Anti-rsv monoclonal antibody formulations

Abstract

The present invention provides a formulation comprising: (i) an anti-RSV monoclonal antibody; and (ii) an ionic excipient; wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or greater and the ionic excipient is present at a concentration of between 50 to 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

Description

[0001] This application is a divisional application of Chinese patent application No. 201880014929.6 (application date: February 28, 2018, invention title: anti-RSV monoclonal antibody preparation).

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 465,379, filed March 1, 2017, which is incorporated herein by reference.

[0004] sequence list

[0005] This application contains a sequence list electronically filed with the U.S. Patent and Trademark Office via EFS-Web as an ASCII text file, named "490-00050201_ST25.txt", 12 kilobytes in size, and created on February 28, 2018. The information contained in this sequence list is incorporated herein by reference. Invention Field

[0006] This invention relates to an anti-RSV antibody formulation (particularly an anti-RSV monoclonal antibody formulation) and its use. This invention also relates to an isolated anti-RSV monoclonal antibody and its use. Background Technology

[0007] Respiratory syncytial virus (RSV) is a common cold virus belonging to the Paramyxoviridae family. RSV is highly virulent, easily transmitted, and is the most common cause of lower respiratory tract infections in children under 2 years of age. In a single RSV season, up to 98% of daycare-attended children can become infected. Between 0.5% and 3.2% of children infected with RSV require hospitalization. Approximately 90,000 hospitalizations and 4,500 deaths are reported annually in the United States. The main risk factors for hospitalization due to RSV are prematurity, chronic lung disease, congenital heart disease, immunocompromised individuals, and being under 6 weeks of age in other healthy children. In addition to supportive care with adequate nutrition and oxygen therapy, further treatment for RSV-positive bronchiolitis is required. Antiviral therapies such as ribavirin have not been proven effective in RSV infection. A monoclonal antibody, palizumab (also known as Synagis), is used. Palizumab is registered for use as a preventative treatment against RSV infection. It is a genetically engineered (humanized) monoclonal antibody targeting the RSV fusion protein. While palizumab has proven to be a highly effective preventative agent, it would be beneficial to offer alternative antibodies and therapies with greater coverage against RSV.

[0008] Because many anti-RSV monoclonal antibodies have isoelectric points (pI) within the preferred drug formulation pH range for proteins (pH 5.5 to pH 7.5), these molecules present unique formulation challenges.

[0009] Colloidal instability of a molecular pI arises from the lack of electrostatic charge on the molecule, which allows for closer protein-protein interactions (so-called "self-association"), leading to physical instability. For this reason, the pH of protein formulations is typically chosen to deviate from the protein's pI by at least one pH unit. This aims to provide colloidal stability and thus prevent physical instabilities such as aggregation, precipitation, opalination, phase separation, and / or particle formation.

[0010] According to the "deviation of 1 pH unit" rule, antibodies with low or neutral pI (e.g., pI between pH 5.5 and pH 7.5) should therefore be formulated with a pH outside the range of 5.5 to 7.5. However, outside this range, additional instability can be observed. At higher acidic pH, an increased fragmentation rate, decreased conformational stability, and increased aggregation can be observed. At higher alkaline pH, there is a possibility of increased oxidation, deamidation, and fragmentation, as well as incompatibility with glass containers.

[0011] The aforementioned instability is particularly problematic in anti-RSV antibody formulations (where the antibody is present at a commercially desirable concentration, such as 50 mg / ml or higher).

[0012] Therefore, there is a demand for improved formulations that provide anti-RSV antibodies with low or neutral pI. Specifically, there is a demand for stable formulations that provide anti-RSV antibodies with low or neutral pI, and particularly for formulations with commercially desirable antibody concentrations. Summary of the Invention

[0013] This invention provides novel anti-RSV antibody formulations, particularly novel anti-RSV monoclonal antibody formulations. Specifically, the formulations of this invention provide a means for improving the colloidal stability of antibodies with low or neutral pIs. Therefore, this invention provides an alternative to the "deviation from 1 pH" rule for providing colloidal stability. Thus, this invention allows the formulation of antibodies with low or neutral pIs within one pH unit of the antibody pI. Therefore, this invention enables the formulation of such antibodies in a pH range of 5.5 to 7.5 and at commercially useful concentrations, while substantially avoiding the instabilities associated with higher acidic or higher alkaline pH values.

[0014] This invention further provides a novel anti-RSV antibody, MEDI8897. According to the teachings of this invention, the formulation of the antibody makes improved, pharmaceutically suitable formulations of the novel anti-RSV antibody MEDI8897 more readily available.

[0015] Specifically, the present invention relates to anti-RSV antibodies with low or neutral pI, particularly the MEDI8897 antibody. MEDI8897 is a human IgG1κ-YTE monoclonal antibody against the RSV-F protein.

[0016] MEDI8897 has Figure 1 The full-length heavy chain sequence of (SEQ ID NO:2) and Figure 2 The full-length light chain sequence of (SEQ ID NO:1).

[0017] MEDI8897 has the following CDR sequences: light chain CDR-L1 of QASQDIVNYLN (SEQ ID NO:3), light chain CDR-L2 of VASNLET (SEQ ID NO:4), light chain CDR-L3 of QQYDNLPLT (SEQ ID NO:5), heavy chain CDR-H1 of DYIIN (SEQ ID NO:6), heavy chain CDR-H2 of GIIPVLGTVHYGPKFQG (SEQ ID NO:7), and heavy chain CDR-H3 of ETALVVSETYLPHYFDN (SEQ ID NO:8). These six CDRs are... Figure 1 and Figure 2 The text is underlined.

[0018] MEDI8897 has Figure 1 The light chain variable sequence of amino acid residues 1 to 107 of (SEQ ID NO:9) and Figure 2 The heavy chain variable sequence of amino acid residues 1 to 126 of (SEQ ID NO:10).

[0019] The pI of MEDI8897, measured by cIEF, ranged from 6.4 to 6.7, with a dominant peak at 6.4. Therefore, the pI overlaps with the desired range for drug formulation buffers and indicates potential issues with manufacturing, formulation, and storage stability if formulated within this range.

[0020] This invention provides a formulation comprising:

[0021] i. Anti-RSV monoclonal antibody; and

[0022] ii. Ionic excipients;

[0023] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml), and the ionic excipient is present at a concentration of about 50 to 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0024] In one embodiment, the anti-RSV monoclonal antibody has a low or neutral pI, for example, in the range of about pH 5.5 to about pH 7.5. In one embodiment, the monoclonal antibody has a pI in the range of about pH 6.0 to about pH 7.5. In one embodiment, the monoclonal antibody has a pI in the range of about pH 6.3 to about pH 7.5. In one embodiment, the monoclonal antibody has a pI in the range of about pH 6.4 to about pH 7.5. In one embodiment, the monoclonal antibody has a pI in the range of about pH 6.4 to about pH 6.7. In one embodiment, the monoclonal antibody has a pI of about pH 6.4. Not wishing to be bound by theory, the protein may have a low to neutral pI if the protein has a net balance of amino acid side chains with opposite charges (positive amine and negative carboxyl groups) or if different domains have an overall opposite charge in the pH range of about 5.5 to about 7.5. Similarly, not wanting to be bound by theory, the ionic excipients in the formulations of this invention may shield these opposing and mutually attractive charges, thereby stabilizing protein colloids having a pI within that range. Therefore, this invention provides the use of ionic excipients in antibody formulations for altering the charge state or distribution of antibodies in the formulation. This invention further provides the use of ionic excipients in antibody formulations for colloidal stabilization of antibodies in the formulation.

