Antibody delivery to the lungs

Abstract

The present invention relates to pulmonary delivery of antibodies or antibody derivatives.

Description

【Technical Field】 【0001】 The present invention relates to pulmonary delivery of antibodies or antibody derivatives. 【Background Art】 【0002】 The highly specific antigen targeting of therapeutic antibodies can provide a very effective treatment for various diseases, and thus its attention has been increasing dramatically year by year. 【0003】 Pulmonary delivery of antibodies such as monoclonal antibodies can be an attractive and non-invasive alternative to parenteral delivery. The pulmonary administration route has been proven effective for local and systemic delivery of various drugs and biopharmaceuticals for treating pulmonary and non-pulmonary diseases. 【0004】 However, administration of proteins such as antibodies to the lungs involves many challenges, such as the need for appropriate formulations of antibodies to overcome strong intermolecular / particle interactions and physicochemical degradation that can cause, for example, aggregation and potential loss of biological / therapeutic activity and / or safety issues. For example, proteins can be sensitive to shear stress and / or temperature increases associated with aerosolization and / or may exhibit reduced stability at the gas-liquid interface in the aerosol. 【0005】 Therefore, the object of the present invention was to identify a formulation system suitable for pulmonary delivery of antibodies and useful for maintaining the stability and activity of antibodies during aerosolization / spraying. 【Summary of the Invention】 【0006】 In one aspect, the present invention is an aerosol comprising droplets containing a liquid formulation, the liquid formulation comprising (i) an antibody or antibody derivative, (ii) a buffer selected from the group consisting of acetates, histidines, and combinations thereof, and (iii) an aqueous medium and The liquid formulation relates to an aerosol having a pH of approximately 5.5 or less. 【0007】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or an antibody derivative. 【0008】 In one embodiment, the antibody is a monoclonal antibody. 【0009】 In one embodiment, the liquid formulation does not contain citrate. 【0010】 In one embodiment, the liquid formulation has a pH in the range of about 3.5 to about 5.5. 【0011】 In one embodiment, the buffer is an acetate, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is an acetate, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0. 【0012】 In one embodiment, the liquid formulation further comprises a surfactant. In one embodiment, the surfactant is selected from the group consisting of polysorbate, poloxamer, polyoxyethylene alkyl ether, alkylphenol polyoxyethylene, and sodium dodecyl sulfate. 【0013】 In one embodiment, the concentration of the surfactant in the liquid formulation is about 0.1% (w / v) or less, or about 0.05% (w / v) or less. 【0014】 In one embodiment, the liquid formulation does not contain any surfactants. 【0015】 In one embodiment, the liquid formulation does not contain NaCl. 【0016】 In one embodiment, the liquid formulation does not contain any non-buffered salts. 【0017】 In one embodiment, the droplets have an average diameter in the range from about 0.5 μm to about 5 μm, from about 0.5 μm to about 4.5 μm, from about 0.5 μm to about 4 μm, from about 0.5 μm to about 3.5 μm, or from about 0.5 μm to about 3 μm. 【0018】 In one embodiment, the droplets have an average diameter less than 5 μm. In one embodiment, the droplets have an average diameter less than 4.5 μm. In one embodiment, the droplets have an average diameter less than 4.0 μm. In one embodiment, the droplets have an average diameter less than 3.5 μm. In one embodiment, the droplets have an average diameter less than 3.0 μm. 【0019】 In another aspect, the present invention relates to a method for preparing an aerosol comprising droplets containing a liquid formulation, the method comprising the following steps: (i) providing a liquid formulation as defined above; (ii) spraying the liquid formulation provided in step (i) with a nebulizer to thereby prepare an aerosol. and comprising. 【0020】 In one embodiment, the nebulizer is a mesh nebulizer. 【0021】 In one embodiment, the method further comprises, between steps (i) and (ii), the following steps: (ia) lyophilizing the liquid formulation provided in step (i) to thereby provide a lyophilized powder, and (ib) reconstituting the liquid formulation provided in step (i) by adding an appropriate amount of an aqueous medium to the lyophilized powder provided in step (ia). and further comprising. 【0022】 In another aspect, the present invention relates to an aerosol comprising droplets containing a liquid formulation, the aerosol being obtainable by the method as defined above. In one embodiment, the droplets have an average diameter in the range from about 0.5 μm to about 5 μm, or from about 0.5 μm to about 3 μm. 【0023】 In another aspect, the present invention relates to the liquid formulation or the aerosol as defined above for use in a method of delivering an antibody or antibody derivative to the lung of a subject, the aerosol being administered to the subject by inhalation and the liquid formulation being administered to the subject by inhalation via a nebulizer. 【0024】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or antibody derivative. 【0025】 In one embodiment, the nebulizer is a mesh nebulizer. 【0026】 In another aspect, the present invention relates to the liquid formulation as defined above for use in a method of treating or preventing a disease in a subject, the aerosol being administered to the subject by inhalation or the liquid formulation being administered to the subject by inhalation via a nebulizer. 【0027】 In one embodiment, the disease is a lung disease. 【0028】 In one embodiment, the nebulizer is a mesh nebulizer. 【0029】 In another aspect, the present invention relates to a method of delivering an antibody or antibody derivative to the lung of a subject, the method comprising administering to the subject by inhalation an effective amount of the aerosol as defined above or administering to the subject by inhalation via a nebulizer an effective amount of the liquid formulation as defined above. 【0030】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or antibody derivative. 【0031】 In one embodiment, the nebulizer is a mesh nebulizer. 【0032】 In another embodiment, the present invention relates to a method for treating or preventing a disease in a subject, the method comprising administering an effective amount of the aerosol defined above to the subject by inhalation, or administering an effective amount of the liquid formulation defined above to the subject by inhalation via a nebulizer. 【0033】 In one embodiment, the disease is a lung disease. 【0034】 In one embodiment, the nebulizer is a mesh nebulizer. 【0035】 In one embodiment, the lung diseases mentioned above are selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), lung cancer, interstitial lung diseases (ILDs) such as cystic fibrosis (CF) and idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis and asbestosis, bacterial infections, viral infections, acute respiratory distress syndrome (ARDS), alveolar proteinosis (PAP), acute bronchitis, bronchiolitis obstructive, and pulmonary hypertension. 【0036】 In another embodiment, the present invention relates to a nebulizer containing the liquid formulation defined above. 【0037】 In one embodiment, the nebulizer is a mesh nebulizer. 【0038】 In another embodiment, the present invention is (i) A container containing the liquid formulation as defined above or a powder obtained by freeze-drying the liquid formulation, and (ii) Nebulizer Regarding the kit that includes this. 【0039】 In one embodiment, the nebulizer is a mesh nebulizer. 【0040】 In another embodiment, the present invention relates to the use of the above-defined liquid formulation for preparing an aerosol by nebulization. 【0041】 In one embodiment, the nebulizer is a mesh nebulizer. 【0042】 In another embodiment, the present invention relates to the use of a buffer selected from the group consisting of acetates, histidines, and combinations thereof, for enhancing the stability of an antibody or antibody derivative when a liquid formulation containing an antibody or antibody derivative is nebulized, wherein the buffer is included in the liquid formulation before spraying. 【0043】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or an antibody derivative. 【0044】 In one embodiment, the nebulizer is a mesh nebulizer. 【0045】 In one embodiment, the liquid formulation has a pH of about 5.5 or less. 【0046】 In one embodiment, the antibody is a monoclonal antibody. 【0047】 In one embodiment, the liquid formulation does not contain citrate. 【0048】 In one embodiment, the liquid formulation has a pH in the range of about 3.5 to about 5.5. 【0049】 In one embodiment, the buffer is an acetate, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is an acetate, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0. 【0050】 In one embodiment, the liquid formulation further comprises a surfactant. In one embodiment, the surfactant is selected from the group consisting of polysorbate, poloxamer, polyoxyethylene alkyl ether, alkylphenol polyoxyethylene, and sodium dodecyl sulfate. 【0051】 In one embodiment, the concentration of the surfactant in the liquid formulation is about 0.1% (w / v) or less, or about 0.05% (w / v) or less. 【0052】 In one embodiment, the liquid formulation does not contain any surfactants. 