "stop" indicator signal after a second (exhalation) duration of 3 seconds or less (e.g., 2 seconds) to warn the user to stop. For example, in some cases, the second indicator signal can include a first stage 113 from the beginning of the exhalation to the end of the exhalation phase (2-3 seconds), after which the second indicator signal can change to emphasize that the exhalation should be completed, such as by changing the volume, tone, intensity, color, continuity (e.g., flashing), etc. The second indicator signal can then be turned off or otherwise stopped 115.

[0075] Thus, during inhalation, the patient may be instructed and / or directed to exhale rapidly through their nose, attempting to complete exhalation within about 3 seconds (about 2 seconds, about 2-3 seconds, etc.) As discussed herein, this may direct the aerosolized medicament (e.g., mist) from the patient's lungs to the nose, where it may be captured and administered treatment to the area.

[0076] After completing the long inhalation / fast exhalation, the patient may be instructed to rest, for example, breathe normally one or more times without the nebulizer, or perform another long inhalation / fast exhalation cycle 117. For example, the patient may need to rest, or if they suffer from a cough or have the urge to cough. The patient may press the on / off button to stop the nebulizer. Treatment may be continued by pressing the on / off button on the nebulizer and / or the dose guidance device again to begin inhaling through the mouthpiece and exhaling through the nose (repeat Figure 6 The patient can take a break as many times as needed.

[0077] Treatment can continue until the desired (e.g., preset, user-set, etc.) dose has been delivered. In some instances, treatment including multiple cycles of long inhalation / rapid exhalation can continue until the nebulizer and / or dose guidance device indicates that the entire therapeutic dose has been delivered. For example, treatment can continue until the nebulizer issues an alarm (e.g., a beep and / or flashes), indicating that the treatment is complete. The device can shut down automatically. Any method described herein (including a user interface) can be implemented in software, hardware, or firmware, and can be described as a non-transitory computer-readable storage medium storing an instruction set that can be executed by a processor (e.g., a computer, a tablet computer, a smart phone, etc.), which, when executed by a processor, causes the processor to control any step, including but not limited to: display, communication with a user, analysis, modification of parameters (including timing, frequency, intensity, etc.), determination, alarm, etc.

[0078] As described above, the device can be configured to perform any method described herein. For example, the device can be configured as a nebulizer integrated with a dosage guidance device (or forming a dosage guidance device). The nebulizer can be configured to emit a first indication signal, such as a tone (e.g., a beep, etc.) or illuminate one or more LEDs (e.g., a countdown of an LED), and a second indication signal, such as a second tone or illuminating a different color or a group of LEDs, etc. As described above, the nebulizer can include one or more sensors for detecting and triggering the start of inhalation and / or exhalation to allow the device to count down and instruct the user to inhale and exhale, as described herein.

[0079] In some instances, a separate dosage guidance device can be used with a nebulizer. For example, the dosage guidance device can be software. In some instances, the software can be executed on a processor of a wearable or handheld computing device (such as a smart phone).

[0080] These methods and apparatus can be used with any type of nebulizer. For example, these apparatus can be used with a jet nebulizer that uses compressed gas to make an aerosol, an ultrasonic nebulizer that forms an aerosol by high frequency vibration, and / or a mesh nebulizer that passes a liquid through a very fine mesh to form an aerosol. In particular, these methods can be used with a continuous nebulizer that continuously forms particles when turned on. Alternatively, these methods can be used with an on-demand nebulizer.

[0081] Typically, the methods and apparatus described herein can be applied to aerosol particles of a specific or predetermined size or size distribution. For example, the particles of the agent (MMAD) can be in the range of about 0.1 to about 200 microns (such as between about 1 to 10 microns, between about 2 to 7 microns, between about 2 to 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, the particles containing the agent can have a particle or droplet size in the range of about 2-7 microns. In some instances, the method described herein can be used with two particle size distributions (including smaller and larger particle sizes).

[0082] Any suitable agent may be used, including but not limited to agents that are mucosal capture agents and / or immunotherapeutic agents. Typically, these agents may be agents for treating respiratory conditions / diseases, including conditions / diseases that are transmitted by respiration.

[0083] In particular, the agents described herein may include agents that are trapped within mucus, as described, for example, in US 10,829,543, US 10,100,102, US 10,793,623, US patent application Ser. No. 16 / 982,682 (titled “COMPOSITIONS AND METHODS FOR INHIBITING PATHOGEN INFECTION” and filed on Mar. 20, 2019), US patent application Ser. No. 17 / 063,122 (titled “OPTIMIZED CROSSLINKERS FOR TRAPPING ATARGET ON A SUBSTRATE” and filed on Oct. 5, 2020), and US patent application Ser. No. 17 / 278,217 (titled “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.