[0025] In one embodiment, the monoclonal antibody is present in the formulation described herein at a concentration of about 75 mg / ml or higher (e.g., about 75 mg / ml to about 200 mg / ml). In one embodiment, the monoclonal antibody is present in the formulation described herein at a concentration of about 100 mg / ml or higher. In one embodiment, the anti-RSV monoclonal antibody is present in the formulation described herein at a concentration of about 100 mg / ml to about 165 mg / ml. In one embodiment, the anti-RSV monoclonal antibody is present at a concentration of about 100 mg / ml. In one embodiment, the ionic excipient is present at a concentration of about 75 mM to about 100 mM. In one embodiment, the ionic excipient is present at a concentration of about 75 mM. In one embodiment, the ionic excipient is present at a concentration of about 80 mM.

[0026] In one embodiment, the monoclonal antibody is an IgG1 monoclonal antibody. Therefore, the present invention provides a formulation comprising:

[0027] i. IgG1 anti-RSV monoclonal antibody; and

[0028] ii. Ionic excipients;

[0029] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0030] In one embodiment, the formulation described herein has a pH in the range of about pH 5.5 to about pH 6.5. In one embodiment, the formulation described herein has a pH in the range of about pH 5.7 to about pH 6.3. In one embodiment, the formulation described herein has a pH in the range of about pH 5.7 to about pH 6.1. A preferred formulation has a pH of about 5.8. Other preferred formulations have a pH of about 6.0.

[0031] In one embodiment, the ionic excipient is a charged amino acid. In one embodiment, the ionic excipient is lysine. In another embodiment, the ionic excipient is arginine.

[0032] In one embodiment, the ionic excipient is a salt. Therefore, the present invention provides a formulation comprising:

[0033] i. Anti-RSV monoclonal antibodies as defined anywhere in this document; and

[0034] ii. Salt;

[0035] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher, and the salt is present at a concentration of about 50 to about 150 mM, and the preparation has a pH of about 5.5 to about 7.5.

[0036] In one embodiment, the salt is present at a concentration of about 75 mM to about 100 mM. In another embodiment, the salt is present at a concentration of about 75 mM or about 80 mM.

[0037] In one embodiment, the salt is arginine hydrochloride, for example, arginine hydrochloride at a concentration of about 75 mM to about 100 mM, suitably at a concentration of about 80 mM.

[0038] In one embodiment, the formulation further comprises sugar. Among other known benefits, the presence of sugar can improve the tonicity of the formulation. This is desirable because the preferred formulation is isotonic or near-isotonic. In one embodiment, the ionic excipient is a salt, and the formulation further comprises sugar.

[0039] Therefore, the present invention provides a formulation comprising:

[0040] i. Anti-RSV monoclonal antibodies as defined anywhere in this document;

[0041] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0042] iii. Sugar as defined anywhere in this document; and

[0043] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher, and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0044] In one embodiment, the formulation further comprises sugar, and the ionic excipient is present at a concentration of about 75 mM to less than 150 mM. In one embodiment, the formulation further comprises sugar, and the ionic excipient is present at a concentration of about 75 mM to about 100 mM. In one embodiment, the formulation further comprises sugar present at a concentration in the range of about 100 mM to about 140 mM, and the ionic excipient is present at a concentration in the range of about 75 mM to about 100 mM.

[0045] In one embodiment, the sugar is sucrose, for example, sucrose at a concentration of about 100 mM to about 140 mM, suitably at a concentration of about 120 mM.

[0046] In one embodiment, the formulation further comprises one or more buffers. In one embodiment, the buffer or these buffers are histidine-containing buffers. In one embodiment, the buffer or these buffers are selected from buffers containing histidine succinate, histidine acetate, histidine citrate, histidine chloride, or histidine sulfate. In one embodiment, the buffer or these buffers are histidine, histidine hydrochloride, or a combination thereof (histidine / histidine hydrochloride). In one embodiment, the buffer or these buffers are L-histidine / L-histidine hydrochloride monohydrate at a concentration of, for example, from about 10 mM to about 50 mM, suitably about 30 mM. It should be understood that the buffer itself may be an ionic excipient. Therefore, in one embodiment, the buffer is an ionic excipient. In this embodiment, the concentration of the buffer should be higher than 50 mM, i.e., consistent with the concentration of ionic excipients disclosed herein. In other words, in one embodiment, the ionic excipient is also used as a buffer in the formulation. In this embodiment, additional buffers may or may not be present.

[0047] In one embodiment, the formulation further comprises a surfactant. In one embodiment, the surfactant is a polysorbate, including, for example, polysorbate-80.

[0048] In one embodiment, the formulation further comprises sugar and one or more buffers. In one embodiment, the ionic excipient is a salt, and the formulation further comprises sugar and one or more buffers.

[0049] In one embodiment, the formulation further comprises a surfactant, a sugar, and one or more buffers. In one embodiment, the ionic excipient is a salt, and the formulation further comprises a surfactant, a sugar, and one or more buffers.

[0050] Therefore, the present invention provides a formulation comprising:

[0051] i. Anti-RSV monoclonal antibodies as defined anywhere in this document;

[0052] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0053] iii. Sugar as defined anywhere in this document;

[0054] iv. One or more buffers as defined anywhere in this document; and

[0055] v. optionally, as defined anywhere in this document, a surfactant.

[0056] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher, and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0057] The present invention also provides a formulation comprising:

[0058] i. An anti-RSV monoclonal antibody having a heavy chain variable region CDR1 sequence (containing at least 70% identical sequences to the heavy chain variable region CDR1 sequence of MEDI8897), a heavy chain variable region CDR2 sequence (containing at least 70% identical sequences to the heavy chain variable region CDR2 sequence of MEDI8897), a heavy chain variable region CDR3 sequence (containing at least 70% identical sequences to the heavy chain variable region CDR3 sequence of MEDI8897), a light chain variable region CDR1 sequence (containing at least 70% identical sequences to the light chain variable region CDR1 sequence of MEDI8897), a light chain variable region CDR2 sequence (containing at least 70% identical sequences to the light chain variable region CDR2 sequence of MEDI8897), and a light chain variable region CDR3 sequence (containing at least 70% identical sequences to the light chain variable region CDR3 sequence of MEDI8897);

[0059] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0060] iii. Sugar as defined anywhere in this document;

[0061] iv. One or more buffers as defined anywhere in this document; and

[0062] v. optionally, as defined anywhere in this document, a surfactant.