【0053】 In one embodiment, the liquid formulation does not contain NaCl. 【0054】 In one embodiment, the liquid formulation does not contain any non-buffered salts. [Brief explanation of the drawing] 【0055】 [Figure 1A] This figure shows the results of stability analysis of two antibodies (mAb1 and mAb3) in formulations containing different buffer systems for lung delivery during spraying, using dynamic light scattering (DLS; A and D), SEC (B and E), flow cell microscopy (FCM; C and F), and visual inspection (B and E). [Figure 1B] This figure shows the results of stability analysis of two antibodies (mAb1 and mAb3) in formulations containing different buffer systems for lung delivery during spraying, using dynamic light scattering (DLS; A and D), SEC (B and E), flow cell microscopy (FCM; C and F), and visual inspection (B and E). [Figure 1C] This figure shows the results of stability analysis of two antibodies (mAb1 and mAb3) in formulations containing different buffer systems for lung delivery during spraying, using dynamic light scattering (DLS; A and D), SEC (B and E), flow cell microscopy (FCM; C and F), and visual inspection (B and E). [Figure 1D]This figure shows the results of stability analysis of two antibodies (mAb1 and mAb3) in formulations containing different buffer systems for lung delivery during spraying, using dynamic light scattering (DLS; A and D), SEC (B and E), flow cell microscopy (FCM; C and F), and visual inspection (B and E). [Figure 1E] This figure shows the results of stability analysis of two antibodies (mAb1 and mAb3) in formulations containing different buffer systems for lung delivery during spraying, using dynamic light scattering (DLS; A and D), SEC (B and E), flow cell microscopy (FCM; C and F), and visual inspection (B and E). [Figure 1F] This figure shows the results of stability analysis of two antibodies (mAb1 and mAb3) in formulations containing different buffer systems for lung delivery during spraying, using dynamic light scattering (DLS; A and D), SEC (B and E), flow cell microscopy (FCM; C and F), and visual inspection (B and E). [Figure 2A] These are the results of analyses of the stability of two antibodies (mAb1 and mAb3) in a PS80-containing formulation for lung delivery during spraying, using DLS (A and D), SEC (B and E), FCM (C and F), and visual inspection (B and E). [Figure 2B] These are the results of analyses of the stability of two antibodies (mAb1 and mAb3) in a PS80-containing formulation for lung delivery during spraying, using DLS (A and D), SEC (B and E), FCM (C and F), and visual inspection (B and E). [Figure 2C] These are the results of analyses of the stability of two antibodies (mAb1 and mAb3) in a PS80-containing formulation for lung delivery during spraying, using DLS (A and D), SEC (B and E), FCM (C and F), and visual inspection (B and E). [Figure 2D] These are the results of analyses of the stability of two antibodies (mAb1 and mAb3) in a PS80-containing formulation for lung delivery during spraying, using DLS (A and D), SEC (B and E), FCM (C and F), and visual inspection (B and E). [Figure 2E]These are the results of analyses of the stability of two antibodies (mAb1 and mAb3) in a PS80-containing formulation for lung delivery during spraying, using DLS (A and D), SEC (B and E), FCM (C and F), and visual inspection (B and E). [Figure 2F] These are the results of analyses of the stability of two antibodies (mAb1 and mAb3) in a PS80-containing formulation for lung delivery during spraying, using DLS (A and D), SEC (B and E), FCM (C and F), and visual inspection (B and E). [Figure 3A] This shows the results of an analysis of the stability of antibody (mAb1) in lung delivery formulations during spraying using two different mesh nebulizers, using DLS (A), SEC (B), FCM (C), and visual inspection (B). [Figure 3B] This shows the results of an analysis of the stability of antibody (mAb1) in lung delivery formulations during spraying using two different mesh nebulizers, using DLS (A), SEC (B), FCM (C), and visual inspection (B). [Figure 3C] This shows the results of an analysis of the stability of antibody (mAb1) in lung delivery formulations during spraying using two different mesh nebulizers, using DLS (A), SEC (B), FCM (C), and visual inspection (B). [Figure 4A] This figure shows the results of analyses of the stability of different isotypes (IgG1 and IgG4) of antibodies in lung delivery formulations during spraying, using DLS (A), SEC (B), FCM (C), and visual inspection (B). [Figure 4B] This figure shows the results of analyses of the stability of different isotypes (IgG1 and IgG4) of antibodies in lung delivery formulations during spraying, using DLS (A), SEC (B), FCM (C), and visual inspection (B). [Figure 4C] This figure shows the results of analyses of the stability of different isotypes (IgG1 and IgG4) of antibodies in lung delivery formulations during spraying, using DLS (A), SEC (B), FCM (C), and visual inspection (B). [Figure 5A]This figure shows the results of analyses of the stability of the antibody (mAb1) in the lung delivery formulation during spraying, using DLS and FCM (A), SEC and visual inspection (B), and additional analytical methods (B). [Figure 5B] This figure shows the results of analyses of the stability of the antibody (mAb1) in the lung delivery formulation during spraying, using DLS and FCM (A), SEC and visual inspection (B), and additional analytical methods (B). [Figure 6A-1] This figure shows the results of analysis of the spray stability of two antibodies (mAb1 and mAb3) in formulations containing different concentrations of PS80 in citrate buffer, using DLS and FCM. Figure 6A shows the results for mAb1. [Figure 6A-2] Continuation of Figure 6A-1. [Figure 6A-3] Continuation of Figure 6A-2. [Figure 6A-4] Continuation of Figure 6A-3. [Figure 6B-1] This figure shows the results of analysis of the spray stability of two antibodies (mAb1 and mAb3) in formulations containing different concentrations of PS80 in citrate buffer, using DLS and FCM. Figure 6B shows the results for mAb3. [Figure 6B-2] Continuation of Figure 6B-1. [Figure 6B-3] Continuation of Figure 6B-2. [Figure 6B-4] Continuation of Figure 6B-3. [Figure 7-1] This figure shows the results of analyses of the stability of antibody (mAb1) in formulations containing different concentrations of PS80 in histidine buffer for lung delivery during spraying, using DLS and FCM. [Figure 7-2] Continuation of Figure 7-1. [Figure 7-3] Continuation of Figure 7-2. [Figure 7-4] Continuation of Figure 7-3. 【0056】 Detailed description of the invention Before describing the present invention in detail below, it should be understood that the specific methodologies, protocols, and reagents described herein are subject to change and are not limited thereto. Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments and are not intended to limit the scope of the invention, and that the invention is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Preferably, terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations), edited by Leuenberger, HGW, Nagel, B., and Kolbl, H. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland." 【0057】 This specification references several documents. Each document referenced herein (including all patents, patent applications, scientific publications, manufacturer specifications, instructions, etc.) is incorporated herein by reference in its entirety, whether above or below. Nothing in this specification shall be construed as acknowledging that the present invention has no prior rights to such disclosures by prior art. 【0058】 The elements of the present invention are described below. While these elements are described in conjunction with specific embodiments, it should be understood that they can be combined in any way and in any number to create additional embodiments. The various examples and preferred / specific embodiments described should not be construed as limiting the invention to only the explicitly described embodiments. This description should be understood as supporting and encompassing embodiments that combine the explicitly described embodiments with any number of disclosed and / or preferred elements. Furthermore, any permutation and combination of all elements described herein shall be deemed disclosed by the description herein unless specifically indicated in the context. 【0059】 Throughout this specification and the accompanying claims, unless otherwise specifically required by the context, the term “comprise,” and variations such as “comprises” and “comprising,” shall be understood to mean including the integer or step or group of integers or steps described, and not to mean excluding other integers or steps or groups of integers or steps. Where used in this specification and the accompanying claims, the singular forms “a,” “an,” and “the” shall include plural referents unless the content clearly indicates something else. 【0060】 In one embodiment, the present invention is an aerosol comprising droplets containing a liquid formulation, wherein the liquid formulation is (i) Antibody or antibody derivative, (ii) A buffer selected from the group consisting of acetates, histidines and combinations thereof, (iii) Aqueous medium Includes, The liquid formulation relates to an aerosol having a pH of approximately 5.5 or less. 【0061】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or an antibody derivative. 