Classifications

• • C07K16/104—
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/543—Mucosal route intranasal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/544—Mucosal route to the airways
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
  • C07K2317/41—Glycosylation, sialylation, or fucosylation

Definitions

• Fc- conjugated proteins given by inhalation typically have Tmax in serum (i.e. time to reach Cmax) in the 10-20 hrs range, and thus have a much faster clearance (on the order of hours or minutes) in the lungs.
• Bitonti and Durmont “Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway,” Advanced Drug Delivery Reviews, Volume 58, Issues 9- 10, 31 October 2006, Pages 1106-1118. Indeed, the therapeutic efficacy of inhaled drugs has long been believed to be limited by their rapid clearance in the lungs.
• recombinant human deoxyribonuclease I is a 37 kDa glycoprotein which cleaves the DNA in respiratory secretions of cystic fibrosis patients and thus, lowers their viscosity.
• This glycoprotein is the mucolytic agent most widely used in the symptomatic treatment of cystic fibrosis.
• it is rapidly cleared from the human lungs: when the daily dose of 2.5 mg is inhaled, a concentration of 3 pg/ml is measured in sputum immediately after inhalation and it is reduced to 0.6 pg/ml after 2 h.
• compositions and particularly mAb compositions, that may remain within the lungs for an extended period of time at clinically significant levels without being cleared.
• Such compositions and methods may provide numerous clinical and compliance benefits.
• the present invention relates to therapeutic inhaled antibodies and methods of delivering these therapeutic antibodies to sustain a concentration of within the upper respiratory tract (URT) and the lower respiratory tract (LRT), as well as the blood, following even a single dose.
• the compositions and methods described herein may provide therapeutically- relevant levels of an inhaled IgG antibody that is delivered by inhalation at a single dose delivered once per day or less frequently (e.g., between once per day and once per five days). These methods may result in a concentration in both the URT and LRT that is greater than a minimum threshold concentration having clinical relevance.
• the persistence of the therapeutic mAb in the URT and LRT appears to be a result of the interaction of the core Fc region of the IgG backbone common to the therapeutic antibodies described herein (including, e.g., regdanvimab), regardless of the target-specific (variable region) of the individual mAbs. This may be because it is the Fc region that is interacting with the mucus and other components driving clearance of the mAb from the lungs.
• the effects described herein are particularly relevant to composition of mAb in which the IgG Fc regions are glycosylated in a manner that modulates the mucin interactions.
• compositions may include an Fc region that is glycosylated with a GO glycosylation, e.g., comprising a biantennary core glycan structure of Manal-6(Manal-5)Manpi-4GlcNAcpi-4GlcNAcpi with terminal N- acetylglucosamine on each branch that enhances the trapping potency of the recombinant antibody in mucus.
• Described herein are methods of treating a subject having, or at risk of having, a respiratory disorder, comprising administering by inhalation to the subject a formulation comprising a therapeutic antibody that binds to a respiratory virus in a dosing regimen comprising a dosing cycle of once per day or twice per day.
• mAb therapeutic human IgG monoclonal antibody
• administering comprises administering in a dose of 0.02 pmol or more of the therapeutic human mAb no more than twice per day to achieve a concentration of greater than 20 ng/mL for the therapeutic human mAb in an upper respiratory tract (URT) and a concentration of greater than 100 ng/mL in a lower respiratory tract (LRT) for 12 hours or more after the dose.
• UTR upper respiratory tract
• LRT lower respiratory tract
• a method of treating a subject having, or at risk of having, a respiratory disorder may include: maintaining a concentration of greater than 20 ng/ml of a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in an upper respiratory tract (URT) of the subject and a concentration of greater than 100 ng/ml in a lower respiratory tract (LRT) of the subject for more than 12 hours after a dose by administering, by inhalation, to the subject the dose of a therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies in which at least 40% are glycosylated with a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal- 3)Manpi-4GlcNAcpi-4GlcNAcpi, wherein administering the dose comprises administering 0.02 pmol or greater of the therapeutic human mAb no more than twice per day.
• mAb therapeutic human IgG mono
• administering may comprise administering the dose no more than once per day.
• the therapeutic antibody may comprise at least 45% of the GO 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.).
• 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 IgGl).
• 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.
• the therapeutic antibody may be regdanvimab.
• the dosing regimen may comprise a dosing cycle of twice per day over a period of two days to seven days.
• the dosing regimen may comprise a dosing cycle of every second day, every third day or every fourth day.
• the dosage regimen may comprise administering the dose of at least 10 mg of the therapeutic mAb.
• the dosage regimen may comprise administering the dose of between about 10 mg and 100 mg of the therapeutic mAb.
• administering comprises sustaining a release of the therapeutic mAb into the blood from the LRT over multiple days.
• Administering may comprise sustaining release of the mAb into the lungs and blood over at least two days.
• the formulation may also comprise a pharmaceutically acceptable diluent, excipient, and/or carrier.