[0063] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5. In one embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 80% of the same sequence as the heavy chain variable region CDR1 sequence of MEDI 8897), a heavy chain variable region CDR2 sequence (containing at least 80% of the same sequence as the heavy chain variable region CDR2 sequence of MEDI 8897), a heavy chain variable region CDR3 sequence (containing at least 80% of the same sequence as the heavy chain variable region CDR3 sequence of MEDI 8897), a light chain variable region CDR1 sequence (containing at least 80% of the same sequence as the light chain variable region CDR1 sequence of MEDI 8897), a light chain variable region CDR2 sequence (containing at least 80% of the same sequence as the light chain variable region CDR2 sequence of MEDI 8897), and a light chain variable region CDR3 sequence (containing at least 80% of the same sequence as the light chain variable region CDR3 sequence of MEDI 8897). In one embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 90% identical sequences to the heavy chain variable region CDR1 sequence of MEDI 8897), a heavy chain variable region CDR2 sequence (containing at least 90% identical sequences to the heavy chain variable region CDR2 sequence of MEDI 8897), a heavy chain variable region CDR3 sequence (containing at least 90% identical sequences to the heavy chain variable region CDR3 sequence of MEDI 8897), a light chain variable region CDR1 sequence (containing at least 90% identical sequences to the light chain variable region CDR1 sequence of MEDI 8897), a light chain variable region CDR2 sequence (containing at least 90% identical sequences to the light chain variable region CDR2 sequence of MEDI 8897), and a light chain variable region CDR3 sequence (containing at least 90% identical sequences to the light chain variable region CDR3 sequence of MEDI 8897).In one embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 95% identical sequences to the heavy chain variable region CDR1 sequence of MEDI 8897), a heavy chain variable region CDR2 sequence (containing at least 95% identical sequences to the heavy chain variable region CDR2 sequence of MEDI 8897), a heavy chain variable region CDR3 sequence (containing at least 95% identical sequences to the heavy chain variable region CDR3 sequence of MEDI 8897), a light chain variable region CDR1 sequence (containing at least 95% identical sequences to the light chain variable region CDR1 sequence of MEDI 8897), a light chain variable region CDR2 sequence (containing at least 95% identical sequences to the light chain variable region CDR2 sequence of MEDI 8897), and a light chain variable region CDR3 sequence (containing at least 95% identical sequences to the light chain variable region CDR3 sequence of MEDI 8897).

[0064] The present invention also provides a formulation comprising:

[0065] i. An anti-RSV monoclonal antibody having a heavy chain variable region CDR1 sequence (different from the heavy chain variable region CDR1 sequence of MEDI 8897 by no more than 1 amino acid), a heavy chain variable region CDR2 sequence (different from the heavy chain variable region CDR2 sequence of MEDI 8897 by no more than 1 amino acid), a heavy chain variable region CDR3 sequence (different from the heavy chain variable region CDR3 sequence of MEDI 8897 by no more than 1 amino acid), a light chain variable region CDR1 sequence (different from the light chain variable region CDR1 sequence of MEDI 8897 by no more than 1 amino acid), a light chain variable region CDR2 sequence (different from the light chain variable region CDR2 sequence of MEDI 8897 by no more than 1 amino acid), and a light chain variable region CDR3 sequence (different from the light chain variable region CDR3 sequence of MEDI 8897 by no more than 1 amino acid);

[0066] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0067] iii. Sugar as defined anywhere in this document;

[0068] iv. One or more buffers as defined anywhere in this document; and

[0069] v. optionally, as defined anywhere in this document, a surfactant.

[0070] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0071] The present invention also provides a formulation comprising:

[0072] i. An anti-RSV monoclonal antibody with 6 CDRs of MEDI 8897;

[0073] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0074] iii. Sugar as defined anywhere in this document;

[0075] iv. One or more buffers as defined anywhere in this document; and

[0076] v. optionally, as defined anywhere in this document, a surfactant.

[0077] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0078] Therefore, the present invention provides a formulation comprising:

[0079] i. Anti-RSV monoclonal antibody with VH and VL sequences of MEDI 8897;

[0080] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0081] iii. Sugar as defined anywhere in this document;

[0082] iv. One or more buffers as defined anywhere in this document; and

[0083] v. optionally, as defined anywhere in this document, a surfactant.

[0084] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher, and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0085] Therefore, the present invention provides a formulation comprising:

[0086] i. An anti-RSV monoclonal antibody containing the full-length heavy and light chain sequences of MEDI 8897;

[0087] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0088] iii. Sugar as defined anywhere in this document;

[0089] iv. One or more buffers as defined anywhere in this document; and

[0090] v. optionally, as defined anywhere in this document, a surfactant.

[0091] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0092] Therefore, the present invention provides a formulation comprising:

[0093] i. Anti-RSV monoclonal antibody MEDI 8897;

[0094] ii. Ionic excipients (e.g., salts) as defined anywhere in this document;

[0095] iii. Sugar as defined anywhere in this document;

[0096] iv. One or more buffers as defined anywhere in this document; and

[0097] v. optionally, as defined anywhere in this document, a surfactant.

[0098] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0099] This invention provides a formulation comprising:

[0100] i. Anti-RSV monoclonal antibody;

[0101] ii. Arginine hydrochloride;

[0102] iii. Sucrose;

[0103] iv. L-histidine / L-histidine hydrochloride monohydrate; and

[0104] v. Polysorbate-80

[0105] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml), and the arginine hydrochloride is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5. In one embodiment, the RSV monoclonal antibody has 6 CDRs of MEDI 8897. In one embodiment, the RSV monoclonal antibody has the VH and VL sequences of MEDI 8897. In one embodiment, the RSV monoclonal antibody has the full-length heavy and light chain sequences of MEDI 8897. In one embodiment, the RSV monoclonal antibody is MEDI 8897.

[0106] This invention provides a formulation comprising:

[0107] i. Anti-RSV monoclonal antibody;

[0108] ii. Arginine hydrochloride;

[0109] iii. Sucrose;

[0110] iv. L-histidine / L-histidine hydrochloride monohydrate; and

[0111] v. Polysorbate-80

[0112] The monoclonal antibody is present at a concentration of about 100 mg / mL, and the arginine hydrochloride is present at a concentration of about 80 mM, and the formulation has a pH of about 6.0. Sucrose preferably has a concentration of about 120 mM. L-histidine / L-histidine hydrochloride monohydrate preferably has a concentration of about 30 mM. Polysorbate preferably has a concentration between 0.02% and 0.04%, more preferably 0.02%. In one embodiment, the RSV monoclonal antibody has the six CDRs of MEDI 8897. In one embodiment, the RSV monoclonal antibody has the VH and VL sequences of MEDI 8897. In one embodiment, the RSV monoclonal antibody has the full-length heavy and light chain sequences of MEDI 8897. In one embodiment, the RSV monoclonal antibody is MEDI 8897.

[0113] The formulations described herein may also contain one or more additional excipients, including, for example, one or more sugars, salts, amino acids, polyols, chelating agents, emulsifiers and / or preservatives.

[0114] The formulation of the present invention is preferably a pharmaceutical formulation.

[0115] This invention provides isolated monoclonal antibodies having the following light chain CDR sequences: CDR-L1 of SEQ ID NO:3, CDR-L2 of SEQ ID NO:4, and CDR-L3 of SEQ ID NO:5, and the following heavy chain CDR sequences: CDR-H1 of SEQ ID NO:6, CDR-H2 of SEQ ID NO:7, and CDR-H3 of SEQ ID NO:8. This invention also provides isolated monoclonal antibodies having the light chain variable region sequence of SEQ ID NO:9 and the heavy chain variable region sequence of SEQ ID NO:10. Furthermore, this invention provides isolated monoclonal antibodies having three CDRs of the light chain variable region of the sequence of SEQ ID NO:9 and three CDRs of the heavy chain variable region sequence of SEQ ID NO:10. Finally, this invention provides isolated monoclonal antibodies having the light chain sequence of SEQ ID NO:1 and the heavy chain sequence of SEQ ID NO:2. Preferably, the antibody is an IgG1 antibody. This invention provides novel and inventive monoclonal antibodies, each based on the novel and inventive monoclonal antibody MEDI-8897 disclosed herein. This invention provides hybridomas capable of expressing the isolated monoclonal antibody according to the invention. This invention provides nucleic acids encoding the isolated monoclonal antibody according to the invention. This invention provides expression vectors comprising the nucleic acids according to the invention. This invention provides host cells comprising the expression vector according to the invention. This invention provides a method for recombinantly producing the isolated monoclonal antibody according to the invention, the method comprising culturing host cells under conditions of antibody expression. This invention provides isolated monoclonal antibodies as defined herein for use as a pharmaceutical. This invention provides isolated monoclonal antibodies as defined herein for use in the treatment of a disease. This invention provides a method for treating a disease in a subject, the method comprising administering the subject an isolated monoclonal antibody as defined herein. This invention provides pharmaceutical compositions comprising isolated monoclonal antibodies as defined herein. This invention provides pharmaceutical compositions as defined herein for use as a pharmaceutical. This invention provides pharmaceutical compositions as defined herein for use in the treatment of a disease. This invention provides a method for treating a disease in a subject, the method comprising administering the subject a pharmaceutical composition as defined herein.