【0062】 The term “antibody” (or “immunoglobulin”) generally refers to a glycoprotein containing at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. The term “antibody” includes monoclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, chimeric antibodies, and any combination of the above. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). In this specification, the variable region and constant region are also referred to as the variable domain and constant domain, respectively. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which are interspersed within more conserved regions called framework regions (FRs). The VH and VL each consist of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The CDRs of the VH are called HCDR1, HCDR2, and HCDR3, and the CDRs of the VL are called LCDR1, LCDR2, and LCDR3. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of an antibody comprises a heavy chain constant region (CH) and a light chain constant region (CL), and the CH can be further subdivided into a constant domain CH1, a hinge region, and constant domains CH2 and CH3 (arranged from the amino terminus to the carboxyl terminus, in the following order: CH1, CH2, CH3). The constant region of an antibody can mediate the binding of immunoglobulins to various cells of the immune system (e.g., effector cells) and host tissues or factors including the first component (Clq) of the classical complement system. 【0063】 Antibodies can originate from different species, including but not limited to mice, rats, rabbits, guinea pigs, and humans. 【0064】 The antibodies described herein include isotype / class antibodies such as IgA (e.g., IgA1 or IgA2), IgG1, IgG2, IgG3, IgG4, IgE, IgM, and IgD. In various embodiments, the antibody is an IgG1 antibody, more specifically an IgG1 kappa or IgG1 lambda isotype (i.e., IgG1, κ, λ), an IgG2a antibody (e.g., IgG2a, κ, λ), an IgG2b antibody (e.g., IgG2b, κ, λ), an IgG3 antibody (e.g., IgG3, κ, λ), or an IgG4 antibody (e.g., IgG4, κ, λ). In one embodiment, the antibody is an IgG1 antibody. 【0065】 As used herein, the term “antibody derivative” refers to a molecule that does not possess the complete structure of an antibody such as IgA, IgD, IgE, IgG, IgM, IgY, or IgW, particularly IgG1, but contains a domain identified as containing at least one such domain, and is still capable of binding to a target molecule. Such derivatives may be, but are not limited to, their functional (i.e., target-binding, particularly specific target-binding) antibody fragments, e.g., Fab2, or such derivatives, e.g., combinations of divalent Fabs. Antibodies to which further antibody domains have been added, such as additional variable domains, are also relevant. In one embodiment, the term “antibody derivative” means, for example, a single-chain antibody as described in Spiess et al. (J Mol Imm. 2015, 67:95-106), WO2009 / 052081A2, Wu et al. (Nat. Biotechnol., 2007 25:1290-1297), Brinkmann & Kontermann (MAbs 2017, 9:182-212), and Fitzgerald et al. (Mol Cancer Ther. 2013, 13:410-25). Other non-limiting examples of antibody derivatives include nanobodies, diabodies, minibodies, and other forms as described in, for example, Spiess et al. (J Mol Imm. 2015, 67:95-106). The term “IgG1 antibody derivative” means, for example, an antibody derivative that is recognizable as derived from an IgG1 antibody due to the presence of one or more IgG1-specific (sequence) elements. 【0066】 In one embodiment, the antibody is a monoclonal antibody. As used herein, the term “monoclonal antibody” means a preparation of an antibody molecule with a single molecular composition. A monoclonal antibody exhibits a single binding specificity and affinity. In one embodiment, the monoclonal antibody is produced by a hybridoma containing B cells obtained from a non-human animal, such as a mouse, fused to immortalized cells. 【0067】 Generally, the terms “antibody” and “antibody derivative” as used herein include both monospecific and multispecific (e.g., bispecific, triplicate, or quadruplicate) antibodies and antibody derivatives. 【0068】 In one embodiment, the antibody or antibody derivative is a pharmaceutically active antibody or antibody derivative. As used herein, the term “pharmaceutically active antibody or antibody derivative” means an antibody or antibody derivative that is suitable for therapeutic use, i.e., can be used to treat a disease or disorder. In one embodiment, the pharmaceutically active antibody or antibody derivative binds to a therapeutically relevant antigen. 【0069】 Exemplary antibodies that can be used in accordance with the present invention include, but are not limited to, anti-respiratory syncytial virus (RSV) antibodies, anti-IL-4 antibodies, anti-IL-4 receptor antibodies, anti-IFN-beta antibodies, anti-IL-13 antibodies, anti-thymocrine interstitial lymphocyte necrotizing factor (TSLP) antibodies, anti-IL-1 receptor antibodies, anti-IL-2 antibodies, and anti-TNF antibodies. 【0070】 In one embodiment, the antibody concentration is in the range of approximately 150 mg / ml to 1 mg / ml; or approximately 150 mg / ml to approximately 5 mg / ml; or approximately 150 mg / ml to approximately 10 mg / ml; or approximately 150 mg / ml to approximately 20 mg / ml; or approximately 150 mg / ml to approximately 50 mg / ml. 【0071】 In one embodiment, the antibody concentration is in the range of approximately 120 mg / ml to 1 mg / ml; or approximately 120 mg / ml to approximately 5 mg / ml; or approximately 120 mg / ml to approximately 10 mg / ml; or approximately 120 mg / ml to approximately 20 mg / ml; or approximately 120 mg / ml to approximately 50 mg / ml. 【0072】 In one embodiment, the antibody concentration is in the range of approximately 100 mg / ml to approximately 1 mg / ml; or approximately 100 mg / ml to approximately 5 mg / ml; or approximately 100 mg / ml to approximately 10 mg / ml; or approximately 100 mg / ml to approximately 20 mg / ml; or approximately 100 mg / ml to approximately 50 mg / ml. 【0073】 In one embodiment, the antibody concentration is in the range of approximately 80 mg / ml to 1 mg / ml; or approximately 80 mg / ml to approximately 5 mg / ml; or approximately 80 mg / ml to approximately 10 mg / ml; or approximately 80 mg / ml to approximately 20 mg / ml; or approximately 80 mg / ml to approximately 50 mg / ml. 【0074】 In one embodiment, the antibody concentration is in the range of approximately 50 mg / ml to approximately 5 mg / ml; or approximately 400 mg / ml to approximately 5 mg / ml; or approximately 30 mg / ml to approximately 5 mg / ml; or approximately 20 mg / ml to approximately 5 mg / ml; or approximately 10 mg / ml to approximately 5 mg / ml. 【0075】 In one embodiment, the antibody concentration is in the range of approximately 50 mg / ml to approximately 1 mg / ml; or approximately 40 mg / ml to approximately 1 mg / ml; or approximately 30 mg / ml to approximately 1 mg / ml; or approximately 20 mg / ml to approximately 1 mg / ml; or approximately 10 mg / ml to approximately 1 mg / ml. 【0076】 In a preferred embodiment, the antibody concentration is approximately 150 mg / ml. In another preferred embodiment, the antibody concentration is approximately 140 mg / ml. In another preferred embodiment, the antibody concentration is approximately 130 mg / ml. In another preferred embodiment, the antibody concentration is approximately 120 mg / ml. In another preferred embodiment, the antibody concentration is approximately 110 mg / ml. In a preferred embodiment, the antibody concentration is approximately 100 mg / ml. In another preferred embodiment, the antibody concentration is approximately 90 mg / ml. In another preferred embodiment, the antibody concentration is approximately 80 mg / ml. In another preferred embodiment, the antibody concentration is approximately 70 mg / ml. In another preferred embodiment, the antibody concentration is approximately 60 mg / ml. In a preferred embodiment, the antibody concentration is approximately 50 mg / ml. In another preferred embodiment, the antibody concentration is approximately 40 mg / ml. In another preferred embodiment, the antibody concentration is approximately 30 mg / ml. In another preferred embodiment, the antibody concentration is approximately 20 mg / ml. In another preferred embodiment, the antibody concentration is approximately 10 mg / ml. In another preferred embodiment, the antibody concentration is approximately 5 mg / ml. In another preferred embodiment, the antibody concentration is approximately 1 mg / ml. 【0077】 In one embodiment, the concentration of the buffer in the liquid formulation is in the range of about 1 mM to about 200 mM, for example, from about 5 mM to about 150 mM, or from about 5 mM to about 100 mM, or from about 5 mM to about 50 mM. In one embodiment, the concentration of the buffer in the liquid formulation is in the range of about 5 mM to about 25 mM, for example, from about 5 mM to about 20 mM, or from about 5 mM to about 15 mM, or from about 7.5 mM to about 12.5 mM. In one embodiment, the concentration of the buffer in the liquid formulation is about 10 mM. In one embodiment, the buffer is an acetate, and the concentration of the acetate in the liquid formulation is in the range of about 1 mM to about 200 mM, for example, from about 5 mM to about 150 mM, or from about 5 mM to about 100 mM, or from about 5 mM to about 50 mM. In one embodiment, the concentration of acetate in the liquid formulation is in the range of about 5 mM to about 25 mM, for example, about 5 mM to about 20 mM, or about 5 mM to about 15 mM, or about 7.5 mM to about 12.5 mM. In one embodiment, the concentration of acetate in the liquid formulation is about 10 mM. 