[0084] For example, the methods described herein can be particularly useful for delivering doses of agents configured to have enhanced capture efficacy in mucus, including but not limited to proteins (e.g., antibodies) comprising one or more glycosylation patterns that enhance capture in mucus. In some instances, the agent can be a recombinant antibody comprising oligosaccharides having a G0 glycosylation pattern, the G0 glycosylation pattern comprising a bi-branched core polysaccharide structure of Manα1-6 (Manα1-5) Manβ1-4GlcNAcβ1-4GlcNAcβ1, with a terminal N-acetylglucosamine on each branch that enhances the capture efficacy of the recombinant antibody in mucus. For example, the agent can be a recombinant antibody comprising a human Fc region or a humanized Fc region, wherein the recombinant antibody comprises an antibody population of which at least 40% comprise oligosaccharides having a G0 glycosylation pattern, wherein the G0 glycosylation pattern comprises a bi-branched core glycan structure of Manα1-6(Manα1-5)Manβ1-4GlcNAcβ1-4GlcNAcβ1 with a terminal N-acetylglucosamine on each branch that enhances the capture efficacy of the recombinant antibody in mucus.

[0085] The techniques and procedures described or referenced herein can be employed using the methods described in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd ed. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel, et al., eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames, and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JE Cellis, ed., 1998) Academic Press, Inc. Press; Animal Cell Culture (RI Freshney), eds., 1987); Current Protocols in Immunology (JE Coligan et al., eds., 1991); ShortProtocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA 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, eds., 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 JD Capra, eds., Harwood Academic Publishers, 1995). 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 the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, 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, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of 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 can also be used to identify CDR sequences in antibodies. Software packages and databases for determining, for example, antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments are available (see, for example, GenBank, Vector NTI® Suite (Informax, Inc, Bethesda, Md.); GCG Wisconsin Package (Accelrys, Inc., San 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 Heijne (1986) Nucleic AcidsRes. 14:4683-4690). . Example

[0086] The use of various mAbs with different variable regions with the same general Fc region (e.g., SEQ ID NO: 1) surprisingly showed that, despite the widely held belief that such proteins would be rapidly cleared from the lungs (within hours if not minutes), such mAb proteins, and particularly those that were glycosylated to increase mucosal capture, persisted at therapeutically appreciable levels for days when inhaled in safe and reasonable amounts during a single therapy, as described herein.

[0087] The results described herein are not limited to mAbs directed against pathogens. For example, the same Fc region can be used with anti-inflammatory mAbs and generally show the same clearance profile as described herein. Anti-pathogen mAbs 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 a separate anti-inflammatory mAb is used.

[0088] As shown in the Examples below, the results described herein are particularly surprising because it has long been believed that increased mucosal adhesion due to mAbs containing "mucosal-trapping" Fc domains, such as through enriched G0 glycosylation, would result in even faster clearance from the mucosa, but surprisingly, the methods and compositions described herein can remain in both the URT and LRT long enough to maintain meaningful concentrations after 24 hours.

[0089] Example 1: Human IgG G1 Fc region As part of a study conducted in Australia, a human IgG G1 Fc region with an Fc region homologous to SEQ ID NO: 1 (IN-006, a reformulated form of regdanvimab) was examined. Research staff and participants were blinded to treatment assignment, except for pharmacy staff who prepared the study drug. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetic evaluations of IN-006 in nasal fluid and serum.

[0090] 23 participants were enrolled and randomly divided into two single-dose cohorts and one multiple-dose cohort. There were no serious adverse events (SAEs). All enrolled participants completed the study without interruption or termination of treatment. All treatment-emergent adverse events were temporary and graded as mild to moderate in severity, with no dose dependency. For the high-dose group, nebulization was well tolerated and completed within an average of 6 minutes. The mean nasal fluid concentration of IN-006 in the multiple-dose cohort was 921 μg / mL at 30 minutes after administration and 5.4 μg / mL at 22 hours. The mean serum level in the multiple-dose cohort peaked at 0.55 μg / mL 3 days after the last dose.

[0091] IN-006 was well tolerated and achieved respiratory tract concentrations several orders of magnitude above its inhibitory concentration. These data support further clinical development of IN-006.

[0092] Like many viruses that cause acute respiratory tract infections (ARIs), SARS-CoV-2 infects cells almost exclusively via the apical (luminal) side of the airway epithelium, and also primarily via apical surface infection buds from infected cells. Then, as the infection spreads from the upper respiratory tract (URT) to the lower respiratory tract (LRT) and deep in the lungs, progeny viruses must pass through the airway mucus to reach uninfected epithelial cells. Therefore, neutralizing monoclonal antibodies (mAbs) must reach the airway lumen in sufficient quantities to effectively neutralize the virus and stop infection.

[0093] Distribution of mAbs from the blood to the respiratory tract is very poor and slow, with concentrations in the airways orders of magnitude lower than those in serum following intravenous (IV) or intramuscular (IM) administration. Despite these limitations, clinical experience to date shows that mAbs that neutralize SARS-CoV-2 can be effective in treating infected individuals at high risk for severe COVID when administered via IV early in the course of infection. However, doing so typically requires high doses of mAb, reducing the available drug supply. Delayed distribution to the lungs also limits the therapeutic window for preventing severe COVID.

[0094] Nebulization has been used to deliver protein therapeutics (e.g., Pulmozyme) directly to the lungs, enabling administration within a few minutes. Importantly, direct inhalation delivery can reach drug concentrations in the lungs that are far higher than those that can be achieved by IV or IM administration, and is achieved within a few minutes. Since the deposition pattern along the respiratory tract is largely determined by the aerosol droplet size, it is possible to deliver the drug from the nasal concha in the URT through the conducting airways in the LRT to the deep lungs through the entire respiratory tract using a nebulizer that produces a wide aerosol size distribution. Therefore, aerosol delivery may be the fastest method to reach high inhibitory concentration mAbs in airway fluid. Nebulization can also be easily self-administered at home, reducing the burden on patients and the healthcare infrastructure associated with systemic delivery.