[0116] This invention provides pharmaceutical formulations as described anywhere herein for use as medicines.

[0117] This invention provides pharmaceutical formulations as described anywhere herein for use in the treatment or prevention of disease.

[0118] This invention provides a method for treating or preventing disease in a subject, the method comprising administering to the subject a pharmaceutical preparation as described anywhere herein. This invention also provides a method for treating or preventing disease in a subject by administering to the subject a therapeutically effective amount of a pharmaceutical preparation as described anywhere herein.

[0119] In one embodiment, the subject is a human. In one embodiment, the subject is a human under 2 years of age. In one embodiment, the subject is a premature infant under 6 weeks of age.

[0120] In one embodiment, the disease is a lower respiratory tract disease.

[0121] In one embodiment, the disease is RSV infection. Attached Figure Description

[0122] Figure 1 The heavy chain nucleotide sequence and translation of MEDI8897 are shown.

[0123] Figure 2 The MEDI8897 light chain nucleotide sequence and translation are shown.

[0124] Figure 3 The stability of MEDI8897 formulations was demonstrated over a 3-month period at 5°C, 25°C, and 40°C. Detailed Implementation

[0125] Formulating many monoclonal antibodies presents challenges due to their pI (pI) being close to physiological pH (i.e., the desired pH typically used for human administration). This invention provides, for the first time, the motivation to formulate these “difficult” antibodies into pharmaceuticals. Prior to this invention, such antibodies had likely been excluded from pharmaceutical candidate selection due to the lack of suitable formulation strategies for commercially useful concentrations and pH ranges.

[0126] This invention provides a novel monoclonal antibody formulation. Suitably, the formulation has a pH within 1.0 pH unit below the isoelectric point of the monoclonal antibody.

[0127] The present invention provides a formulation comprising: (i) an anti-RSV monoclonal antibody; and (ii) an ionic excipient (e.g., a salt); wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or higher and the ionic excipient is present at a concentration between 50 and 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0128] The present invention further provides a formulation comprising: (i) an anti-RSV monoclonal antibody; and (ii) an ionic excipient (e.g., a salt); wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5; and wherein the aggregation rate of the monoclonal antibody in the formulation is reduced compared to the aggregation rate of the same antibody in the same formulation but without the ionic excipient.

[0129] Aggregation rate can be measured according to standard techniques as described herein. Surprisingly, formulations according to the invention have been shown to have good stability and reduced self-aggregation, for example, showing ≤2.0% aggregation when stored at room temperature for 3 months. Therefore, the present invention provides the use of ionic excipients in antibody formulations to improve the stability of antibodies in such formulations. The present invention further provides the use of ionic excipients in antibody formulations to reduce the self-aggregation of antibodies in such formulations.

[0130] Antibody

[0131] The formulations of the present invention are particularly suitable for anti-RSV antibodies having a low or neutral pI (e.g., in the range of about pH 5.5 to about pH 7.5, about pH 6.0 to about pH 7.5, about pH 6.3 to about pH 7.5, or about pH 6.4 to about pH 7.5). The pI of the antibody can be measured according to standard techniques, for example by capillary isoelectric focusing (cIEF). Therefore, the present invention provides a formulation comprising: (i) a monoclonal antibody having a low or neutral pI; and (ii) an ionic excipient; wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5. The present invention further provides a formulation comprising: (i) a monoclonal antibody having a low or neutral pI; and (ii) an ionic excipient; wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or higher and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5; and wherein the aggregation rate of the monoclonal antibody in the formulation is lower than that of the same formulation but without the ionic excipient.

[0132] In one embodiment, the monoclonal antibody has a pI in the range of pH 6.4 to pH 7.5.

[0133] In one embodiment, the monoclonal antibody is an IgG1 or IgG4 monoclonal antibody. Most preferably, the monoclonal antibody is an IgG1 monoclonal antibody. Therefore, the present invention provides a formulation comprising: (i) an IgG1 monoclonal anti-RSV antibody having a low or neutral pI; and (ii) an ionic excipient; wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5. Therefore, the present invention further provides a formulation comprising: (i) an IgG1 monoclonal antibody having a low or neutral pI; and (ii) an ionic excipient; wherein the monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml) and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5; and wherein the aggregation rate of the monoclonal antibody in the formulation is reduced compared to the aggregation rate of the same antibody in the same formulation but without the ionic excipient.

[0134] Specifically, the present invention relates to formulations comprising antibody MEDI-8897 or a variant thereof. In one embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 70% identical sequences to the heavy chain variable region CDR1 sequence of MEDI 8897), a heavy chain variable region CDR2 sequence (containing at least 70% identical sequences to the heavy chain variable region CDR2 sequence of MEDI 8897), a heavy chain variable region CDR3 sequence (containing at least 70% identical sequences to the heavy chain variable region CDR3 sequence of MEDI 8897), a light chain variable region CDR1 sequence (containing at least 70% identical sequences to the light chain variable region CDR1 sequence of MEDI 8897), a light chain variable region CDR2 sequence (containing at least 70% identical sequences to the light chain variable region CDR2 sequence of MEDI 8897), and a light chain variable region CDR3 sequence (containing at least 70% identical sequences to the light chain variable region CDR3 sequence of MEDI 8897).

[0135] In another embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 80% of the same sequence as the heavy chain variable region CDR1 sequence of MEDI8897), a heavy chain variable region CDR2 sequence (containing at least 80% of the same sequence as the heavy chain variable region CDR2 sequence of MEDI8897), a heavy chain variable region CDR3 sequence (containing at least 80% of the same sequence as the heavy chain variable region CDR3 sequence of MEDI8897), a light chain variable region CDR1 sequence (containing at least 80% of the same sequence as the light chain variable region CDR1 sequence of MEDI8897), a light chain variable region CDR2 sequence (containing at least 80% of the same sequence as the light chain variable region CDR2 sequence of MEDI8897), and a light chain variable region CDR3 sequence (containing at least 80% of the same sequence as the light chain variable region CDR3 sequence of MEDI8897).

[0136] In one embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 90% identical sequences to the heavy chain variable region CDR1 sequence of MEDI8897), a heavy chain variable region CDR2 sequence (containing at least 90% identical sequences to the heavy chain variable region CDR2 sequence of MEDI8897), a heavy chain variable region CDR3 sequence (containing at least 90% identical sequences to the heavy chain variable region CDR3 sequence of MEDI8897), a light chain variable region CDR1 sequence (containing at least 90% identical sequences to the light chain variable region CDR1 sequence of MEDI8897), a light chain variable region CDR2 sequence (containing at least 90% identical sequences to the light chain variable region CDR2 sequence of MEDI8897), and a light chain variable region CDR3 sequence (containing at least 90% identical sequences to the light chain variable region CDR3 sequence of MEDI8897).