• the formulation further comprises one or more of: citrate, arginine, mannitol, sorbitol, trehalose.
• the therapeutic antibody formulation may be administered to the subject via a nebulizer, such as a vibrating mesh nebulizer.
• a nebulizer such as a vibrating mesh nebulizer.
• the therapeutic antibody formulation is administered via inhalation or via direct instillation into an upper airway.
• the therapeutic antibody formulation may be self-administered by the subject.
• the respiratory disorder may comprise a lower airway disorder.
• the respiratory disorder may comprise an upper airway disorder.
• the respiratory disorder comprises an inflammatory disorder.
• the respiratory virus may comprise a coronavirus.
• the respiratory virus may comprise severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• the respiratory virus may comprise respiratory syncytial virus (RSV).
• the respiratory virus may comprise one or more of: influenza, metapneumovirus, parainfluenza, (specific coronavirus). In some examples the respiratory virus comprises a paramyxovirus.
• the formulation may comprise a second or more therapeutic agent in addition to the therapeutic antibody.
• the formulation may comprise 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.
• the formulation comprises a second therapeutic antibody in addition to the first therapeutic antibody, further wherein the first antibody and the second antibody bind to different viruses.
• the formulation comprises a biologic in addition to the therapeutic mAb.
• a method of treating a subject having, or at risk of having, a respiratory disorder may include: maintaining a concentration of greater than 25 ng/ml of a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in an upper respiratory tract (URT) of the subject and a concentration of greater than 25 ng/ml in a lower respiratory tract (LRT) of the subject for more than 12 hours after the dose by administering, by inhalation, to the subject the dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus, wherein administering comprises administering 0.02 pmol or greater of the therapeutic human mAb no more than twice per day.
• mAb therapeutic human IgG monoclonal antibody
• Also described herein are methods of treating a subject having, or at risk of having, a respiratory disorder the method comprising administering, by inhalation, to the subject a formulation comprising a therapeutic human IgG monoclonal antibody (mAh) that binds to a respiratory virus, wherein administering comprises administering a dose of 0.02 pmol or greater of the therapeutic human mAb no more than once per day to achieve a concentration of greater than 25 ng/ml for the therapeutic human mAb in an upper respiratory tract (URT) and a concentration of greater than 25 ng/ml in a lower respiratory tract (LRT) for more than 24 hours after the dose.
• UTR upper respiratory tract
• LRT lower respiratory tract
• Also described herein are methods of treating a subject having, or at risk of having, a respiratory disorder the method comprising administering, by inhalation, to the subject a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that is glycosylated with a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal-3)Manpi-4GlcNAcpi-4GlcNAcpi, wherein administering comprises administering in a dose of 0.02 pmol or more of the therapeutic human mAb no more than once per day to achieve a concentration of greater than 20 ng/mL for the therapeutic human mAb in an upper respiratory tract (URT) and a concentration of greater than 100 ng/mL in a lower respiratory tract (LRT) for more than 24 hours after the dose.
• mAb therapeutic human IgG monoclonal antibody
• a method of treating a subject having, or at risk of having, a respiratory disorder may include maintaining a concentration of greater than 25 ng/ml of a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in an upper respiratory tract (URT) of the subject and a concentration of greater than 25 ng/ml in a lower respiratory tract (LRT) of the subject for more than 24 hours after a dose by administering, by inhalation, to the subject the dose of a formulation comprising a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus, wherein administering comprises administering 0.02 pmol or greater of the therapeutic human mAb no more than once per day.
• mAb therapeutic human IgG monoclonal antibody
• a method of treating a subject having, or at risk of having, a respiratory disorder may include maintaining a concentration of greater than 20 ng/ml of a therapeutic human IgG monoclonal antibody (mAb) that binds to a respiratory virus in an upper respiratory tract (URT) of the subject and a concentration of greater than 100 ng/ml in a lower respiratory tract (LRT) of the subject for more than 24 hours after a dose by administering, by inhalation, to the subject the dose of a therapeutic human IgG monoclonal antibody (mAb) that is glycosylated with a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal-3)Manpi-4GlcNAcpi-4GlcNAcpi, wherein administering the dose comprises administering 0.02 pmol or greater of the therapeutic human mAb no more than once per day.
• mAb therapeutic human IgG monoclonal antibody
• UTR upper respiratory tract
• the therapeutic antibody may be a therapeutic human IgG monoclonal antibody (mAb).
• the therapeutic human IgG monoclonal antibody (mAb) is a human IgGl mAb.
• the therapeutic antibody comprises an Fc sequence that is at least X% (e.g., 80%, 85%, 90%, 95%) homologous to the sequence of SEQ ID NO. 1 (e.g., human IgG Gl).
• the therapeutic antibody may comprise regdanvimab.
• the Fc sequence may be at least X% homologous to the sequence of one or more of SEQ ID NO.: 1, SEQ ID NO.: 2, SEQ ID NO.: 3, and/or SEQ ID NO.: 4.