【0078】 In one embodiment, the buffer is histidine, and the concentration of histidine in the liquid formulation is in the range of about 1 mM to about 200 mM, for example, from about 5 mM to about 150 mM, or from about 5 mM to about 100 mM, or from about 5 mM to about 50 mM. In one embodiment, the concentration of histidine in the liquid formulation is in the range of about 5 mM to about 25 mM, for example, from about 5 mM to about 20 mM, or from about 5 mM to about 15 mM, or from about 7.5 mM to about 12.5 mM. In one embodiment, the concentration of histidine in the liquid formulation is about 10 mM. In one embodiment, the concentration of histidine in the liquid formulation is about 20 mM. 【0079】 In one embodiment, the acetate acting as a buffer is, for example, sodium acetate (or another suitable acetate, such as potassium acetate) combined with acetic acid (i.e., in the form of an acetate buffer). Methods for preparing a suitable acetate buffer are well known to those skilled in the art. 【0080】 In one embodiment, the histidine acting as a buffer is, for example, L-histidine sodium (or another suitable histidine salt) in the form of a histidine buffer. Methods for preparing a suitable histidine buffer are well known to those skilled in the art. 【0081】 In one embodiment, the liquid formulation does not contain citrate. 【0082】 As used herein, the term “aqueous medium” (or “aqueous solution”) means a liquid medium or solution in which water is the solvent. In one embodiment, the aqueous medium is / consists of water, in particular purified water or water for injection (WFI). In one embodiment, the aqueous medium is sterile. In one embodiment, the liquid formulation is sterile. 【0083】 In one embodiment, the liquid formulation has a pH in the range of about 3.5 to about 5.5. 【0084】 In one embodiment, the buffer is an acetate, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is an acetate, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0. 【0085】 In one embodiment, the buffer is a 10 mM concentration of acetate, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is a 10 mM concentration of acetate, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0, and the buffer is a 10 mM concentration of acetate. 【0086】 In one embodiment, the buffer is histidine, and the liquid formulation has a pH of about 5.5 or less. In one embodiment, the buffer is histidine, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is histidine, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0. 【0087】 In one embodiment, the buffer is histidine at a concentration of 10 mM, and the liquid formulation has a pH of about 5.5 or less. In one embodiment, the buffer is histidine at a concentration of 10 mM, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is histidine at a concentration of 10 mM, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0, and the buffer is histidine at a concentration of 10 mM. 【0088】 In one embodiment, the buffer is histidine at a concentration of 20 mM, and the liquid formulation has a pH of about 5.5 or less. In one embodiment, the buffer is histidine at a concentration of 20 mM, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is histidine at a concentration of 20 mM, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0, and the buffer is histidine at a concentration of 20 mM. 【0089】 Liquid formulations may contain one or more other excipients, provided they are pharmaceutically acceptable and do not impair the suitability of the liquid formulation for administration by inhalation, particularly by nebulizer inhalation. Suitable excipients are listed in the pharmacopoeia or, for example, in REMINGTON's PHARMACEUTICAL SCIENCES (18th edition, edited by A.R. Gennaro, Mack Publishing Company 1990) and subsequent editions. As used herein, the term “pharmaceutically acceptable” means that the substance is non-toxic and, in one embodiment, does not interact with the action of the activator of the liquid formulation. 【0090】 In one embodiment, the liquid formulation further comprises a surfactant. 【0091】 As used herein, the term “surfactant” (or “surface-activating agent”) means a compound that reduces the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. In one embodiment, the compound reduces the surface tension (or interfacial tension) between a gas (e.g., air) and a liquid. In one embodiment, the surfactant is a nonionic surfactant. In one embodiment, the surfactant is a polysorbate (e.g., polysorbate 20 or polysorbate 80), a poloxamer (e.g., poloxamer 188, marketed as Pluronic® F68, or poloxamer 407, marketed as Pluronic® F127), a polyoxyethylene alkyl ether (e.g., Brij® surfactant), an alkylphenol polyoxyethylene (e.g., Triton® X100), and sodium dodecyl sulfate (SDS). In one embodiment, the surfactant is polysorbate 80 (PS80). 【0092】 In one embodiment, the concentration of the surfactant in the liquid formulation is about 0.1% (w / v) or less, or about 0.05% (w / v) or less, for example, about 0.04% (w / v) or less, or about 0.03% (w / v) or less, or about 0.02% (w / v) or less, or about 0.01% (w / v) or less. In one embodiment, the concentration of the surfactant in the liquid formulation is less than about 0.01% (w / v). 【0093】 In one embodiment, the concentration of polysorbate in the liquid formulation is about 0.1% (w / v) or less, or about 0.05% (w / v) or less, for example, about 0.04% (w / v) or less, or about 0.03% (w / v) or less, or about 0.02% (w / v) or less, or about 0.01% (w / v) or less. In one embodiment, the concentration of polysorbate in the liquid formulation is less than about 0.01% (w / v). 【0094】 In one embodiment, the concentration of PS80 in the liquid formulation is about 0.1% (w / v) or less, or about 0.05% (w / v) or less, for example, about 0.04% (w / v) or less, or about 0.03% (w / v) or less, about 0.02% (w / v) or less, or about 0.01% (w / v) or less. In one embodiment, the concentration of PS80 in the liquid formulation is less than about 0.01% (w / v). 【0095】 In one embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0096】 In one embodiment, the liquid formulation does not contain any surfactants, such as those defined above. 【0097】 In one embodiment, the liquid formulation does not contain NaCl. 【0098】 In one embodiment, the liquid formulation contains no non-buffered salts. As used herein, the term "non-buffered salt" means a salt that does not, or substantially does not, contribute to maintaining the pH of the liquid formulation when an acid or base is added. In one embodiment, the non-buffered salt is a halogen salt (e.g., Cl - Or Br - (including) In one embodiment, the non-buffered salt is sodium (Na) + ), potassium (K + ), calcium (Ca 2+ ) or magnesium (Mg 2+ It is a halogen salt containing one or more cations of ) (Na). In one embodiment, the non-buffered salt is sodium (Na + ) or potassium (K + A halogen salt containing one or more cations of the following: In yet another embodiment, a non-buffered salt is selected from the group consisting of NaCl, KCl, CaCl2, and MgCl2. 【0099】 Generally, an aerosol is a suspension of fine solid particles or droplets in air or another gas. According to the present invention, the term “aerosol” means a suspension of droplets of a liquid formulation as defined above in a gas, for example, air. 【0100】 In one embodiment, the droplets have an average diameter of less than 5 μm. In one embodiment, the droplets have an average diameter of less than 4.5 μm. In one embodiment, the droplets have an average diameter of less than 4.0 μm. In one embodiment, the droplets have an average diameter of less than 3.5 μm. In one embodiment, the droplets have an average diameter of less than 3.0 μm. 【0101】 In one embodiment, the droplets have an average diameter ranging from about 0.5 μm to about 5 μm. In one embodiment, the droplets have an average diameter ranging from about 0.5 μm to about 4.5 μm. In one embodiment, the droplets have an average diameter ranging from about 0.5 μm to about 4 μm. In one embodiment, the droplets have an average diameter ranging from about 0.5 μm to about 3.5 μm. In one embodiment, the droplets have an average diameter ranging from about 0.5 μm to about 3 μm. In one embodiment, the average diameter is the median volume diameter (VMD; also called the Dv50 value). In one embodiment, the VMD is determined by laser diffraction, for example, as described in United States Pharmacopeia (USP) 429. Droplet size can also be measured, for example, by interferometric laser imaging. Results may vary depending on the measurement method used. 