[0137] In one embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (containing at least 95% identical sequences to the heavy chain variable region CDR1 sequence of MEDI8897), a heavy chain variable region CDR2 sequence (containing at least 95% identical sequences to the heavy chain variable region CDR2 sequence of MEDI8897), a heavy chain variable region CDR3 sequence (containing at least 95% identical sequences to the heavy chain variable region CDR3 sequence of MEDI8897), a light chain variable region CDR1 sequence (containing at least 95% identical sequences to the light chain variable region CDR1 sequence of MEDI8897), a light chain variable region CDR2 sequence (containing at least 95% identical sequences to the light chain variable region CDR2 sequence of MEDI8897), and a light chain variable region CDR3 sequence (containing at least 95% identical sequences to the light chain variable region CDR3 sequence of MEDI8897).

[0138] In another embodiment, the anti-RSV monoclonal antibody has a heavy chain variable region CDR1 sequence (different from the heavy chain variable region CDR1 sequence of MEDI 8897 by no more than 1 amino acid), a heavy chain variable region CDR2 sequence (different from the heavy chain variable region CDR2 sequence of MEDI 8897 by no more than 1 amino acid), a heavy chain variable region CDR3 sequence (different from the heavy chain variable region CDR3 sequence of MEDI 8897 by no more than 1 amino acid), a light chain variable region CDR1 sequence (different from the light chain variable region CDR1 sequence of MEDI 8897 by no more than 1 amino acid), a light chain variable region CDR2 sequence (different from the light chain variable region CDR2 sequence of MEDI 8897 by no more than 1 amino acid), and a light chain variable region CDR3 sequence (different from the light chain variable region CDR3 sequence of MEDI 8897 by no more than 1 amino acid).

[0139] In another embodiment, the anti-RSV monoclonal antibody has 6 CDRs of MEDI 8897.

[0140] In another embodiment, the anti-RSV monoclonal antibody has 6 CDRs of MEDI 8897 and binds with 70% identity to the frame region sequence of MEDI8897.

[0141] In another embodiment, the anti-RSV monoclonal antibody has 6 CDRs of MEDI 8897 and binds with 80% identity to the frame region sequence of MEDI8897.

[0142] In another embodiment, the anti-RSV monoclonal antibody has 6 CDRs of MEDI 8897 and binds with 90% identity to the frame region sequence of MEDI8897.

[0143] In another embodiment, the anti-RSV monoclonal antibody has 6 CDRs of MEDI 8897 and binds with 95% identity to the frame region sequence of MEDI8897.

[0144] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 1 below:

[0145] Position relative to SEQ ID NO:2 amino acids 28 P 30 R 31 N 37 L 61 A 81 I 82 H 84 I 106 T

[0146] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 2 below:

[0147] Position relative to SEQ ID NO:2 amino acids 28 P 30 R 31 N 61 A 106 T

[0148] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 3 below:

[0149] Position relative to SEQ ID NO:2 amino acids 28 P 30 R 31 N 45 L 61 A 106 T

[0150] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 4 below:

[0151] Position relative to SEQ ID NO:2 amino acids 19 K 23 K 28 T 29 F 30 S 31 N 45 L 61 A 106 T

[0152] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 5 below:

[0153] Position relative to SEQ ID NO:2 amino acids 28 P 106 T

[0154] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 6 below:

[0155] Position relative to SEQ ID NO:2 amino acids 28 P 106 T 109 R

[0156] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 7 below:

[0157] Position relative to SEQ ID NO:2 amino acids 19 K 23 K 77 S 82 H 98 R 106 T

[0158] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 8 below:

[0159] Position relative to SEQ ID NO:2 amino acids 19 K 23 K 82 H 106 T

[0160] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 9 below:

[0161] Position relative to SEQ ID NO:2 amino acids 19 K 23 K 77 S 106 T

[0162] In one embodiment, the anti-RSV monoclonal antibody has six CDRs of MEDI 8897, combined with alterations to the heavy chain region of MEDI 8897 selected from those shown in Table 10 below:

[0163] Position relative to SEQ ID NO:2 amino acids 19 K 23 K 77 S 82 H 106 T

[0164] In another embodiment, the anti-RSV monoclonal antibody has the VH and VL sequences of MEDI 8897.

[0165] Preferably, the antibody is an IgG1 antibody.

[0166] Preferably, the anti-RSV monoclonal antibody as defined anywhere in this document has the heavy chain variable region CDR3 sequence ETALVVSETYLPHYFDN (SEQ ID NO:8).

[0167] In one embodiment of the anti-RSV monoclonal antibody as defined anywhere herein, the CDR3 of the heavy chain does not contain the sequence ETALVVS*TYLPHYFDN. Preferably, any modified heavy chain variable region CDR3 sequence in the anti-RSV monoclonal antibody as defined anywhere herein (i.e., a variant of SEQ ID NO:8) retains E:ETALVVS*TYLPHYFDN at the position marked with *. Preferably, any modified heavy chain variable region CDR3 sequence in the anti-RSV monoclonal antibody as defined anywhere herein (i.e., a variant of SEQ ID NO:8) does not have T:ETALVVS*TYLPHYFDN at the position marked with *.

[0168] In one embodiment, the anti-RSV monoclonal antibody has a modified Fc region in which one or more amino acids have been inserted, deleted, or substituted to increase the antibody's half-life. In one embodiment, the anti-RSV monoclonal antibody has three amino acid substitutions (M252Y / S254T / T256E; referred to as YTE) in the CH2 region of the Fc domain.

[0169] In another embodiment, the anti-RSV monoclonal antibody has the full-length heavy and light chain sequences of MEDI 8897. Anti-RSV antibodies include antibody functional portions, such as antibodies or antigen-binding fragments, variants, or derivatives thereof. Anti-RSV antibodies further include, but are not limited to, polyclonal antibodies, monoclonal antibodies, human antibodies, humanized or chimeric antibodies, single-chain antibodies, bispecific antibodies, epitope-binding fragments such as Fab, Fab', and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments containing VL or VH domains, and fragments generated from Fab expression libraries. ScFv molecules are known in the art and described, for example, in U.S. Patent 5,892,019. The immunoglobulin or antibody molecules covered by this disclosure can be any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecules.

[0170] antibody concentration

[0171] Suitable, monoclonal antibodies are administered at concentrations of approximately 50 mg / ml to approximately 300 mg / ml, approximately 50 mg / ml to approximately 200 mg / ml, approximately 100 mg / ml to approximately 200 mg / ml, approximately 100 mg / ml to approximately 165 mg / ml, approximately 100 mg / ml to approximately 150 mg / ml, or approximately 50 mg / ml, approximately 75 mg / ml, approximately 100 mg / ml, approximately 105 mg / ml, approximately 110 mg / ml, approximately 115 mg / ml, approximately 120 mg / ml, approximately 125 mg / ml. The concentrations of about 130 mg / ml, about 135 mg / ml, about 140 mg / ml, about 145 mg / ml, about 150 mg / ml, about 155 mg / ml, about 160 mg / ml, about 165 mg / ml, about 170 mg / ml, about 175 mg / ml, about 180 mg / ml, about 185 mg / ml, about 190 mg / ml, about 195 mg / ml, or about 200 mg / ml (inclusive) are present in the formulations described herein.