• the subject may be any subject in need of the therapy.
• the subject may be an adult subject and young-adult subjects.
• a young-adult subject may refer to any individual 12 and older.
• the therapeutic antibody may comprise an oligosaccharide that enhances the trapping potency of the recombinant antibody in mucus.
• the therapeutic antibody may comprise a population of mAbs in which at least 40% comprises an oligosaccharide having a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal-5)Manpi-4GlcNAcpi-4GlcNAcpi with terminal N- acetylglucosamine on each branch that enhances the trapping potency of the recombinant antibody in mucus.
• the dosing regimen may comprise a dosing cycle of once per day over a period of two days to seven days.
• the dosing regimen may comprise a dosing cycle of every second day, every third day or every fourth day.
• the dosing regimen may comprise administering a total of two, three, or four doses.
• the dosing regimen may comprise administering only a single dose.
• the dosage regimen may comprise administering the dose of at least 30 mg of the therapeutic mAb.
• the dosage regimen may comprise administering the dose of between about 30 mg and 90 mg of the therapeutic mAb.
• administering may comprise sustaining a release of the therapeutic mAb into the blood from the LRT over multiple days.
• Administering may comprise sustaining release of the mAb into the lungs and blood over at least two days.
• the formulation further comprises a pharmaceutically acceptable diluent, excipient, and/or carrier.
• the formulation may further comprise one or more of: citrate, arginine, mannitol, sorbitol, trehalose.
• the therapeutic antibody formulation may be administered to the subject via a nebulizer.
• the therapeutic antibody formulation may be administered to the subject via a vibrating mesh nebulizer.
• the therapeutic antibody formulation may be administered to the subject via a nebulizer.
• the therapeutic antibody formulation may be administered via inhalation or via direct instillation into an upper airway.
• the therapeutic antibody formulation may be self-administered by the subject.
• the respiratory disorder comprises a lower airway disorder.
• the respiratory disorder may comprise an upper airway disorder.
• the respiratory disorder may comprise an inflammatory disorder.
• the respiratory virus may comprise a coronavirus.
• the respiratory virus may comprise severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• the respiratory virus may comprise respiratory syncytial virus (RSV).
• the respiratory virus may comprise one or more of: influenza, metapneumovirus, parainfluenza, (specific coronavirus).
• the respiratory virus may comprise a paramyxovirus.
• the formulation may comprise a second or more therapeutic agent in addition to the therapeutic antibody.
• the formulation may comprise 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.
• the formulation may comprise a second therapeutic antibody in addition to the first therapeutic antibody, further wherein the first antibody and the second antibody bind to different viruses.
• the formulation may comprise a biologic in addition to the therapeutic mAb.
• compositions e.g., therapeutic human IgG monoclonal antibodies, and in particular, therapeutic human IgG monoclonal antibody (mAb) comprising a population of antibodies in which at least 40% are glycosylated with a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal-3)Manpi-4GlcNAcpi- 4GlcNAcpi, for use in a method of treating any of the respiratory disorders described herein by performing any of the methods described.
• mAb therapeutic human IgG monoclonal antibody
• therapeutic human IgG monoclonal antibody comprising a population of antibodies in which at least 40% are glycosylated with a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal-3)Manpi-4GlcNAcpi-4GlcNAcpi, for use in a method of treatment of a respiratory disorder by administering, by inhalation, the therapeutic human IgG monoclonal antibody (mAb), wherein administering comprises administering in a dose of 0.02 pmol or more of the therapeutic human mAb no more than twice per day to achieve a concentration of greater than 20 ng/mL for the therapeutic human mAb in an upper respiratory tract (URT) and a concentration of greater than 100 ng/mL in a lower respiratory tract (LRT) for 12 hours or more after the dose.
• UTR upper respiratory tract
• LRT lower respiratory tract
• therapeutic human IgG monoclonal antibody comprising a population of antibodies in which at least 40% are glycosylated with a GO glycosylation pattern comprising a biantennary core glycan structure of Manal-6(Manal- 3)Manpi-4GlcNAcpi-4GlcNAcpi, for use in a method of treatment of a respiratory disorder by maintaining a concentration of greater than 20 ng/ml of the therapeutic human IgG mAb in an upper respiratory tract (URT) of the subject and a concentration of greater than 100 ng/ml in a lower respiratory tract (LRT) of the subject for more than 12 hours after a dose by administering, by inhalation, the dose of the therapeutic human IgG mAb, wherein administering the dose comprises administering 0.02 pmol or greater of the therapeutic human mAh no more than twice per day.
• UTR upper respiratory tract
• LRT lower respiratory tract
• FIG. 1 is table 1, describing the demographics of patients enrolled in the study described in Example 1, showing the persistence of a therapeutic mAb having a human IgG Fc region that has been glycosylated (e.g., so that greater than 40% of the mAb is glycosylated) in the upper respiratory and lower respiratory tract (as seen in the serum level).