[0095] IN-006 is a reformulation of regdanvimab configured as described herein, specifically for nebulized delivery as an inhaled treatment for COVID-19. Regdanvimab, an IV-administered human IgG1 mAb directed against the SARS-COV-2 spike protein receptor binding domain (RBD), is approved in the EU for adults with COVID-19 who do not require supplemental oxygen and are at increased risk of developing severe COVID-19.

[0096] A double-blind, placebo-controlled, first-in-human, ascending-dose pharmacokinetic and safety study was conducted in a Phase 1 unit in Melbourne, Australia. This study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and in compliance with local regulatory requirements and approved by The Alfred Hospital Office of Ethics and Research Governance, Melbourne, VIC, Australia. Informed consent was obtained prior to all study-related procedures. Eligible participants were sequentially enrolled in three cohorts: a single low-dose cohort (30 mg), a single high-dose cohort (90 mg), and multiple high-dose cohorts (7 daily 90 mg doses). For each single-dose cohort, the sentinel pairs (with one active and one placebo recipient) were initially dosed, followed by a two-day safety monitoring period before dosing the rest of the cohort. Entry into the subsequent cohort occurred after reviewing safety parameters 7 days after dosing of the previous cohort. Figure 3 Diagram showing the study structures and timing of pharmacokinetic evaluations.

[0097] Eligibility criteria required participants to be adults aged 18-55 years with a body mass index of 18-32 kg / m 2 Participants were required to be in good health as determined by medical history, physical examination, clinical chemistry and hematology evaluation, electrocardiogram, forced expiratory volume in one second (FEV1) ≥ 90% predicted, and negative serology for HBsAg, HCV, and HIV antibodies. Participants were required to be nonsmokers or light smokers. After the inclusion of the first 7 participants, the FEV1 threshold was changed to ≥ 80% predicted. The following participants were excluded: known or suspected symptomatic viral infection or signs of active lung infection or pulmonary inflammatory conditions within 14 days of the start of dosing, airway hyperresponsiveness, angioedema, history of anaphylaxis, or positive urine drug screen for alcohol breath test and / or substances of abuse. Participants who had received the COVID-19 vaccine were excluded during the recruitment of the 7 participants who made up the first single-dose cohort. However, due to the rapid increase in local vaccine availability and utilization, this criterion was modified to exclude only those vaccinated within two weeks of the initial dose, or those scheduled to be vaccinated within two weeks after the completion of dosing.

[0098] 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, FEV1, SpO2, hematology and chemistry safety blood tests, and physical examinations. Follow-up lasted 28 days. Figure 3 The randomization schedule was prepared by a member of the statistical team who was not responsible for monitoring and data management of the study using validated software (SAS), specifying that each sentinel pair consisted of one active and one saline placebo assignment, and that the overall ratio of active to placebo assignments for each cohort was 3:1. The randomization codes were held by unblinded pharmacy staff, who prepared the doses in matching syringes of identical appearance for clinical staff to load into the nebulizers.

[0099] IN-006 is produced in accordance with good manufacturing practices (GMP) and is provided from the manufacturer as a liquid formulation in a glass vial. IN-006 is provided in a syringe for loading into the InnoSpire Go vibrating mesh nebulizer (KoninklijkePhilips NV). Placebo participants received the same syringe containing saline instead of IN-006. Participants were instructed to inhale slowly through the nebulizer mouthpiece and exhale through their nose. Nasal fluid was obtained by rotating a flocked swab (Copans catalog number 56380CS01) at the depth of the middle turbinate (4-5 cm) for 10-15 seconds. Sampling was alternated between the left and right nostrils during consecutive sample collection time points. The amount of nasal fluid sample collected by each individual swab was determined by comparing the before and after weights. This was achieved by weighing the swabs and sample tubes containing the samples before and after incubation of the swabs containing the samples in buffer for extraction, rinsing, and oven drying. The sampling times for nasal fluid and serum are shown in Figure 3 Methods: The nebulizer was used for the study. Vital signs and FEV1 were measured before nebulization and 15 and 30 minutes after completion. IN-006 concentrations were measured in human serum and nasal fluid. Sample size was selected according to the conventions for Phase I first-in-human studies. No formal sample size and power calculations were performed. Continuous variables were summarized using descriptive statistics, including the number of non-missing observations, mean, SD, median, minimum, and maximum. Categorical variables were summarized using frequency counts and percentages. Placebo recipients were pooled across cohorts. 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 for IN-006 were determined using Phoenix WinNonlin version 8.3.

[0100] Of the 102 adults screened, 23 participants were sequentially assigned to one of three cohorts. The first participant was randomized on September 22, 2021, and the last participant visit was on December 29, 2021. Of these participants, 17 were randomized to receive IN-006 and 6 were randomized to receive placebo. All 23 participants received their assigned treatment as expected and completed their final study visit on Study Day 29. The study was completed on December 29, 2021. Participant flow is mapped on Figure 3 , and the participant demographics are listed in Table 1 ( Figure 1 ).