[0172] Suitably, the monoclonal antibody is present in the formulations described herein at a concentration of about 100 mg / ml to about 165 mg / ml.

[0173] pH

[0174] Suitably, to provide near-optimal or optimal chemical stability (hydrolysis, deamidation, isomerization), the formulations described herein have a pH in the range of about pH 5.5 to about pH 6.5. In one embodiment, the formulations described herein have a pH in the range of about pH 5.7 to about pH 6.3. In another embodiment, the formulations described herein have a pH in the range of about pH 5.7 to about pH 6.1. Preferred formulations have a pH of about 5.8. Other preferred formulations have a pH of about 6.0.

[0175] Suitably, the formulations described herein have a pH in the range of about pH 5.5 to about pH 6.0, about pH 5.7 to about pH 6.0, or about pH 5.5, about pH 5.6, about pH 5.7, about pH 5.8, about pH 5.9, about pH 6.0, about pH 6.1, about pH 6.2, about pH 6.3, about pH 6.4, or about pH 6.5. In the embodiments, the formulations provided herein have a pH of 5.7 to 6.0, and more suitably, the formulation has a pH of about 5.8.

[0176] A pH close to approximately 7.4 is also desirable for the tolerability of the preparation at the injection site.

[0177] Ionic excipients

[0178] Exemplary ionic excipients used in formulations include salts and charged amino acids. Ionic excipients may comprise a combination of salts and charged amino acids.

[0179] Exemplary charged amino acids include arginine and lysine.

[0180] Exemplary salts include salts of charged amino acids, such as succinates, acetates, and sulfates of arginine and lysine.

[0181] Furthermore, exemplary salts are those described herein, including but not limited to: sodium chloride and other salts of sodium, potassium, calcium, magnesium, etc., such as chlorides, carbonates, sulfates, acetates, gluconates, lactates, malates, and other adjuvants conventionally used in the field of parenteral administration. Suitably, the salt is selected from sodium chloride (NaCl), lysine hydrochloride, and arginine hydrochloride. In one embodiment, the salt is NaCl. In another embodiment, the salt is arginine hydrochloride.

[0182] The concentration range of the ionic excipient (suitable salt) in the pharmaceutical formulations described herein is typically from about 50 mM to about 300 mM, more preferably from about 50 mM to about 200 mM, from about 50 mM to about 150 mM, from about 50 mM to about 100 mM, from about 60 mM to about 80 mM, or from about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, or about 100 mM, including any range or value within these ranges. In one embodiment, the ionic excipient is present at a concentration of from about 50 mM to about 125 mM.

[0183] In one embodiment, the ionic excipient is present at a concentration of about 50 mM to about 100 mM.

[0184] In one embodiment, the ionic excipient is present at a concentration of about 75 mM to about 100 mM.

[0185] In suitable embodiments, the salt is NaCl, with a concentration of, for example, about 50 mM to about 100 mM, suitably about 70 mM.

[0186] In suitable embodiments, the salt is arginine hydrochloride at a concentration of, for example, about 50 mM to about 100 mM, suitably about 80 mM.

[0187] buffer

[0188] The formulations described herein suitably comprise one or more buffers. As used herein, "buffer" refers to an excipient used to maintain the pH of the formulation. Exemplary buffers used in the formulations provided herein include, but are not limited to: histidine, histidine hydrochloride (histidine HCl), sodium succinate, sodium acetate, sodium acetate / acetic acid, sodium phosphate, citrate, phosphate, succinate, glycine, and acetate. In one embodiment, the buffer used in the formulations described herein is sodium acetate / acetic acid. In one embodiment, this or these buffers are buffers containing histidine. In one embodiment, this or these buffers are selected from buffers containing histidine succinate, histidine acetate, histidine citrate, histidine chloride, or histidine sulfate. In one embodiment, this or these buffers are histidine, histidine hydrochloride, or a combination thereof (histidine / histidine hydrochloride). In one embodiment, this or these buffers are L-histidine / L-histidine hydrochloride monohydrate.

[0189] The concentration range of the buffer (suitably sodium acetate / acetic acid) in the pharmaceutical formulations described herein is generally from about 10 mM to about 100 mM, more preferably from about 15 mM to about 80 mM, from about 25 mM to about 75 mM, from about 30 mM to about 60 mM, from about 40 mM to about 60 mM, from about 40 mM to about 50 mM, or from about 15 mM, from about 20 mM, from about 25 mM, from about 30 mM, from about 35 mM, from about 40 mM, from about 45 mM, from about 50 mM, from about 55 mM, from about 60 mM, from about 65 mM, from about 70 mM, or from about 75 mM, including any range or value within these ranges.

[0190] In one embodiment, the buffer is L-histidine / L-histidine hydrochloride monohydrate at a concentration of, for example, about 10 mM to about 50 mM, suitably about 30 mM.

[0191] The pH of the buffer is preferably in the range of pH 5.5 to pH 6.0.

[0192] It should be understood that the buffer itself can be an ionic excipient. Therefore, in one embodiment, the buffer is an ionic excipient. In this embodiment, the concentration of the buffer should be higher than 50 mM, consistent with the concentration of ionic excipients disclosed herein. The preferred concentration of the buffer in this embodiment is as discussed anywhere herein regarding ionic excipients.

[0193] In other words, in one embodiment, the ionic excipient is also used as a buffer in the formulation. In this embodiment, an additional buffer may or may not be present.

[0194] Sugars and surfactants

[0195] Suitably, the formulations described herein comprise sugars, such as, but not limited to, trehalose, lactose, mannitol, melibiose, maltotriose, raffinose, mannotriose, stachyose, and sucrose. In other embodiments, polyols, such as ternary or higher molecular weight sugar alcohols, such as glycerin, dextran, erythritol, glycerol, arabinitol, xylitol, sorbitol, and mannitol, may be used. Examples of reducing sugars include, but are not limited to, glucose, maltose, maltulose, isomaltulose, and lactulose. Examples of non-reducing sugars include, but are not limited to, trehalose, and non-reducing glycosides selected from polyhydroxy compounds of sugar alcohols and other linear polyols. Examples of sugar alcohols include, but are not limited to, monoglycosides, and compounds obtained by the reduction of disaccharides (e.g., lactose, maltose, lactulose, and maltulose). The side group of the glycoside may be glycosidic or galactoside. Further examples of sugar alcohols include, but are not limited to, glucositol, maltitol, lactitol, and isomaltulose. In one embodiment, the sugar is selected from the group consisting of trehalose, lactose, mannitol, raffinose, and sucrose. In a specific embodiment, trehalose is used as a sugar in the formulations described herein. In a specific embodiment, sucrose is used as a sugar in the formulations described herein.

[0196] Suitablely, the amount of sugar (e.g., trehalose) in the formulations described herein is from about 1% (w / v) to about 10% (w / v). Unless otherwise stated, percentages (%) of components are used herein to express weight / volume (w / v)%. In exemplary embodiments, the amount of sugar in the pharmaceutical formulations described herein is from about 1% (w / v) to about 8% (w / v), or from about 2% (w / v) to about 6% (w / v), from about 2% (w / v) to about 5% (w / v), from about 3% (w / v) to about 5% (w / v), or from about 1% (w / v), from about 2% (w / v), from about 3% (w / v), from about 4% (w / v), from about 5% (w / v), from about 6% (w / v), from about 7% (w / v), from about 8% (w / v), from about 9% (w / v), or from about 10% (w / v), including any values ​​and ranges within these ranges.