• FIG. 2 is table 2 summarizing adverse events from the study described in Example 1. Side effects marked by a (*) occurred within 2-hours of completing nebulization; (cough, FEV1 decreased). Complications marked by (**) included contraceptive IUD use.
• FIG. 3 shows an example of a process flow for the example method of treatment described in Example 1.
• FIG. 3 shows an example of the study schema and sample collection timepoints used in Example 1.
• FIGS. 4A-4C illustrate nasal fluid concentrations.
• FIG. 4A shows concentrations in single dose cohorts.
• FIG. 4B shows concentrations in daily multiple dose cohort (e.g., seven days of 90 mg). Arrows on the X axis indicated the 7 times of 90 mg dose administration in FIG. 4B.
• FIG. 4C show a comparison of nasal concentrations between single dose and multiple dose cohorts. Average LLOQ for all nasal fluid samples is shown at 450 ng/g, but LLOQ varied by sample, depending on the mass of nasal fluid collected on swab, resulting in some detectable samples below the overall average LLOQ. The fractions below each timepoint represent the number of samples that fell below the LLOQ at that time.
• FIGS. 5A-5B show serum IN-006 concentrations in single dose cohorts (FIG. 5A), and a multiple dose cohort (FIG. 5B, last dose administered at 144 h). Symbols plotted below the dashed LLOQ line at 25 ng/mL represent the number of samples in each group that were BLQ at each timepoint.
• FIG. 6 is a schematic illustrating one example of a method as described herein.
• Described herein are methods, compositions and apparatuses (e.g., devices, systems, etc.) useful for treating a subject having, or at risk of having, a respiratory disorder.
• Methods provided herein may be especially useful for treating a subject having or at risk of having a respiratory disorder affecting both the upper respiratory tract (upper airway) and the lower respiratory tract (lower airway).
• Applicant has surprisingly and unexpectedly found using the methods, compositions, and apparatuses described herein the ability to achieve prolonged coverage with a therapeutic antibody that allows for an infrequent or episodic dosage regimen frequency (such as one-time delivery, once- daily delivery not more than twice-daily delivery).
• antibody refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen.
• Basic antibodies have a Y- shape with a stem region and two arm regions and can be classified into different categories, called isotypes, based on features found in the antibody stem region.
• Basic antibodies are heterotetrameric glycoproteins composed of two identical light (L) chains and two identical heavy (H) chains. Each of the four chains has a variable (V) region at its amino terminus, which contributes to the antigen-binding site, and a constant (C) region, which determines the isotype.
• 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 are composed of a light chain and a fragment of the broken heavy chain approximately equal in mass to the light chain. Each of these two units can separately bind antigen and are called Fab fragments (i.e., the “antigen binding” fragments).
• Fab fragments i.e., the “antigen binding” fragments.
• humans may be capable of producing as many as 10 18 , or one quintillion, distinct antibodies and each antibody would have unique Fab fragments.
• the third of the three units is composed of two equal segments of the heavy chain. This third unit is typically not involved in antigen binding but is important in later processes in the body involved in ridding the body of the antigen.
• the third unit from the antibody typically has one of only five types of physicochemical properties and thus is called the Fc fragment (i.e., the “crystalalizable” fragment).
• the types of human antibodies containing one of the five types of Fc fragments are referred to as IgA, IgD, IgE, IgG, and IgM isotypes. These isotypes also may have several subclasses. For example, IgG antibodies in humans may be further divided into the subclasses IgGl, IgG2, IgG3, and IgG4. IgG antibodies in mice can be further subdivided into the subclasses IgGl, 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 e.g., Fab', F(ab')2, Fab, Fv, rlgG, and scFv fragments (e.g., a single chain Fv) fragment including a VL domain linked to a VH domain by a linker.
• a “blocking” antibody (also referred to as an “antagonist” antibody) is an antibody that inhibits or reduces the biological activity of the antigen it binds. In some embodiments, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.
• Carriers are generally designed to interact with, and enhance the properties, of active pharmaceutical ingredients (APIs) (e.g., antibodies). Carriers are generally safe and nontoxic to the subject and cells being exposed thereto at the dosages and concentrations employed.
• An example of a physiologically acceptable carrier is an aqueous pH buffered solution, such as a saline solution.
• physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
• buffers such as phosphate, citrate, and other organic acids
• antioxidants including ascorbic acid
• proteins such as serum albumin, gelatin, or immunoglobulins
• hydrophilic polymers such
• Cmax refers to a standard pharmacokinetic measure used to determine drug dosing.
• Cmax is the peak (highest) concentration maximum (or peak) concentration that a drug achieves in a specified compartment or test area of the body (e.g., blood, serum, nasal cavity, etc.) after the drug has been administered and before the administration of a subsequent (second) dose.
• an effective amount is at least the minimum agent concentration required to cause a measurable improvement or prevention of a particular disorder.