【0102】 In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 5.0 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 5 μm. In one embodiment, the liquid formulation contains an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those two values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 5 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0103】 In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation contains an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 4.5 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0104】 In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH in the range of about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH in the range of about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 4 μm. In one embodiment, the liquid formulation contains an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those two values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 4 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0105】 In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between about 3.7 and less than about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation contains an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 3.5 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0106】 In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 3 μm. In one embodiment, the liquid formulation contains an acetate buffer as a buffering agent, has a pH between about 3.9 and about 4.1, i.e., between those values, and contains droplets with an average diameter in the range of about 0.5 μm to about 3 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0107】 In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 5 μm. In one embodiment, the liquid formulation contains a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 5 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0108】 In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH in the range of about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH in the range of about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation comprises an acetate buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 4.5 μm. In one embodiment, the liquid formulation contains a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 4.5 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0109】 In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 4 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 4 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 4 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 4 μm. In one embodiment, the liquid formulation contains histidine buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4 μm. In one embodiment, the liquid formulation contains histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 4 μm. In one embodiment, the liquid formulation contains histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 4 μm. In one embodiment, the liquid formulation contains histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 4 μm. In one embodiment, the liquid formulation contains a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 4 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0110】 In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH in the range of about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH in the range of about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3.5 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 3.5 μm. In one embodiment, the liquid formulation contains a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 3.5 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0111】 In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH of about 5.0 or less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH ranging from about 3.5 to less than about 4.5, and includes droplets with an average diameter ranging from about 0.5 μm to about 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between about 3.7 and about 4.3, i.e., between those two values, and includes droplets with an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.7 and approximately 4.3, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter of less than 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.8 and approximately 4.2, i.e., between those values, and includes droplets having an average diameter in the range of approximately 0.5 μm to approximately 3 μm. In one embodiment, the liquid formulation comprises a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and includes droplets having an average diameter of less than 3 μm. In one embodiment, the liquid formulation contains a histidine buffer as a buffer, has a pH between approximately 3.9 and approximately 4.1, i.e., between those values, and contains droplets with an average diameter in the range of approximately 0.5 μm to approximately 3 μm. In another embodiment, the liquid formulation contains only one surfactant. In one embodiment, this surfactant is PS80. 【0112】 According to the present invention, antibodies or antibody derivatives present in aerosols or liquid formulations described herein are characterized by lower aggregation compared to, for example, the same antibodies or antibody derivatives incorporated in formulations containing citrate. 【0113】 In one embodiment, the antibody or antibody derivative present in the aerosol or liquid formulation described herein has one or more of the following properties: The polydispersity index (PDI) of the antibody or antibody derivative present in the aerosol or liquid formulation described herein is less than 0.5, less than 0.4, less than 0.3, less than 0.2, or less than 0.1, as determined, for example, by DLS (for example, essentially as described in Example 1). The percentage of polydispersity of monomers of antibodies or antibody derivatives present in the aerosol or liquid formulations described herein is, for example, less than 30%, less than 25%, less than 20%, or less than 15%, as determined by DLS (for example, essentially as described in Example 1). The mass percentage of monomers of antibodies or antibody derivatives present in the aerosol or liquid formulations described herein is 99.7% or higher, or 99.8% or higher, or 99.8% or higher, as determined, for example, by DLS (for example, essentially as described in Example 1). The strength percentage of the monomers of the antibody or antibody derivative present in the aerosol or liquid formulation described herein is 80.0% or higher, 85.0% or higher, 90.0% or higher, or greater than 90.0%, as determined, for example, by DLS (for example, essentially as described in Example 1). For example, as determined by FCM (for example, essentially as described in Example 1), The number of 2μm particles is less than 10,000 / mL, or less than 7,500 / mL, or less than 5,000 / mL, or less than 4,000 / mL, or less than 3,000 / mL, or less than 2,000 / mL. The number of particles >10 μm is less than 500 / mL, or less than 400 / mL, or less than 300 / mL, or less than 200 / mL; and The number of particles measuring >25 μm is less than 100 / mL, or less than 50 / mL, or less than 40 / mL, or less than 30 / mL, or less than 20 / mL. 【0114】 In another embodiment, the present invention relates to a method for preparing an aerosol comprising droplets containing a liquid formulation, the method comprising the following steps: (i) the step of providing the liquid formulation defined above, (ii) A step of preparing an aerosol by spraying the liquid formulation provided in step (i) using a nebulizer. Includes. 【0115】 In one embodiment, the nebulizer is a mesh nebulizer. 【0116】 Nebulizers enable the aerosolization of liquid formulations and the dispersion of the liquid into a gas for inhalation into the target respiratory system. Examples of nebulizers include soft mist nebulizers, mesh nebulizers (e.g., vibrating mesh nebulizers), jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include Aerogen® Solo (Aerogen), Pari eFlow® (Pari GmbH), Philips I-neb® (Philips), Pari LC Sprint (Pari GmbH), AERxRTM Pulmonary Delivery System (Aradigm), and Pari LC Plus Reusable Nebulizer (Pari GmbH). In one embodiment, the nebulizer is a mesh nebulizer, particularly a vibrating mesh nebulizer. Nebulizers typically contain liquid formulations ranging from about 1 mL to about 200 mL, more typically from 1 mL to 20 mL. 【0117】 In one embodiment, the method includes the following steps between steps (i) and (ii): (ia) a step of freeze-drying the liquid formulation provided in step (i) to provide a freeze-dried powder, and (ib) A step of reconstituting the liquid formulation provided in step (i) by adding an appropriate amount of aqueous medium to the lyophilized powder provided in step (ia). It also includes. 【0118】 In another embodiment, the present invention relates to an aerosol comprising droplets containing a liquid formulation, wherein the aerosol is available by the method defined above. In one embodiment, the droplets have an average diameter ranging from about 0.5 μm to about 5 μm, or from about 0.5 μm to about 3 μm. 【0119】 In another aspect, the present invention relates to a defined liquid formulation or a defined aerosol for use in a method of delivering an antibody or antibody derivative to the lungs of a subject, wherein the aerosol is administered to the subject by inhalation, and the liquid formulation is administered to the subject by inhalation via a nebulizer. 【0120】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or an antibody derivative. 【0121】 In one embodiment, the nebulizer is a mesh nebulizer. 【0122】 The term “subject” according to the present invention means a subject for treatment, in particular a diseased subject (also called “patient”), and includes humans, non-human primates or other animals, in particular mammals, such as cattle, horses, pigs, sheep, goats, dogs, cats, rabbits or rodents, such as mice, rats, guinea pigs and hamsters. In one embodiment, the subject / patient is a human. 【0123】 In another embodiment, the present invention relates to the above-defined liquid formulations for use in a method of treating or preventing a disease in a subject, wherein the aerosol is administered to the subject by inhalation, or the liquid formulation is administered to the subject by inhalation via a nebulizer. 【0124】 In one embodiment, the disease is a lung disease. 【0125】 In one embodiment, the nebulizer is a mesh nebulizer. 【0126】 As used herein, the term "treatment" refers to any treatment that improves a patient's health and / or extends (increases) their lifespan. 