[0101] Treatment-emergent adverse events (TEAEs) are listed in Table 2 ( Figure 2). Nebulization of IN-006 was well tolerated, and the 90 mg dose was completed in an average of 6 minutes (range 4-9 minutes). Of the 15 participants included in the single-dose escalation cohort, 8 (53.3%) experienced at least 1 TEAE (6 receiving IN-006 and 2 receiving placebo). The most commonly reported TEAEs were headache (4 / 15; 26.7%) and oropharyngeal pain (2 / 15; 13.3%). With the exception of 1 TEAE, all TEAEs were mild. 1 participant receiving the low dose of IN-006 (30 mg) experienced a moderate event (increased transaminases on Day 29), which the investigator considered to be unrelated to the study drug. 3 (3 / 15; 20.0%) participants experienced at least 1 TEAE that the investigator considered to be related to the study drug. These events included headache, cough, and oropharyngeal pain. All 3 related TEAEs were mild and resolved. There was no evidence of a dose-related effect.

[0102] In the multi-dose cohort, participants receiving placebo reported no TEAEs. Of the six participants receiving IN-006, 4 (66.7%) participants experienced at least 1 TEAE. The most commonly reported TEAE was dizziness (2 / 6; 33.3%). All TEAEs except 1 TEAE were mild. One participant receiving IN-006 experienced a moderate event (limb pain). The investigator considered the event unlikely to be related to the study drug. Two (33.3%) subjects experienced at least 1 TEAE that the investigator considered to be related to the study drug. These drug-related TEAEs were dizziness and decreased FEV1: the latter was recorded 15 minutes after nebulization, was not associated with abnormal symptoms or vital signs, subsided within 15 minutes, and did not recur with subsequent dosing. Both events were mild.

[0103] No serious TEAEs, SAEs, or TEAEs leading to discontinuation were reported in either the single-dose or multiple-dose cohorts. There were no unexpected safety signals.

[0104] For the single-dose cohort, the average nasal concentrations measured 3 hours after administration of the 30 mg and 90 mg doses were 261 μg / g and 710 μg / g, respectively; These values ​​are consistent with a 3-fold increase in the administered dose. In the multiple-dose cohort, repeated dosing provides additional opportunities for more nasal concentration measurements across more time points. The nasal concentration 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 occurs immediately after dosing, and nasal concentrations are significantly reduced 3 hours after dosing. Since the IN-006 concentration measured 22 hours after dosing is <2% of the concentration immediately after dosing ( Figure 4A-4C), so there is minimal intranasal accumulation. The difference in nasal concentrations between 30 minutes and 22 hours after dosing suggests that this interval spans ~6-7 half-lives, and the difference between 30 minutes and 3 hours after dosing is about half. Both are consistent with an intranasal half-life of approximately 3-4 hours, significantly longer than the time scale of ~5-15 minutes of mucociliary clearance transit time estimated by saccharin transit time testing.

[0105] like Figure 5A-Figure 5B As shown in the , serum concentrations of IN-006 were detectable by 12 hours after nebulization at a 90 mg dose and continued to increase by 120 hours after a single dose (Cohorts 1 and 2) or by 216 hours after the first dose in patients who received multiple doses (Cohort 3). The elimination half-life of IN-006 in serum was estimated to be ~253, 292, and 402 h in the 30 mg single dose, 90 mg single dose, and 7 daily 90 mg dose cohorts, consistent with the previously estimated elimination half-life of regdanvimab from serum after intravenous administration (288 h). Although serum concentrations of IN-006 were significantly lower than those in nasal fluid (serum C max 52 μg / mL, compared with 990 μg / mL in nasal fluid), but they were still significantly higher than the IC of IN-006. 50 (~0.01 μg / mL).

[0106] It has long been dogma that stably nebulizing mAbs is extremely challenging (see, 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 delivery: what are the next steps? Expert Opin Drug Deliv, 2018. 15(8):729-736), and the biopharmaceutical will be rapidly eliminated from the respiratory tract by systemic absorption, physical mucociliary clearance, or degradation by alveolar macrophages, making it difficult to maintain therapeutic concentrations. See, e.g., Loira-Pastoriza, C., J. Todoroff, and R. Vanbever, Delivery strategies for sustained drug release in the lungs. Adv Drug Deliv Rev, 2014. 75:81-91, and Suri, R., The use of human deoxyribonuclease (rhDNase) in the management of cystic fibrosis. BioDrugs, 2005. 19(3):135-44.

[0107] Surprisingly, as described herein, IN-006 (a reformulation of regdanvimab for aerosol delivery) was safe and well tolerated in healthy adults, with minimal side effects and high concentrations of drug recovered from nasal and serum samples, and was able to maintain therapeutic concentrations. This may be due in part to the glycosylation of the therapeutic antibody as described herein, combined with the administration technique. The treatment was easily self-administered by all participants and completed within a few minutes. Encouragingly, the concentration of IN-006 measured in nasal secretions was well above its IC even 22-24 hours after administration. 50 In the multi-dose cohort that received seven daily 90 mg doses, mean nasal fluid IN-006 concentrations of 920 μg / mL were observed 30 minutes after the initial dose and remained at a mean concentration of 5.4 μg / mL until the second dose 22 hours later. Maintaining ICs higher than regdanvimab and other COVID mAbs against susceptible variants 50 The ability to deliver mAb concentrations 3-7 orders of magnitude higher (~4-20 ng / mL) strongly supports our proposed once-daily dosing regimen. Since SARS-CoV-2 infection and replication begins in the upper respiratory tract, our highly efficient delivery of IN-006 to the nasal passages suggests that it could provide highly effective treatment for early COVID-19, allowing infection to resolve earlier and reducing the risk of progression to severe COVID.