[0197] The formulations described herein suitably contain surfactants.

[0198] The term "surfactant" as used in this article refers to organic substances with an amphiphilic structure; that is, they consist of groups with opposite solubility tendencies, typically oil-soluble hydrocarbon chains and water-soluble ionic groups. Surfactants can be classified into anionic, cationic, and nonionic surfactants based on the charge of their active moieties. Surfactants are commonly used as wetting agents, emulsifiers, solubilizers, and dispersants in various pharmaceutical formulations and preparations of biomaterials. Pharmaceutically acceptable surfactants (such as polysorbates (e.g., polysorbate 20, 40, 60, or 80); poloxamer (e.g., poloxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or octadecyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or octadecyl-sarcosine; linoleyl-, myristyl, or cetyl-betaine; lauroamide propyl-, cocamidopropyl-, linoleamide propyl-, myristamide propyl-, palmitamide propyl-, or isostearamide propyl-betaine (e.g., lauroylaminopropyl); myristylaminopropyl-, palmitamide propyl-, or isostearamide propyl-dimethylamine; sodium methylcocoyl taurate or disodium methyloleylenyl taurate; and the MONAQUA™ series (Mona Industries, Inc.) Industries, Inc. (Patterson, NJ), polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., Pluronics, PF68, etc.) can be used in the pharmaceutical formulations described herein. Suitably, the surfactant is a polysorbate, including, for example, polysorbate-20, polysorbate-40, polysorbate-60, and polysorbate-80. In one embodiment, the surfactant is polysorbate-80.

[0199] Suitably, the formulations described herein comprise about 0.001% to about 0.5% (w / v), more preferably about 0.002% to about 0.1% of a surfactant (suitably polysorbate-80), such as about 0.01% to about 0.2%, about 0.02% to about 0.1%, about 0.02% to about 0.07%, about 0.03% to about 0.06%, about 0.04% to about 0.06%, or about 0.00%. Surfactants of 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045%, about 0.05%, about 0.055%, about 0.060%, about 0.065%, about 0.07%, about 0.075%, about 0.08%, about 0.085%, about 0.09%, about 0.095%, or about 0.1%, including any range or value within these ranges.

[0200] The formulations described herein suitably include surfactants and sugars. The formulations described herein suitably include surfactants and one or more buffers. The formulations described herein suitably include sugars and one or more buffers. The formulations described herein suitably include surfactants, sugars, and one or more buffers.

[0201] The formulations described herein may also contain one or more additional excipients, including, for example, one or more sugars, salts, amino acids, polyols, chelating agents, emulsifiers and / or preservatives.

[0202] Drug Use

[0203] The formulations of the present invention are preferably pharmaceutical formulations. Suitably, the pharmaceutical formulations described herein are "pharmaceutical acceptable" and will therefore meet the necessary approval requirements required by federal or state regulatory agencies or listed in the United States Pharmacopeia, European Pharmacopeia or other recognized pharmacopoeias for use in animals, and more specifically in humans.

[0204] This invention provides pharmaceutical formulations as described anywhere herein for use as a medicine. This invention provides pharmaceutical formulations as described anywhere herein for use in the treatment of a disease. This invention provides a method of treating a disease in a subject, the method comprising administering the subject a pharmaceutical formulation as described anywhere herein. This invention also provides a method of treating a subject by administering a therapeutically effective amount of a pharmaceutical formulation as described anywhere herein.

[0205] As used herein, the term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, such as, but not limited to, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. In one embodiment, the subject is a human.

[0206] This invention provides a method for treating or preventing disease in a subject, the method comprising administering to the subject a pharmaceutical preparation as described anywhere herein. This invention also provides a method for treating or preventing disease in a subject by administering to the subject a therapeutically effective amount of a pharmaceutical preparation as described anywhere herein.

[0207] In one embodiment, the subject is a human. In one embodiment, the subject is a human under 2 years of age. In one embodiment, the subject is a premature infant under 6 weeks of age.

[0208] In this embodiment, the preparation is administered to the subject subcutaneously or by injection.

[0209] Appropriately, the preparation is a liquid preparation or a frozen preparation.

[0210] This article also provides a method for preparing a pharmaceutical formulation, which includes preparing a pharmaceutical formulation as described herein and suitably loading the pharmaceutical formulation into a syringe to form a pre-filled syringe.

[0211] Suitable, the pharmaceutical preparations described herein are prepared in sterile water or suspended in sterile water for injection at the desired volume weight.

[0212] In exemplary embodiments, the pharmaceutical preparation has volumes of about 0.1 mL to about 20.0 mL, more preferably about 0.5 mL to about 15.0 mL, about 0.5 mL to about 12.0 mL, about 1.0 mL to about 10.0 mL, about 1.0 mL to about 5.0 mL, about 1.0 mL to about 2.0 mL, or about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, or about 1.1 mL. Volumes of approximately 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, 2.0 mL, 2.1 mL, 2.2 mL, 2.3 mL, 2.4 mL, 2.5 mL, 2.6 mL, 2.7 mL, 2.8 mL, 2.9 mL, or 3.0 mL, including any range or value within these ranges.

[0213] Although, in suitable embodiments, the pharmaceutical formulations described herein are liquid formulations, i.e., pharmaceutical formulations prepared in sterile water or water for injection (WFI), the pharmaceutical formulations may also be frozen formulations or previously freeze-dried formulations.

[0214] The present invention also provides freeze-dried cakes that can be reconstituted using only sterile water to form a formulation according to the invention as described herein. It should be understood that the antibody:ionic excipient ratio in the freeze-dried cake is the same as in the freeze-dried formulation. In one embodiment, the antibody:ionic excipient ratio is in the range of 450:1 to 40:1. When the formulation has been freeze-dried, the concentrations provided herein for the formulation are reconstituted concentrations, and therefore concentrations in the so-called "pharmaceutical product." For example, if a semi-reconstruction strategy is used (where half the volume of water removed during freeze-drying is recovered during reconstruction), the antibody concentration after reconstruction will be twice that before freeze-drying, i.e., twice the concentration in the so-called pre-freeze-dried "pharmaceutical substance" composition. Therefore, it should be understood that the present invention further provides compositions that can be freeze-dried to form freeze-dried cakes, wherein the freeze-dried cakes can be reconstituted using only sterile water to form a formulation according to the invention as described herein. Suitable reconstruction strategies are known to those skilled in the art. In the embodiments, it is desirable to prepare frozen formulations by providing a liquid pharmaceutical formulation as described herein and freezing the formulation under suitable conditions. For example, frozen formulations can be provided by freezing the liquid formulation to less than 0°C, more suitably to about -20°C, about -40°C, about -60°C, or suitably to about -80°C. Pharmaceutical formulations are also suitably prepared as liquid formulations and stored at about 2°C to about 8°C, or about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, or about 8°C.

[0215] Suitable schemes and methods for preparing freeze-dried pharmaceutical preparations from liquid and / or frozen preparations are known in the art.