• An effective amount herein may vary according to factors such as the particular disorder (e.g., disease state), age, sex, and weight of the subject, and the ability of the agent (e.g., antibody) to elicit a desired response in the individual.
• An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
• beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disorder (disease), including biochemical, histological and/or behavioral symptoms of the disorder (disease), its complications and intermediate pathological phenotypes presenting during development of the disorder (disease).
• beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disorder (disease), increasing the quality of life of those suffering from the disorder (disease), decreasing the dose of other medications required to treat the disorder (disease), enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
• An effective amount can be administered in one or more administrations.
• an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
• an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
• an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
• excipient refers to substances in a formulation other than the active pharmaceutical ingredient(s) (e.g., antibody). Examples of excipients include antioxidants, buffering agents, emulsifiers, penetration enhancers, preservatives, release controlling reagents, and viscosity modifiers.
• humanized antibodies or “humanized” forms of non-human (e.g., murine) antibodies refers to chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
• a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and/or capacity.
• donor antibody such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and/or capacity.
• the humanized antibody can also comprise at least a portion of an Fc, typically that of a human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art.
• framework (“FR”) residues of the human immunoglobulin are replaced by corresponding non-human residues.
• humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody
• the term “ka” (M ⁇ ec 1 ) is intended to refer to the association rate constant of a particular antibody-antigen interaction.
• the term “KA” (M), as used herein, is intended to refer to the association equilibrium constant of a particular antibody-antigen interaction.
• the term “kd” (sec x ), as used herein, is intended to refer to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the off value.
• KD (M -1 ), as used herein, is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction.
• antibodies of the disclosure are monoclonal antibodies.
• the term “monoclonal antibody” as used herein includes but is not limited to antibodies produced through hybridoma technology.
• the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
• Monoclonal antibodies useful in connection with the present disclosure can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof.
• the antibodies of the disclosure include chimeric, primatized, humanized, or human antibodies.
• nebulizer refers to a device configured to change a medication (formulation) from a liquid to an aerosol or suspension of fine particles or droplets (also referred to herein as a mist) and to deliver the aerosol to a subject for breathing the aerosol into the lungs.
• Nebulizer devices include jet nebulizers, mesh nebulizers, and ultrasonic nebulizers. Nebulizers can also be heated or refillable.
• a jet nebulizer also sometimes referred to as a compressor, nozzle, pneumatic, or venturi nebulizer uses a compressed gas (such as air or oxygen) to form an aerosol.
• a nebulizer reservoir can be filled with medication (formulation).
• Compressed gas can be applied to an inlet of the reservoir and traveling at high velocity, exit through a narrow orifice, creating an area of low pressure at the outlet.
• the resulting pressure differential causes fluid from the reservoir to be drawn up into and out of reservoir.
• the fluid can then be shattered into droplets of various sizes by the nebulizer walls or internal baffles.
• An ultrasonic nebulizer uses high-frequency vibrations such as 2-3 million/second from a piezoelectric vibrator. The vibrations can be transferred through a cooling water tank to the medication (formulation) to form an aerosol.
• a mesh nebulizer uses a very fine mesh to form a mist.
• a vibrating element pushes a medication (formulation) through microscopic holes in a membrane (e.g., a mesh). This generates an aerosol of small droplets.
• a medication formulation
• a membrane e.g., a mesh
• pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
• peak level refers to the highest concentration in an individual’s body of a therapeutic agent (e.g., antibody).
• salts refers to pharmaceutically acceptable organic or inorganic salts 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, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., l,l'-methylene-bis-(2-
• a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
• the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
• a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
• the term “specific binding” of an antibody refers to antibody binding to a predetermined antigen.
• the antibody binds with an affinity corresponding to a KD of about IO -8 M or less and binds to the predetermined antigen with an affinity (as expressed by KD) that is at least 10 fold less, and preferably at least 100 fold less than its affinity for binding to a nonspecific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
• a nonspecific antigen e.g., BSA, casein
• the antibody can bind with an affinity corresponding to a KA of 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 (as expressed by KA) that is at least 10 fold higher, and preferably at least 100 fold 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.
• a non-specific antigen e.g., BSA, casein
• treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology or to prevent a course of clinical pathology from occurring. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
• an individual is successfully “treated” if one or more symptoms associated with a respiratory disorder are ameliorated, reduced, eliminated, or prevented, such as aches, bronchitis, chills, confusion, coughing, death, diarrhea, difficulty breathing, fatigue, fever, headache, inflammation, pale/gray/blue-colored skin/lips/nail beds, pneumonia, rhinorrhea (nasal congestion), shortness of breath, sneezing, sore throat, vomiting, weakness.
• trough level refers to the lowest concentration in an individual’s body of a therapeutic agent while the therapeutic agent is in a therapeutic range or of a concentration of therapeutic agent concentration prior to giving a further dose of the therapeutic agent.