【0127】 According to the present invention, the term "disease" refers to any pathological condition, particularly cancer, infectious diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, degenerative diseases, apoptosis-related diseases, and transplant rejection. 【0128】 Furthermore, the term "cancer" according to the present invention includes cancer metastasis. "Metastasis" means the spread of cancer cells from their original site to another part of the body. The formation of metastasis is a very complex process and depends on the detachment of malignant cells from the primary tumor, invasion into the extracellular matrix, penetration of the endothelial basement membrane to enter body cavities and blood vessels, and then transport by the blood before invading the target organ. Ultimately, the growth of a new tumor at the target site, i.e., a secondary tumor or metastatic tumor, depends on angiogenesis. Tumor metastasis often occurs even after the removal of the primary tumor, as tumor cells or components may remain and develop metastatic potential. In one embodiment, the term "metastasis" according to the present invention refers to "distant metastasis," which is a metastasis away from the primary tumor and the regional lymph node system. 【0129】 The term "infectious disease" refers to any illness that can be transmitted from individual to individual or from organism to organism and is caused by a microbial agent (e.g., the common cold). Examples of infectious diseases include viral infections, such as AIDS (HIV), hepatitis A, hepatitis B, or hepatitis C, herpes, shingles (varicella), rubella (rubella virus), yellow fever, dengue fever, etc., flaviviruses, influenza viruses, respiratory syncytial virus (RSV), hemorrhagic infections (Marburg virus or Ebola virus), and severe acute respiratory syndrome (SARS), bacterial infections, such as legionellosis (Legionella bacteria), sexually transmitted infections (e.g., chlamydia, gonorrhea), gastric ulcers (Helicobacter), cholera (Vibrio), tuberculosis, diphtheria, and Escherichia coli (E. coli). This includes infections caused by bacteria such as *Cryptococcus pallidum*, *Staphylococcus*, *Salmonella*, or *Streptococcus* (tetanus); infections caused by protozoan pathogens such as malaria, sleeping sickness, and leishmaniasis; toxoplasmosis, i.e., infections caused by *Plasmodium*, *Trypanosoma*, *Leishmania*, and *Toxoplasma*; or fungal infections caused by, for example, *Cryptococcus neoformans*, *Histoplasma capsulatum*, *Coccidioides immitis*, *Blastomyces dermatitidis*, or *Candida albicans*. 【0130】 The term “inflammatory disease” refers to any disease characterized by or associated with a high level of inflammation or degeneration of tissues, particularly connective tissue. Chronic inflammatory diseases are medical conditions characterized by persistent inflammation. Examples of (chronic) inflammatory diseases include celiac disease, vasculitis, lupus, chronic obstructive pulmonary disease (COPD), asthma, irritable bowel disease, atherosclerosis, arthritis, ankylosing spondylitis, Crohn's disease, colitis, chronic active hepatitis, dermatitis, and psoriasis. 【0131】 The term "metabolic disease" refers to any disease or disorder that disrupts normal metabolism. Examples include cystinosis, diabetes mellitus, dyslipidemia, hyperthyroidism, hypothyroidism, hyperlipidemia, hypolipidemia, galactosemia, Gaucher disease, obesity, and phenylketonuria. 【0132】 The term "autoimmune disease" refers to any disease or disorder in which the body has an immunogenic (i.e., immune system) reaction to some component of its own tissues. In other words, the immune system loses its ability to recognize certain tissues or systems in the body as self, and targets and attacks them as if they were foreign. Autoimmune diseases are classified into those that primarily affect one organ (such as hemolytic anemia and anti-immune thyroiditis) and those in which the autoimmune disease process spreads through many tissues (such as systemic lupus erythematosus). For example, multiple sclerosis is thought to be caused by T cells attacking the sheaths surrounding nerve fibers in the brain and spinal cord. This results in loss of coordination, weakness, and blurred vision. Autoimmune diseases are well known in this field and include, for example, Hashimoto's thyroiditis, Graves' disease, lupus, multiple sclerosis, rheumatoid arthritis, hemolytic anemia, anti-immune thyroiditis, systemic lupus erythematosus, celiac disease, Crohn's disease, colitis, diabetes mellitus, scleroderma, and psoriasis. 【0133】 The term "degenerative disease" refers to any disease in which the function or structure of the affected tissue or organ gradually deteriorates over time. Examples include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, macular degeneration, multiple sclerosis, muscular dystrophy, Niemann-Pick disease, osteoporosis, and rheumatoid arthritis. 【0134】 The term "apoptosis-related diseases" refers to any disease in which changes in apoptosis are involved. Examples include cancer, neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and stroke, heart diseases such as ischemia-reperfusion, chronic heart failure, infections, and autoimmune diseases. 【0135】 The term "transplant rejection" refers to the rejection of transplanted tissue or organ by the recipient's immune system, which can ultimately destroy the transplanted tissue or organ. 【0136】 The term “lung disease” (also referred to herein as “pulmonary disease”) generally refers to a disease or disorder affecting the lungs in question. In one embodiment, lung disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), lung cancer (e.g., non-small cell lung cancer), cystic fibrosis (CF), interstitial lung disease (ILD), e.g., idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis and asbestosis, bacterial infections (e.g., mycobacterial infections), viral infections (e.g., influenza virus infection or respiratory syncytial virus (RSV) infection), acute respiratory distress syndrome (ARDS), alveolar proteinosis (PAP), acute bronchitis, obstructive bronchitis and pulmonary hypertension. 【0137】 In another embodiment, the present invention relates to a method for delivering an antibody or antibody derivative to the lungs of a subject, the method comprising administering an effective amount of the defined aerosol to the subject by inhalation, or administering an effective amount of the defined liquid formulation to the subject by inhalation via a nebulizer. 【0138】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or an antibody derivative. 【0139】 In one embodiment, the nebulizer is a mesh nebulizer. 【0140】 As used herein, the term “effective dose” means, in particular, “therapeutably effective dose,” which is the amount that achieves the desired therapeutic response or effect, either alone or in combination with additional doses, without causing particularly unacceptable side effects. In the case of treatment of a particular disease or condition, the desired response is particularly related to inhibiting the course of the disease. This includes slowing the progression of the disease, in particular interrupting or reversing its progression. The desired response in the treatment of a disease or condition may also be the delay or prevention of the onset of the disease or condition described herein. The effective dose of the aerosol or liquid formulation described herein, and therefore the antibody or antibody derivative contained therein, will depend on the individual parameters of the subject, including the condition being treated, the severity of the disease, age, physiological state, body size and weight, the duration of treatment, the type of accompanying therapy (if any), the specific route of administration, and similar factors. Therefore, the administered dose of the aerosol or liquid formulation described herein may depend on some of these parameters. If the response of the subject is insufficient with the initial dose, a higher dose may be used. 【0141】 In another embodiment, the present invention relates to a method for treating or preventing a disease in a subject, the method comprising administering an effective amount of the above-defined aerosol to the subject by inhalation, or administering an effective amount of the above-defined liquid formulation to the subject by inhalation via a nebulizer. 【0142】 In one embodiment, the disease is a lung disease. 【0143】 In one embodiment, the nebulizer is a mesh nebulizer. 【0144】 In another embodiment, the present invention relates to a nebulizer containing a liquid formulation as defined above. 【0145】 In one embodiment, the nebulizer is a mesh nebulizer. 【0146】 In another embodiment, the present invention is: (i) A container containing the liquid formulation as defined above or a powder that can be obtained by freeze-drying the liquid formulation, and (ii) Nebulizer Regarding the kit that includes this. 【0147】 In one embodiment, the nebulizer is a mesh nebulizer. 【0148】 As used herein, the term “parts kit (abbreviated as kit)” means a manufactured article comprising one or more containers, a nebulizer (e.g., a mesh nebulizer), and optionally a data carrier. The one or more containers are filled with the liquid formulations defined above and / or powders obtained by lyophilization of the liquid formulations. Additional containers may be included in the kit, for example, a diluent (e.g., an aqueous medium), a buffer, and further reagents as defined herein. The data carrier may be a non-electronic data carrier, such as a graphic data carrier such as an information leaflet, information sheet, barcode, or access code, or an electronic data carrier such as a compact disc (CD), digital versatile disc (DVD), microchip, or other semiconductor-based electronic data carrier. The access code may enable access to a database, such as an internet database, a centralized database, or a distributed database. The data carrier may include instructions for the use of the kit in the manner and applications described herein. 