[0108] Although mAbs have been shown to be effective therapeutic agents for COVID-19, the necessity of administration by IV, IM or SC routes limits their scope of use in clinical practice. The requirements for intravenous administration to infusion centers and post-administration observations have severely limited the number of patients treated and greatly increased costs. Although IM injections shorten the administration time, they are limited by the volume that can be administered per injection (~5 mL), which in turn limits the dose of mAb that can be administered per injection and can be painful when the maximum injection volume is used. In contrast, aerosol delivery using a handheld nebulizer enables the convenience of home administration and only takes a few minutes to complete. In addition, the IV, IM and SC routes provide mAbs only to the airway lining fluid after a delay of one or more days, and even then, only airway concentrations that are a fraction of the concentration in plasma are achieved. 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 reached until 2 days after infusion, and the nasal peak concentration of 0.597 μg / mL was ∼10-fold lower than the concentration observed with IN-006 at our daily dosing trough (∼5.4 μg / mL), despite the much lower total dose of IN-006 compared with CR6261 (90 mg IN-006 vs. ∼2,000-4,000 mg CR6261). Increased convenience, more efficient pulmonary delivery, and superior pharmacokinetics may make inhalation a preferred route of mAb delivery for the treatment of acute respiratory infections.

[0109] COVID-19 is primarily a respiratory infection, but currently available treatments are administered systemically. Methods and compositions of mAbs constructed using human IgG that bind to the spike protein of SARS-CoV-2 are described herein. The methods and compositions described herein can provide inhalation delivery of mucosal capture monoclonal antibodies (including Fc regions with G0 glycosylation), which can provide more convenient and effective treatment for COVID-19. The results described in Example 1 show the safety, tolerability and pharmacokinetics of an example of a human IgG G1 Fc region (IN-006, a reformulation of regdanvimab, regdanvimab is an approved intravenous treatment for COVID-19) that can be used for aerosol delivery by a handheld nebulizer.

[0110] Severe disease caused by SARS-Cov-2 is accompanied by the spread of the virus from the initial upper respiratory tract infection site to the deep lungs. Unfortunately, the exact timeline of such transmission may be highly variable between individuals. In fact, there is evidence that the virus can reach the LRT even during the early stages of the disease, that is, when symptoms appear. Similarly, rapid spread of infection to the LRT may also be common for other viruses such as influenza. Therefore, dosing both URT and LRT, rather than focusing only on URT (e.g., via nasal spray), may be important for widening the therapeutic window and reducing the risk of COVID-induced pneumonia and hospitalization. Although IN-006 levels in the LRT were not directly measured in this study, both the obvious serum concentration and the delayed serum Tmax strongly indicate that IN-006 is efficiently delivered to the LRT and deep lungs. In fact, in a multi-dose nebulization study of the toxicokinetics of IN-006 in rats, the concentration of IN-006 in the airway fluid exceeded the serum concentration by ~100 times. Efficient delivery to the LRT is a direct result of our design requirements for the vibrating mesh nebulizer. The droplet size (fine particle fraction, i.e., droplets <5 um, and particularly those <2.5 um) produced by the nebulizer was intentionally selected to deliver the mAb throughout the LRT and deep lung. Furthermore, the fact that a slow steady increase in serum concentrations was observed over ~4 days in the single-dose cohort and that peak serum concentrations were observed at ~9 days (or 2 days after the last dose) in the multiple-dose cohort implies that high levels of IN-006 persisted in the deep lung for at least that duration, i.e., over many days. Assuming that the ratio of airway fluid to serum concentrations in humans is similar to that observed in rats at 100:1, mean human serum concentrations of 200 ng / mL 2 days after the first dose and 550 ng / mL on day 9 should translate to lung concentrations on the order of 50 μg / mL, which is above the IC 50 > 3 orders of magnitude and comparable to serum concentrations achieved by some mAbs administered IV / IM. 50 )The very high mAb levels maintained may continue to provide effective treatment against variants, even in the presence of appreciable genetic drift, and may reduce the risk of inducing viral escape. It also suggests that shorter duration therapy, perhaps as short as a one-time administration, may provide substantial protection from hospitalization.

[0111] Despite the prominent extrapulmonary manifestations of severe COVID-19, and despite the frequent detection of SARS-CoV-2 RNA in the blood, infectious SARS-CoV-2 was rarely detected in the blood of infected patients, suggesting that the extrapulmonary symptoms may be caused by indirect factors such as inflammatory responses rather than extrapulmonary viral infection. Nevertheless, the observed serum levels of IN-006 achieved after aerosol delivery exceeded IC50 At least one order of magnitude is reassuring.