• the total amount of therapeutic agent delivered in two doses can be less than the amount of therapeutic agent that would be delivered in a single once per day dose, and a two (or optionally more) dose per day delivery regimen can lead to lower cost.
• a two (or optionally more) dose per day delivery regimen can lead to lower cost.
• a single high dose once a day, or a substantially lower dose twice a day can be administered.
• Each of these two doses can be so much lower that it more than makes up for inconvenience of administering doses twice per day.
• antiinfluenza B antibody As disclosed in US20210171612A1 (Regeneron Pharmaceuticals Inc., Tarrytown, NY).
• the anti -influenza B antibody can be an IgGl or an IgG4 antibody that confers an increase in protection from influenza B virus in an animal (e.g., a mammal) when administered either subcutaneously or intravenously and/or when administered prior to infection, or after infection with influenza B virus and may reduce symptoms of headache, fever, aches, rhinorrhea (nasal congestion), chills, fatigue, weakness, sore throat, cough, shortness of breath, vomiting, diarrhea, pneumonia, bronchitis, and/or death.
• the anti -influenza B antibody binds to influenza B HA with an EC50 of less than about 10-9 M.
• anti-PCRV antibody Another antibody that can be used with the methods and devices herein is anti-PCRV antibody as disclosed in US20200392210A1 (Regeneron Pharmaceuticals Inc. Tarrytown, NY).
• the anti-PCRV antibody can bind / ⁇ aeruginosa's V-tip protein (PcrV) and inhibit or neutralize the activity of the bacterial type 3 secretion system (T3SS) in P. aeruginosa. It is thought that the antibodies are useful for blocking translocation of toxins from the bacteria to the host cell and/or for preventing death of the host cells.
• the anti-PCRV antibodies may function by blocking pore- mediated membrane permeability in the host cell.
• Eli Lilly s monoclonal antibody bamlanivimab (also known as LY-CoV555, aka LY3819253) was originally derived from the blood of one of the first U.S. patients who recovered from COVID-19. It is a recombinant neutralizing monoclonal antibody directed against the SARS-CoV-2 spike protein.
• Eli Lilly s etesevimab (LY-C0VOI6, aka JS016, aka LY3832479) is a monoclonal antibody directed against the SARS-CoV-2 surface spike protein’s receptor binding domain. Another antibody that can be used with the methods and devices herein is Bebtelovimab.
• the patient may be instructed to either rest, e.g., breathe normally for one or more breaths, without the nebulizer, or to perform another cycle of long inhalation/rapid exhalation 117.
• the patient may need to take a rest or if they have a cough or urge to cough.
• the patient may press the on/off button to stop the nebulizer.
• the treatment may be continued by once again pressing the on/off button on the nebulizer and/or dose guide apparatus to begin breathing in through the mouthpiece and out through the nose (repeating steps 107 to 117 in FIG. 6).
• the patient may take as many rests as needed.
• SARS-CoV-2 like many viruses that cause acute respiratory infections (ARIs), infects cells almost exclusively via the apical (luminal) side of the airway epithelium and also buds from infected cells primarily via the apical surface. Progeny virus must then travel through airway mucus to reach uninfected epithelial cells as the infection spreads from the upper respiratory tract (URT) to the lower respiratory tract (LRT) and the deep lung. Neutralizing monoclonal antibodies (mAbs) must therefore reach the airway lumen in sufficient quantities to effectively neutralize the virus and halt the infection.
• UTR upper respiratory tract
• LRT lower respiratory tract
• mAbs Neutralizing monoclonal antibodies
• a double-blind, placebo-controlled, first-in-human, ascending-dose pharmacokinetic and safety study was conducted in a Phase 1 unit in Melbourne Australia. The study was carried out according to the International Council for Harmonisation Good Clinical Practice guidelines and in compliance with local regulatory requirements and was approved by The Alfred Hospital Office of Ethics and Research Governance, Melbourne, VIC, Australia. Informed consent was obtained in advance of all study-related procedures. Eligible participants were enrolled sequentially into three cohorts: a single low dose cohort (30 mg), a single high-dose cohort (90 mg), and a multiple high-dose cohort (seven daily 90 mg doses).
• FIG. 3 shows a diagram of the study structure and times of pharmacokinetic evaluations.
• Participants were excluded for known or suspected symptomatic viral infection or signs of active pulmonary infection or pulmonary inflammatory conditions within 14 days of dosing initiation, a history of airway hyperresponsiveness, angioedema, anaphylaxis, or a positive alcohol breathalyzer test and/or urine drug screen for substances of abuse.
• participants who had received a COVID-19 vaccine were excluded.
• this criterion was modified to exclude only those vaccinated within two weeks of initial dosing, or those with plans to be vaccinated within two weeks after completion of dosing.
• the primary endpoint for 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, FEVi, SpO 2 , hematology and chemistry safety blood tests, and physical examinations. Following-up continued for 28 days, with assessments on the days indicated in FIG. 3. Exploratory outcomes were drug levels in nasal fluid and serum pre dose and at intervals post dose.