【0149】 In another aspect, the present invention relates to the use of a liquid formulation as defined above for preparing an aerosol by spraying using a nebulizer. 【0150】 In one embodiment, the nebulizer is a mesh nebulizer. 【0151】 In another embodiment, the present invention relates to the use of a buffer selected from the group consisting of acetates, histidines, and combinations thereof, for enhancing the stability of an antibody or antibody derivative when a liquid formulation containing an antibody or antibody derivative is nebulized, wherein the buffer is included in the liquid formulation before spraying. 【0152】 In one embodiment, the antibody or antibody derivative is an IgG1 antibody or an antibody derivative. 【0153】 In one embodiment, the nebulizer is a mesh nebulizer. 【0154】 In one embodiment, the term "enhance stability" refers to preventing or reducing the degree of aggregation of an antibody or antibody derivative. 【0155】 In one embodiment, the liquid formulation has a pH of about 5.5 or less. 【0156】 In one embodiment, the antibody is a monoclonal antibody. 【0157】 In one embodiment, the liquid formulation does not contain citrate. 【0158】 In one embodiment, the liquid formulation has a pH in the range of about 3.5 to about 5.5. 【0159】 In one embodiment, the buffer is an acetate, and the liquid formulation has a pH of less than about 5.0 or less than about 4.5. In one embodiment, the buffer is an acetate, and the liquid formulation has a pH in the range of about 3.5 to less than about 4.5, or about 3.7 to about 4.3, or about 3.8 to about 4.2, or about 3.9 to about 4.1. In one embodiment, the liquid formulation has a pH of about 4.0. 【0160】 In one embodiment, the liquid formulation further comprises a surfactant. In one embodiment, the surfactant is selected from the group consisting of polysorbate, poloxamer, polyoxyethylene alkyl ether, alkylphenol polyoxyethylene, and sodium dodecyl sulfate. 【0161】 In one embodiment, the concentration of the surfactant in the liquid formulation is about 0.1% (w / v) or less, or about 0.05% (w / v) or less. 【0162】 In one embodiment, the liquid formulation does not contain any surfactants. 【0163】 In one embodiment, the liquid formulation does not contain NaCl. 【0164】 In one embodiment, the liquid formulation does not contain any non-buffered salts. 【0165】 Next, the present invention will be further described with reference to the following embodiments, which are intended to illustrate the scope of the invention rather than limit it. [Examples] 【0166】 Example 1: Materials and Method The immunoglobulins used in the examples are shown in Table 1 below. [Table 1] 【0167】 Dynamic light scattering (DLS) DLS measurements were performed using a DynaPro NanoStar (Wyatt Technology) instrument with a 663 nm wavelength laser. Each sample was placed in a disposable cuvette (Uvette, Eppendorf), and measurements were taken in 10 7-second intervals. The data were analyzed using Dynamics 7.1.9 software (Wyatt Technology) to determine the particle size distribution in the submicron region. 【0168】 The results are expressed as the Z-mean, polydispersity index (PDI), monomer radius, percentage of polydispersity of monomer peaks (PIC), percentage of intensity, and monomer mass. 【0169】 Polydispersibility is considered low when the PDI is less than 0.1 and high when the sample is diverse. 【0170】 If the proportion of polydispersity among monomers is less than 15%, the level of homogeneity is considered high. If the level of homogeneity is low (the proportion of polydispersity is greater than 30%), the particle population can be considered to contain significantly different sizes, i.e., to be polydisperse. 【0171】 Aggregation is considered low if the monomer mass percentage exceeds 99.8%, and high if it is less than 99.6%. Similarly, aggregation is considered low if the monomer intensity percentage exceeds 90.0%, and high if it is less than 80.0%. 【0172】 Flow cell microscopy (FCM) Flow cell microscopy measurements were performed using a Flowcell FC200-IPAC (Occhio) instrument. Each analysis was performed on a 200 μL sample introduced into a disposable cone. The data were analyzed using Callisto software (Occhio) to determine the particle size distribution in areas invisible to the naked eye. 【0173】 The results are displayed as particle concentrations (particles / mL) for particles >2μm, >10μm, and >25μm. 【0174】 Aggregation is considered low if the particle size >2μm is less than 2000 / mL, the particle size >10μm is less than 200 / mL, and the particle size >25μm is less than 20 / mL. Aggregation is considered high if the particle size >2μm exceeds 10000 / mL, the particle size >10μm exceeds 500 / mL, and the particle size >25μm exceeds 100 / mL. 【0175】 Size exclusion chromatography (SEC) SEC measurements were performed using the Agilent 1200 ultra-high-performance chromatograph chain. Results are expressed as a percentage of high molecular weight (HMW). 【0176】 Regarding mAb1: Measurements were performed at 24°C with a mobile phase consisting of 0.3 M NaClO4 and acetonitrile at 0.1 M phosphate buffer, pH 6.2, at a flow rate of 0.3 mL / min. Samples were stored in vials, and 10 μL were injected into a series of columns consisting of a Guard column Prosec 300S 50x7.5 mm (Agilent) and two Prosec 300S 300x7.5 mm (Agilent) columns. Detection was performed at 280 nm. Results were processed with Empower software. 【0177】 Regarding mAb3: SEC measurements were performed using an Agilent 1200 ultrafast chromatography chain. The measurements were performed at 30°C with a mobile phase consisting of 50 mM sodium phosphate, 300 mM sodium perchlorate, and pH 7 at a flow rate of 0.3 mL / min. The sample was stored in a vial, and 1 μL was injected into an Aquity UPLC BEH200 SEC 200A, 1.7 μm, 4.6 mm x 300 mm column (Waters). Detection was performed at 280 nm. The results were processed with Empower software. 【0178】 Visual inspection Visual inspection was performed on samples placed in glass vials, illuminated against a black background using an MLC-150 cold light source (Motic). 【0179】 Example 2: Effect of buffer and pH on IgG1 stability This example demonstrates that at an acidic pH, acetate and histidine buffers enhance the stability of IgG1 antibodies against aggregation during spraying compared to citrate buffers. 【0180】 Without using PS80, two IgG1 immunoglobulins (mAb1 and mAb3) prepared with different buffers at different pH levels were sprayed, and their post-spray stability was evaluated. mAb1 and mAb3 were prepared at a concentration of 10 mg / mL using six different buffer / pH systems: acetate pH 4.0, acetate pH 5.5, histidine pH 5.5, histidine pH 7.0, citrate pH 5.5, and citrate pH 6.5. The buffer concentration was 10 mM for each system. Spraying was performed using a Solo (Aerogen) vibrating mesh nebulizer with 2 mL of IgG1 prepared with different buffers. The degree of aggregation was measured by dynamic light scattering (DLS), flow cell microscopy (FCM), SEC, and visual inspection. The results are summarized in Figures 1A-C (mAb1) and 1D-F (mAb3). 【0181】 Visual inspection revealed the presence of visible particles in the mAb1 citrate formulation. DLS results showed low aggregation of submicron particles in acetate and histidine buffer, particularly at acidic pH, whereas the citrate formulation was unsuitable for analysis without filtration (likely due to the high particle content in the sample). FCM results confirmed high aggregation in the citrate buffer. 【0182】 Example 3: Effect of polysorbate 80 (PS80) on IgG1 stability This example demonstrates that while a large amount of PS80 (1000 ppm) helps limit the aggregation of IgG1 during spraying in citrate buffer, it is not perfect because the submicron particles of mAb1 exceed the level of quantification by DLS. 【0183】 Two immunoglobulins (mAb1 and mAb3) were prepared in different buffers of different pH levels in the presence of polysorbate 80 (PS80). Acetate, histidine, and citrate buffers were used, with PS80 used as a surfactant. Two IgGs were prepared at a concentration of 10 mg / mL using six different buffer / pH systems: acetate pH 4.0, acetate pH 5.5, histidine pH 5.5, histidine pH 7.0, citrate pH 5.5, and citrate pH 6.5. A buffer concentration of 10 mM was used. PS80 was added to obtain a concentration of 1000 ppm in the formulation. 2 mL of IgG1 prepared in different buffers was sprayed using a Solo (Aerogen) vibrating mesh nebulizer. The degree of aggregation was measured by dynamic light scattering (DLS), flow cell microscopy (FCM), SEC, and visual inspection. The results are summarized in Figures 2A-C (mAb1) and 2D-F (mAb3). 【0184】 Visual inspection showed that all formulations using PS80 were free of visible particles. DLS results indicated that the citrate formulations were unsuitable for analysis without filtration, likely due to high particle content / large particle size in the sample. FCM results demonstrated lower levels of aggregation compared to the same formulation without PS80 tested in Example 2. 