[0112] In a global Phase 3 study, Regdanvimab (IV administration) was shown to be very effective in preventing severe COVID-19, resulting in it being formally approved in the Republic of Korea and the European Union (EMEA / H / C / 005854) for the prevention of severe disease in patients presenting mild to moderate COVID-19, and obtaining emergency use authorization (EUA) or conditional marketing authorization in several other countries around the world. IN-006 can be combined with a second potent neutralizing mAb to produce a mAb mixture with potent binding activity for each variant tested so far. The surprisingly long airway retention of IN-006 observed here can be used for virtually any mAb (e.g., SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4) comprising an Fc region. It was found that IN-006, a re-prepared product of regdanvimab for inhalation delivery, was safe and well tolerated in healthy participants with a single dose of 30 mg and 90 mg and 7 consecutive daily doses of 90 mg. Nebulization resulted in IN-006 levels in nasal fluid and likely lungs that were several orders of magnitude higher than inhibitory concentrations for sensitive SARS-CoV-2 variants within 30 minutes, and persistent elevations in serum concentrations for several days after dosing suggested that IN-006 levels in the lungs were quite persistent.

[0113] Example 2 The methods described herein can be used to provide adequate levels of antibodies in both the upper and lower respiratory tracts.

[0114] Subjects will receive the first dose of IN-006 or placebo via a nebulizer on the first day of administration. Placebo will be 0.9% saline, and will be administered via a nebulizer in the same manner as IN-006. Subjects will receive the second dose of IN-006 or placebo via a nebulizer on at least one day of administration on the 3rd day to the 8th day. Placebo will be 0.9% saline, and will be administered via a nebulizer in the same manner as IN-006. Antibody measurements will be performed using bronchoscopy and bronchoalveolar lavage (BAL) before and after treatment for 2 weeks. Warm sterile PBS will be infused into the segmental middle lobe bronchus with a bronchoscope, and bronchoalveolar lavage will be performed. Liquid will be recovered and collected in a sterile container by gently aspiration. It will be filtered through a sterile 100-μm mesh to remove mucus and cell debris, and analyzed using the method described herein.

[0115] Example 3 Methods described herein can be used to provide at least two therapeutic agents at sufficient levels in both the upper respiratory tract and the lower respiratory tract. Subjects can receive a first dose of IN-006 and a second therapeutic agent (e.g., non-mAb) or a placebo via a nebulizer on the first day of administration. Placebo will be 0.9% saline and will be administered via a nebulizer in the same manner as IN-006. Nasal swabs will be collected on at least one day of administration day 3-administration day 8, and antibody levels will be measured. Subjects will receive a second dose of IN-006 or a placebo via a nasal sprayer on at least one day of administration day 3-administration day 8. Placebo will be 0.9% saline and will be administered via a nebulizer in the same manner as IN-006.

[0116] Example 4 The methods described herein can be used to provide sufficient levels of antibodies in at least one or both of the upper and lower respiratory tracts by dosing 1X (once) or 2X (twice) per day.

[0117] Subjects will receive the first dose of antibody (e.g., IN-006 or other) or placebo via a nebulizer at time 0 on the first day of administration. The antibody can be an antibody glycosylated with a G0 glycosylation pattern. The placebo will be 0.9% saline and will be administered via a nebulizer in the same manner as the antibody (e.g., IN-006 or other). The first cohort of subjects will receive the second dose of antibody (e.g., IN-006 or other) or placebo via a nebulizer 12 hours after the first dose. The placebo will be 0.9% saline and will be administered via a nebulizer in the same manner as the antibody (e.g., IN-006 or other). Antibody measurements will be performed using bronchoscopy and bronchoalveolar lavage (BAL) before administration, immediately after administration, 12 hours (before the second dose), and 24 hours. Warm sterile PBS is infused into the segmental middle lobe bronchus with a bronchoscope for bronchoalveolar lavage. The liquid will be recovered by gentle suction and collected in a sterile container. It was filtered through a sterile 100-um mesh to remove mucus and cellular debris and analyzed using the methods described herein.

[0118] Table 3

[0119] The methods and compositions described herein can allow delivery of inhaled therapeutic mAbs, including those with a G0 glycosylation pattern (which would have been expected to be cleared within minutes based on published work), to achieve sustained high concentrations for 24 hours or longer, allowing for once-daily or twice-daily dosing at relatively low (and therefore affordable) concentrations. Thus, the dose can deliver a therapeutic mAb such that adequate levels are maintained until the next dose (i.e., trough concentrations).

[0120] As described herein, the peak concentration achieved in the upper respiratory tract is proportional to the amount of mAb inhaled (e.g., a ˜3× increase from 30 mg to 90 mg inhaled). Second, clearance is surprisingly independent of dose, with comparable clearance for 30 mg and 90 mg single doses, as well as comparable clearance between different days of 90 mg single dose and 90 mg repeated doses. Rather than being cleared within minutes (e.g., faster than 30 minutes) as previously suggested due to the turnover rate of nasal secretions in the nasal turbinates, “mucosal trapped” mAbs (those with a G0 glycosylation pattern) have half-lives in the range of 3.5-4 hours.

[0121] This allows the dosing regimen to not only reach a sufficiently excessive mAb dose above IC50 immediately after administration, but also allows sufficient mAb to be maintained at the trough before the next administration. Therefore, the dosage of different mAbs can be selected according to their effectiveness to achieve a sufficiently excessive concentration relative to their inherent effectiveness (e.g., maintaining 10-100x above the IC50 of the mAb when IC50 is ~100 ng / mL). For example, the methods and compositions described herein indicate that a 15 mg dose twice a day provides a significant dose.