• a randomization schedule was prepared using validated software (SAS) by statistical team members who had no responsibility for monitoring and data management of this study, with provisions for each sentinel pair to include one active and one saline placebo assignment, and for the overall ratio of active to placebo assignment of each cohort to be 3 : 1.
• SAS validated software
• the randomization code was held by unblinded pharmacy staff who prepared the doses in matching syringes with identical appearances for loading into the nebulizer by clinical staff.
• IN-006 was produced under Good Manufacturing Practices (GMP) and supplied as a liquid formulation in glass vials from the manufacturer.
• GMP Good Manufacturing Practices
• IN-006 was provided in a syringe to be loaded into the InnoSpire Go vibrating mesh nebulizer (Koninklijke Philips N.V.). Placebo participants received an identical syringe containing saline instead of IN-006. Participants were instructed to breathe in slowly through the nebulizer mouthpiece and to breathe out through their nose. Nasal fluid was obtained by rotating a flocked swab (Copans Cat. # 56380CS01) for 10-15 seconds at mid-turbinate depth (4-5 cm).
• Continuous variables were summarized using descriptive statistics including number of non-missing observations, mean, SD, median, minimum, and maximum values.
• Categorical variables were summarized with frequency counts and percentages. Placebo recipients in different cohorts were pooled.
• the safety analysis 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 conducted. Serum PK parameters of IN-006 were determined using Phoenix WinNonlin version 8.3.
• Treatment emergent adverse events are listed in Table 2 (FIG. 2). Nebulization of IN-006 was well-tolerated and completed in an average of 6 minutes for the 90 mg dose (range 4-9 minutes). Eight (53.3%) of the 15 participants included in the single ascending dose cohorts experienced at least 1 TEAE (6 receiving IN-006, 2 receiving placebo). The most frequently reported TEAEs were headache (4/15; 26.7%) and oropharyngeal pain (2/15; 13.3%). All but 1 TEAE were mild.
• One participant receiving IN-006 low dose (30 mg) experienced a moderate event (increased transaminases on Day 29), which was not considered to be related to study drug by the investigator.
• the mean nasal concentrations were 261 pg/g and 710 pg/g for the 30 mg and 90 mg dose, respectively, measured 3 hrs after dosing; these values are consistent with a 3 -fold increase in the dose administered.
• the repeated dosing provided additional opportunities for more nasal concentration measurements across more time points.
• mAbs have proven to be effective therapeutics for COVID-19, the necessity for administration by IV, IM, or SC routes has limited the scope of their use in clinical practice. The requirement for infusion centers and post-dosing observation for intravenous administration have severely limited the number of patients that have received treatment, and greatly increased costs.
• IM injections although shortening administration time, are limited by the volume that can be administered per injection (-5 mL), which in turns limit the dose of mAb that can be dosed per injection, and can be painful when maximum injection volumes are used.
• nebulized delivery using a handheld nebulizer enables the convenience of at-home dosing, and only takes minutes to complete.
• IV, IM, and SC routes provide mAb to the airway lining fluid only after a delay of one or more days, and even then only achieve airway concentrations that are a fraction of the concentrations in plasma.
• the peak nasal concentration was not achieved until 2 days after infusion, and the peak nasal concentration of 0.597 pg/mL was -10-fold lower than the concentrations observed for IN-006 at the trough of our daily dosing (-5.4 pg/mL), despite the much lower total dose of IN-006 compared to CR6261 (90 mg IN-006 vs.
• Example 1 show the safety, tolerability, and pharmacokinetics of one example of a Human IgG G1 Fc region (IN-006, a reformulation of regdanvimab, an approved intravenous treatment for COVID-19) that may be used for nebulized delivery by a handheld nebulizer.
• a Human IgG G1 Fc region IN-006, a reformulation of regdanvimab, an approved intravenous treatment for COVID-19
• the mean human serum concentrations of 200 ng/mL at 2 days after first dose and 550 ng/mL at Day 9 should translate to pulmonary concentrations on the order of 50 pg/mL, which is >3 orders of magnitude above the IC50, and comparable to the serum concentrations achieved with some IV/IM-dosed mAbs.
• the very high mAb levels sustained relative to the intrinsic activity of the mAb (IC50) 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 dosing, could afford appreciable protection against hospitalization.
• Regdanvimab administered IV was shown to be highly efficacious for preventing severe CO VID-19 in a global Phase 3 study, leading to its formal approval in Republic of Korea and European Union (EMEA/H/C/005854) for preventing severe disease in patients presenting with mild to moderate COVID-19, and emergency use authorization (EUA) or conditional marketing authorization in several additional countries worldwide.
• IN-006 may be combined with a second potent neutralizing mAb to create a mAb cocktail that possesses potent binding activity against every variant tested to date.
• the surprisingly long airway retention of IN-006 observed here may be used for virtually and mAb including the Fc region (e.g., SEQ. ID NO. 1, SEQ. ID NO.