【0185】 Example 4: Spraying using two different mesh vibrating nebulizers In this example, the stabilization properties of acetate and histidine buffer are described using two different vibrating mesh nebulizers: a Solo nebulizer (see previous example) and an eFlow nebulizer from PARI. The stabilization effect of acetate and histidine buffer on IgG1 antibody (compared to citrate buffer) was also confirmed in the eFlow system. 【0186】 Acetate, histidine, and citrate buffers were used. Two IgG1 samples were prepared at a concentration of 10 mg / mL using six buffer / pH systems: acetate pH 4.0, acetate pH 5.5, histidine pH 5.5, histidine pH 7.0, citrate pH 5.5, and citrate pH 6.5. Two mL samples of IgG1 prepared with different buffers were subjected to spray stress using a customized eFlow (PARI) vibrating mesh nebulizer. The degree of aggregation was measured by dynamic light scattering (DLS), flow cell microscopy (FCM), SEC, and visual inspection. The results are summarized in Figures 3A-C (mAb1). 【0187】 Example 5: Stability of different IgG isotypes (IgG1 and IgG4) in acetate buffer pH 5.5 This example demonstrates the stabilizing effect of acidic acetate buffers on several IgG1 antibodies. The stabilizing properties of these buffers are not as pronounced with IgG4 antibodies. 【0188】 Four IgG1 strains (mAb1, mAb2, mAb3, and mAb4) and one IgG4 strain (mAbX) were subjected to spray stress at a concentration of 10 mg / mL (pH 5.5 acetate buffer) in the same formulation, and sprayed at a rate of 2 mL using a Solo (Aerogen) vibrating mesh nebulizer. The degree of aggregation was measured using dynamic light scattering (DLS), flow cell microscopy (FCM), SEC, and visual inspection. The results are summarized in Figures 4A-C. 【0189】 Visual inspection revealed the presence of visible particles in the IgG4 X sample. DLS results indicated that the IgG4 X sample was unsuitable for analysis without filtration, likely due to particles in the sample. FCM counting revealed high aggregation in the IgG4 X sample and low aggregation in the four IgG1 samples. 【0190】 Example 6: Stabilizing effect of histidine This example demonstrates the stabilization properties of histidine buffer in formulations containing excipients (polyols and nonionic surfactants) that enable the manufacture and long-term storage of pharmaceuticals before nebulizer use. 【0191】 IgG1 antibody (mAb1) was prepared at a concentration of 20 g / L in 20 mM histidine buffer (pH 6.0) with additional excipients: a nonionic surfactant and a polyol. This combination provided long-term storage stability to the formulation solution. 2 mL of the mAb1 formulation was subjected to spray stress using a Solo (Aerogen) vibrating mesh nebulizer. The aerosol droplet size was determined by laser diffraction. The VMD obtained after spraying was 4.4 μm, with most droplets having a diameter of less than 5 μm. Approximately 30% of the droplets had a diameter ranging from 0.5 μm to 3 μm. The degree of aggregation was evaluated by dynamic light scattering (DLS), flow cell microscopy (FCM), SEC, and visual inspection. Additional analytical methods were performed. This formulation can be stored at 2–8°C for 24 months. The results are summarized in Figures 5A and 5B. 【0192】 Example 7: Effect of PS80 concentration on IgG1 in citrate buffer The effect of PS80 concentration on the stability of IgG1 sprayed in citrate was evaluated. Spray stress was applied to two different IgG1 samples (mAb 1 and mAb 3) prepared in citrate pH 5.5 with different PS80 concentrations. PS80 concentrations of 0, 200, and 1000 ppm were used. Both IgG1 samples were prepared in citrate buffer at a concentration of 10 mg / mL, and PS80 was added at the target concentration. Spray stress was applied to 2 mL of each IgG1 sample prepared in citrate with different PS80 concentrations using a vibrating mesh nebulizer. The degree of aggregation was measured using dynamic light scattering (DLS) and flow microscopy (FCM; Figure 6). Figure 6 shows that IgG1 in citrate buffer exhibited a high level of aggregation at 0 ppm PS80. High concentrations (1000 ppm) of PS80 were required to stabilize IgG1 in citrate. DLS results indicated that citrate formulations are unsuitable for analysis without filtration, likely due to particles in the sample. FCM results showed high particle concentrations with 0 ppm PS80. The number of particles per mL decreased with increasing PS80 concentration. 200 ppm PS80 was not sufficient to stabilize mAb 1. DLS results suggest that, in most cases (n=5 / 6), citrate formulations are unsuitable for analysis without filtration because particles are present in the sample even with 0 ppm PS80. Aggregation was observed with 200 ppm PS80. Aggregation was low with 1000 ppm PS80. FCM results showed high particle concentrations with 0 ppm PS80. The concentration of particles decreased with the addition of 200 ppm and 1000 ppm PS80. 【0193】 Example 8: Effect of PS80 concentration on IgG1 in histidine buffer The effect of PS80 concentration on the stability of IgG1 sprayed in histidine was evaluated. To this end, spray stress was applied to one IgG1 molecule (mAb 1) formulated in histidine pH 5.5 with different PS80 concentrations. PS80 concentrations of 0, 50, 200, and 1000 ppm were used. IgG1 was prepared at a concentration of 10 mg / mL in histidine buffer, and PS80 was added at the target concentration. Spray stress was applied to 2 mL of IgG1 prepared in histidine with different PS80 concentrations using a vibrating mesh nebulizer. The degree of aggregation was measured using dynamic light scattering (DLS) and flow microscopy (FCM; Figure 7). Figure 7 shows that IgG1 in histidine buffer showed moderate aggregation with 0 ppm PS80. Low concentrations of PS80 (50 ppm) are considered sufficient to stabilize IgG1 in histidine. DLS results showed moderate aggregation with 0 ppm PS80. Aggregation levels were low and similar across different concentrations with 50, 200, and 100 ppm PS80. FCM results showed moderate particle concentrations with 0 ppm PS80. Adding 50, 200, and 1000 ppm PS80 reduced particle concentrations in comparable methods.

Claims

[Claim 1] an aerosol containing droplets of a liquid formulation The liquid formulation is (i) antibody, (ii) Buffering material, and (iii) Aqueous medium Includes, (1) The liquid formulation has a pH of less than 5.0 or less than 4.5, (2) The buffer is an acetate, (3) The droplets have an average diameter in the range of 0.5 μm to 5 μm, 0.5 μm to 4.5 μm, 0.5 μm to 4 μm, 0.5 μm to 3.5 μm, or 0.5 μm to 3 μm, (4) The antibody is an IgG1 antibody, aerosol. [Claim 2] The aerosol according to claim 1, wherein the liquid formulation does not contain citrate. [Claim 3] The aerosol according to claim 1 or 2, wherein the liquid formulation further comprises a surfactant. [Claim 4] The aerosol according to claim 3, wherein the concentration of the surfactant in the liquid formulation is 0.1% (w / v) or less, or 0.05% (w / v) or less. [Claim 5] The surfactants are polysorbate, poloxamer, and polyoxyethylene alkyl ether. The aerosol according to claim 3 or 4, selected from the group consisting of alkylphenol polyoxyethylene and sodium dodecyl sulfate. [Claim 6] The aerosol according to claim 1 or 2, wherein the liquid formulation does not contain a surfactant. [Claim 7] A method for preparing an aerosol containing droplets of a liquid formulation, comprising the following steps: (i) A step of providing a liquid formulation as defined in any one of claims 1 to 6, (ii) A step of preparing an aerosol by spraying the liquid formulation provided in step (i) using a nebulizer. Methods that include... [Claim 8] Depending on the circumstances, the following steps may be taken between steps (i) and (ii): (ia) a step of freeze-drying the liquid formulation provided in step (i) to provide a freeze-dried powder, and (ib) A step of reconstituting the liquid formulation provided in step (i) by adding an appropriate amount of aqueous medium to the lyophilized powder provided in step (ia). The method according to claim 7, further comprising: [Claim 9] An aerosol or liquid formulation according to any one of claims 1 to 6, for use in a method of delivering an antibody to the lungs of a target, wherein the antibody is an IgG1 antibody, and the aerosol is administered to the target by inhalation, or the liquid formulation is administered to the target by inhalation via a nebulizer. [Claim 10] An aerosol or liquid formulation according to any one of claims 1 to 6, for use in a method of treating or preventing a target disease, characterized in that the aerosol is administered to the target by inhalation, or the liquid formulation is administered to the target by inhalation via a nebulizer. [Claim 11] A nebulizer containing a liquid formulation according to any one of claims 1 to 6. [Claim 12] It's a kit, (i) A container containing a liquid formulation according to any one of claims 1 to 6 or a powder obtained by freeze-drying the liquid formulation, and (ii) Nebulizer A kit that includes this. [Claim 13] Use of the liquid formulation according to any one of claims 1 to 6 for preparing an aerosol by spraying with a nebulizer. [Claim 14] The use of a buffer selected from acetates to enhance the stability of an antibody or antibody derivative when a liquid formulation containing an antibody or antibody derivative is nebulized, wherein the use satisfies the following conditions: (1) Add a buffer to the liquid formulation before spraying. (2) The antibody is an IgG1 antibody. (3) The pH of the liquid formulation is less than 5.0 or less than 4.5.

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