[0122] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and can be used to achieve the benefits described herein.

[0123] The process parameters and step sequences described and / or illustrated herein are given by way of example only and may be changed as desired. For example, although the steps illustrated and / or described herein may be shown or discussed in a particular order, the steps do not necessarily need to be performed in the order illustrated or discussed. The various exemplary methods described and / or illustrated herein may also omit one or more steps described or illustrated herein, or include additional steps in addition to the disclosed steps.

[0124] When a feature or element is referred to herein as "on another feature or element", it can be directly on the other feature or element, or there may also be intermediate features or elements. On the contrary, when a feature or element is referred to as "directly on another feature or element", there is no intermediate feature or element. It will also be understood that when a feature or element is referred to as "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to other features or elements, or there may be intermediate features or elements. On the contrary, when a feature or element is referred to as "directly connected", "directly attached" or "directly coupled" to another feature or element, there is no intermediate feature or element. Although described or shown with respect to one embodiment, the features and elements described or shown in this way can be applied to other embodiments. It will also be understood by those skilled in the art that the structure or feature set with reference to "adjacent" another feature can have a part overlapping with an adjacent feature or below an adjacent feature.

[0125] The terms used herein are used only for the purpose of describing specific embodiments and are not intended to limit the present invention. For example, unless the context clearly indicates otherwise, as used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well. It will also be understood that the terms "comprises" and / or "comprising" when used in this specification specify the presence of stated features, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more 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 " / ".

[0126] Although the terms "first" and "second" may be used herein to describe multiple features / elements (including steps), these features / elements should not be limited by these terms unless the context otherwise indicates. These terms may be used to distinguish one feature / element from another feature / element. Therefore, without departing from the teachings of the present invention, the first feature / element discussed below may be referred to as the second feature / element, and similarly, the second feature / element discussed below may be referred to as the first feature / element.

[0127] Throughout this specification and the appended claims, unless the context 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., compositions and equipment including devices, and methods). For example, the term "comprising" will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.

[0128] In general, any apparatus and method described herein should be understood to be inclusive, but all or a subset of components and / or steps may optionally be exclusive and may be expressed as "consisting of" or, alternatively, "consisting essentially of": a plurality of components, steps, sub-components or sub-steps.

[0129] As used herein in the specification and claims, including those used in the examples, and unless otherwise expressly stated, all numbers may be understood to be prefixed with the word "about" or "approximately", even if the term does not appear explicitly. The wording "about" or "approximately" may be used when describing amplitude and / or position to indicate that the value and / or position described is within the reasonable expected range of value and / or position. For example, a numerical value may have a value of + / -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), etc. Any numerical value given herein is also understood to include about or approximately that value, unless otherwise indicated by the context. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range listed herein is intended to include all subranges contained therein. It should also be understood that when a value is disclosed, "less than or equal to" the value, "greater than or equal to the value," and possible ranges between values ​​are also disclosed, as appropriately understood by the skilled artisan. For example, if a value "X" is disclosed, then "less than or equal to X" and "greater than or equal to X" (e.g., where X is a numerical value) are also disclosed. It should also be understood that throughout the application, data is provided in a variety of different formats, and that the data represents endpoints and starting points and ranges for any combination of data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, it should be understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15, and between 10 and 15 are considered to be disclosed. It should also be understood that every 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.

[0130] Although various illustrative embodiments are described above, any of many changes may be made to the various embodiments without departing from the scope of the invention as described in the claims. For example, in selectable embodiments, the order in which the various described method steps are performed may generally be changed, and in other selectable embodiments, one or more method steps may be skipped together. Optional features of various device and system embodiments may be included in some embodiments and not included in other embodiments. Therefore, the previous description is provided primarily for exemplary purposes and should not be construed as limiting the scope of the invention as set forth in the claims.

[0131] The examples and descriptions included herein show by way of illustration and not limitation the specific embodiments in which the subject matter can be put into practice. As mentioned, other embodiments can be utilized and derived therefrom so that structural and logical replacements and changes can be made without departing from the scope of the present disclosure. If in fact more than one is disclosed, only for convenience, such embodiments of the subject matter of the invention can be referred to individually or collectively by the term "invention" herein, and it is not intended that the scope of the present application be voluntarily limited to any single invention or inventive concept. Therefore, although specific embodiments have been illustrated and described herein, any arrangement that is considered to achieve the same purpose can replace the specific embodiments shown. The present disclosure is intended to cover any and all modifications or variations of a variety of embodiments. After reading the above description, the combination of the above embodiments and other embodiments not specifically described herein will be apparent to those skilled in the art. Sequence Listing

[0132] 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) APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK.

Claims

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

2. A method of treating a subject having or at risk of having a respiratory condition, the method comprising administering to the subject by inhalation a dose of a therapeutic human IgG monoclonal antibody (mAb) that binds respiratory viruses greater than 20 ng / ml in the subject's upper respiratory tract (URT) and greater than 100 ng / ml in the subject's lower respiratory tract (LRT) for more than 12 hours after administration, the therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies in which at least 40% are glycosylated with a G0 glycosylation pattern comprising a bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice a day.