• Subjects will receive a first dose of IN-006 or placebo via a nebulizer on Dosing Day 1. Placebo will be 0.9% normal saline and will be administered via a nebulizer in an identical manner as IN-006. Subjects will receive a second dose of IN-006 or placebo via a nebulizer on at least one of Dosing Day 3-Dosing Day 8. Placebo will be 0.9% normal saline and will be administered via a nebulizer in an identical manner as IN-006. Measurement of antibody will be performed using bronchoscopy with bronchoalveolar lavage (BAL) before and 2 weeks after treatment.
• BAL bronchoalveolar lavage
• Bronchoalveolar lavage will be performed infusions of warmed sterile PBS into a segmental middle-lobe bronchus with the bronchoscope.
• the fluid will be recovered by gentle suction and collected in a sterile container. It will be filtered through a sterile 100-pm mesh to remove mucus and cell debris and analyzed using the methods described herein.
• Subjects may receive a first dose of IN-006 and a second therapeutic agent (e.g., non-mAb) or placebo via a nebulizer on Dosing Day 1. Placebo will be 0.9% normal saline and will be administered via a nebulizer in an identical manner as IN-006. Nasal swabs will be taken on at least one Dosing Day 3-Dosing Day 8 and measure for levels of antibody. Subjects will receive a second dose of IN-006 or placebo via a nasal sprayer on at least one of Dosing Day 3-Dosing Day 8. Placebo will be 0.9% normal saline and will be administered via a nebulizer in an identical manner as IN-006.
• a second therapeutic agent e.g., non-mAb
• the methods described herein can be used to provide sufficient levels of antibody in at least one or both of the upper and lower respiratory tracts with IX (once) or 2X (twice) per day dosing.
• Subjects will receive a first dose of antibody (e.g., IN-006 or other) or placebo via a nebulizer at time 0 on Dosing Day 1.
• the antibody may be an antibody glycosylated with the GO glycosylation pattern.
• Placebo will be 0.9% normal saline and will be administered via a nebulizer in an identical manner as antibody (e.g., IN-006 or other).
• a first cohort of Subjects will receive a second dose of antibody (e.g., IN-006 or other) or placebo via a nebulizer at 12 hours after the first dose.
• Placebo will be 0.9% normal saline and will be administered via a nebulizer in an identical manner as antibody (e.g., IN-006 or other). Measurement of antibody will be performed using bronchoscopy with bronchoalveolar lavage (BAL) before, immediately after dosing, at 12 hours (prior to the second dose), and at 24 hours. Bronchoalveolar lavage will be performed infusions of warmed sterile PBS into a segmental middle-lobe bronchus with the bronchoscope. The fluid will be recovered by gentle suction and collected in a sterile container. It will be filtered through a sterile 100-um mesh to remove mucus and cell debris and analyzed using the methods described herein.
• BAL bronchoalveolar lavage
• the methods and compositions described herein may allow delivery of the inhaled therapeutic mAh, including those having the GO glycosylation pattern, which are otherwise expected to be cleared within minutes based on published work, to achieve sustained high concentrations for 24 hours or more, allowing once daily or twice daily dosing with relatively low (and therefore affordable) concentrations.
• the dose may deliver the therapeutic mAb so that sufficient levels are maintained until the next dosing (i.e. trough concentration).
• the peak concentration achieved in the upper respiratory tract scales with the amount of mAb-inhaled (e.g., going from 30 mg to 90 mg inhaled resulted in ⁇ 3x increase).
• the rate of clearance was surprisingly dose independent, with comparable clearance rates of the 30 mg and 90 mg once dose, as well as comparable clearance between the 90 mg once vs. different days of the repeated 90 mg dose.
• the ‘muco-trapping’ mAbs are not cleared within minutes as previously suggested (e.g., faster than 30 minutes) for the turnover rate of the nasal secretions in the nasal turbinate, but rather, have a half-life in the range of 3.5-4 hrs.
• the dose for different mAbs may be selected, depending on their potencies, to achieving sufficient excess of the concentrations relative to their inherent potencies (for example, maintain 10-100x above IC50 of a mAb where the IC50 is -100 ng/mL).
• the methods and compositions described herein indicate that twice per day, 15 mg dose each time provide a significant dose.
• first and second may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.
• any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and/or steps may alternatively be exclusive and may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components or sub-steps.
• a numeric value may have a value that is +/- 0.1% of the stated value (or range of values), +/- 1% of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc.
• Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value " 10" is disclosed, then “about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.
• Organism Homo sapiens (Human) (CH2 is residues 1-113, CH3 is residues 114-219
• Organism Homo sapiens (Human) (CH2 is residues 1-109, CH3 is residues 110-216)
• Organism Homo sapiens (Human) (CH2 is residues 1-110, CH3 is residues 111-216
• Organism Homo sapiens (Human) (CH2 is residues 1-110, CH3 is residues 111-217

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