3. The method of claim 1 or claim 2, wherein administering comprises administering the dose no more than once a day.

4. The method of claim 1, wherein the therapeutic antibody comprises at least 50% of the G0 glycosylation pattern.

5. The method of any one of claims 1-4, 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).

6. The method according to any one of claims 1-5, wherein the subject is an adult.

7. The method of any one of claims 1-4, wherein the therapeutic antibody comprises regdanvimab.

8. The method of any one of claims 1-7, wherein the dosing regimen comprises a twice-daily dosing cycle over a period of two to seven days.

9. The method of any one of claims 1-7, wherein the dosing regimen comprises a dosing cycle of every other day, every other day, or every third day.

10. The method of any one of claims 1-9, wherein the dosing regimen comprises administering a dose of at least 10 mg of the therapeutic mAb.

11. The method of any one of claims 1-11, wherein the dosing regimen comprises administering a dose of between about 10 mg and 100 mg of the therapeutic mAb.

12. The method of any one of claims 1-11, wherein administering comprises maintaining release of the therapeutic mAb from the LRT into the blood over multiple days.

13. The method of any one of claims 1-11, wherein administering comprises maintaining release of the mAb into the lungs and blood for at least two days.

14. The method according to any one of claims 1-13, wherein the formulation further comprises a pharmaceutically acceptable diluent, excipient and / or carrier.

15. The method according to any one of claims 1-14, wherein the formulation further comprises one or more of the following: citrate, arginine, mannitol, sorbitol, trehalose.

16. The method of any one of claims 1-15, wherein the therapeutic antibody formulation is administered to the subject via a nebulizer.

17. The method of any one of claims 1-15, wherein the therapeutic antibody formulation is administered to the subject via a vibrating mesh nebulizer.

18. The method of any one of claims 1-15, wherein the therapeutic antibody formulation is administered via inhalation or via direct instillation into the upper airways.

19. The method of any one of claims 1-15, wherein the therapeutic antibody formulation is self-administered by the subject.

20. The method of any one of claims 1-19, wherein the respiratory tract disorder comprises a lower airway disorder.

21. The method of any one of claims 1-19, wherein the respiratory tract disorder comprises an upper airway disorder.

22. The method of any one of claims 1-19, wherein the respiratory tract disorder comprises an inflammatory disorder.

23. The method of any one of claims 1-19, wherein the respiratory virus comprises a coronavirus.

24. The method of any one of claims 1-19, wherein the respiratory virus comprises severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

25. The method of any one of claims 1-19, wherein the respiratory virus comprises respiratory syncytial virus (RSV).

26. The method of any one of claims 1-19, wherein the respiratory viruses comprise one or more of the following: influenza virus, metapneumovirus, parainfluenza virus, (specific coronaviruses).

27. The method of any one of claims 1-19, wherein the respiratory virus comprises a paramyxovirus.

28. The method of any one of claims 1-27, wherein the formulation comprises a second therapeutic agent or more therapeutic agents in addition to the therapeutic antibody.

29. The method of any one of claims 1-27, wherein the formulation comprises the therapeutic mAb and a second therapeutic antibody, and the first therapeutic antibody and the second therapeutic antibody bind to the same virus but do not compete for binding to the virus.

30. The method of any one of claims 1-27, wherein the formulation comprises a second therapeutic antibody in addition to the first therapeutic antibody, further wherein the first antibody and the second antibody bind different viruses.

31. The method of any one of claims 1-30, wherein the formulation comprises a biologic agent in addition to the therapeutic mAb.

32. A method of treating a subject having or at risk of having a respiratory condition, the method comprising administering to the subject by inhalation a dose of a formulation that maintains a concentration of a therapeutic human IgG monoclonal antibody (mAb) that binds a respiratory virus in the subject's upper respiratory tract (URT) of greater than 25 ng / ml and in the subject's lower respiratory tract (LRT) of greater than 25 ng / ml for more than 12 hours after administration, the formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds a respiratory virus, wherein administration comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice a day.

33. A therapeutic human IgG monoclonal antibody (mAb) for use in a method of treating a respiratory condition by administering the therapeutic human IgG monoclonal antibody (mAb) by inhalation, the therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies in which at least 40% are glycosylated with a G0 glycosylation pattern comprising a bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, wherein administration comprises administering the therapeutic human mAb no more than twice a day at a dose of 0.02 μmol or more to achieve a concentration of the therapeutic human mAb in the upper respiratory tract (URT) of greater than 20 ng / mL and in the lower respiratory tract (LRT) of greater than 100 ng / mL for 12 hours or more after administration.

34. A therapeutic human IgG monoclonal antibody (mAb) for use in a method of treating a respiratory condition, the therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies in which at least 40% are glycosylated with a G0 glycosylation pattern comprising a bi-branched core glycan structure of Manα1-6(Manα1-3)Manβ1-4GlcNAcβ1-4GlcNAcβ1, the method administering by inhalation a dose of the therapeutic human IgG mAb that maintains a concentration of the therapeutic human IgG mAb greater than 20 ng / ml in the upper respiratory tract (URT) of the subject and greater than 100 ng / ml in the lower respiratory tract (LRT) of the subject for more than 12 hours after administration, wherein administering the dose comprises administering 0.02 μmol or more of the therapeutic human mAb no more than twice a day.

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