[0216] Stability of preparations

[0217] In exemplary embodiments, the formulations described herein are stable at room temperature or in a temperature range of about 2°C to about 8°C, suitably at a temperature of about 5°C, for extended storage. As used herein, room temperature is typically in the range of about 22°C to about 25°C. Suitably, pharmaceutical formulations are stable after storage at about 2°C to about 8°C (e.g., 5°C) for at least six (6) months. As used herein, for storage (or “stability”), the term “stable” is used to indicate that the formulation resists aggregation, degradation, hemiantibody formation, and / or fragmentation. The stability of monoclonal antibodies can be assessed by the degree of aggregation, degradation, hemiantibody formation, or fragmentation, as measured by high performance size exclusion chromatography (HPSEC), static light scattering (SLS), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), urea unfolding technique, endogenous tryptophan fluorescence, differential scanning calorimetry, and / or ANS binding technique, compared to references.

[0218] The overall stability of pharmaceutical formulations containing monoclonal antibodies can be assessed by various immunological assays, including, for example, ELISA and radioimmunoassays using isolated antigen molecules.

[0219] As used herein, the phrase "low to undetectable aggregation levels" means, as measured by high-performance size exclusion chromatography (HPSEC) or static light scattering (SLS), that the pharmaceutical preparation contains no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, or no more than about 0.5% of aggregates by weight of protein. Suitably, the pharmaceutical preparation exhibits ≤5.0% aggregation, more preferably ≤4.0%, ≤3.0%, ≤2.0%, ≤1.0%, or 0.5% aggregation. Suitably, liquid pharmaceutical preparations and / or frozen pharmaceutical preparations exhibit ≤5.0% aggregation, more preferably ≤4.0%, ≤3.0%, ≤2.0%, ≤1.0%, or 0.5% aggregation.

[0220] As used herein, the term "low to undetectable fragmentation level" refers to a pharmaceutical formulation containing, for example, a single peak determined by HPSEC or reducing capillary gel electrophoresis (rCGE) containing equal to or greater than about 80%, about 85%, about 90%, about 95%, about 98%, or about 99% of total monoclonal antibody, representing undegraded monoclonal antibody or its non-degraded fragments, and without containing any other single peaks containing more than about 5%, more than about 4%, more than about 3%, more than about 2%, more than about 1%, or more than about 0.5% of the total monoclonal antibody. Fragmentation can be appropriately measured in IgG4 monoclonal antibodies.

[0221] Not wanting to be bound by theory, we believe that the reduced self-aggregation is due to improved colloidal stability, as demonstrated by the increase in the kD value.

[0222] In exemplary embodiments, the formulations described herein, based on visual observation, light scattering, turbidimetry, and turbidity measurement, exhibit reduced opalescence and decreased phase separation.

[0223] Referring to the accompanying drawings, further embodiments, features, and advantages of these embodiments are described in detail below, along with the structure and operation of the different embodiments.

[0224] Example

[0225] Example 1 - IgG1 formulation

[0226] MEDI8897 is a human IgG1κ-YTE monoclonal antibody against the RSV-F protein. Three amino acid substitutions (M252Y / S254T / T256E; referred to as YTE) were introduced into the CH2 region of the Fc domain to increase the serum half-life of MEDI8897. Figure 1 and Figure 2 The sequence information for MEDI8897 is provided. The pI of MEDI8897, measured by cIEF, is 6.4–6.7, with the main peak at 6.4. The pI overlaps with the range of formulation buffers (5.5–6.5), indicating potential issues with manufacturing, formulation, and storage stability.

[0227] The thermal stability of MEDI8897 was measured using differential scanning calorimetry. The results showed that Tm1 was 61℃, while Tm2 was 82℃. Tm1 at 61℃ meets the CDTP standard of Tm1 > 50℃.

[0228] Stability Summary

[0229] Phase separation was observed at 2–8 °C after MEDI8897 was received in the default developing buffer (25 mM histidine, 7% sucrose, pH 6.0). The supernatant layer had a protein concentration of 75 mg / ml, while the sublayer had 125 mg / ml. Upon equilibration at 25 °C, the two distinct phases disappeared, and only a single phase was observed. The phase separation at 2–8 °C was attributed to the formulation pH of MEDI8897 being close to 6.0. Investigative studies were initiated to find a more suitable formulation buffer for the stability assessment of MEDI8897, targeting conditions that maintain the solubility of MEDI8897 (at 100 mg / ml) and prevent phase separation.

[0230] At pH < 5.9 or > 6.7, formulation in the default developer buffer (25 mM histidine, 7% sucrose) alleviated phase separation. Adding 75 mM NaCl to the developer buffer between pH 5.0 and 6.7 also alleviated phase separation. Finally, acetate and phosphate buffers with pH values ​​deviating from the pI also alleviated phase separation. Based on these screening studies and prior knowledge of mAbs with pIs within the formulation space, alternative developer buffers (25 mM His / HisHCl, 75 mM NaCl, 4% sucrose, 0.02% PS80, pH 6.0) were selected for evaluation.

[0231] kD research

[0232] For the first kD screening, all samples were evaluated at 25°C in a 25 mM histidine pH 5.5 base buffer ranging from 2–10 mg / ml. This buffer was chosen instead of pH 6.0 because MEDI8897 is more soluble at pH 5.5, which is beneficial for DLS measurements sensitive to insoluble particles. Ionic excipients, including arginine-HCl, lysine-HCl, and NaCl, were evaluated at concentrations of 10, 25, 50, 75, and 100 mM. Additionally, proline, alanine, Na₂SO₄, and histidine were evaluated only at a concentration of 100 mM. Finally, 2%, 4%, and 6% sucrose were evaluated to determine whether sucrose affected protein-protein interactions. All conditions were compared to a buffer control (25 mM histidine, pH 5.5).

[0233] The control samples showed varying protein-protein interactions, with the hydrodynamic radius increasing from 6.2 to 7.8 nm across the 2–10 mg / ml concentration range. As demonstrated by the lack of increase in hydrodynamic size across the 2–10 mg / ml concentration range, arginine-HCl, lysine-HCl, and NaCl showed a reduction in protein-protein interactions starting at 25 mM. No further effects were observed between 25 and 100 mM. At 100 mM, proline and alanine showed similar PPIs to the control, while Na2SO4 and histidine alleviated PPI. Finally, sucrose concentration showed no effect on PPI. These data suggest that charged excipients (Arg-HCl, Lys-HCl, histidine, and Na2SO4) alleviate protein-protein interactions, while neutral excipients (sucrose, proline, and alanine) do not alleviate PPI. Therefore, the addition of ionic excipients at pH 5.5 reduced phase separation at 100 mg / ml.

[0234] Stability assessment at 40℃

[0235] Based on kD screening, several conditions were selected for stability assessment at 40°C. Table 11 summarizes the formulation conditions and degradation rates observed at 40°C over one month.

[0236] Table 11 Stability rate at 40℃, formulation screening 1 - excipient screening

[0237] serial number excipient Concentration (mM) %Mon / mo %Agg / mo %Frag / mo 1 NaCl 25 -5.9 4.2 1.8 2 NaCl 75 -6.1 4.1 1.9 3 NaCl 95 -5.4 3.5 1.9 4 NaCl 120 -5.4 3.5 1.9 5 Arg-HCl 25 -5.4 3.5 1.8 6 Arg-HCl 75 -4.8 2.8 2.0 7 Arg-HCl 95 -4.5 2.6 1.9 8 Arg-HCl 120 -4.8 2.8 2.0 9 Lys-HCl 25 -5.7 3.9 1.9 10 Lys-HCl 75 -5.0 2.7 2.3 11 Lys-HCl 95 -5.1 3.1 2.0 12 Lys-HCl 120 -4.9 2.9 2.0

[0238] The buffer base used in this study was 25 mM histidine (pH 6.0).

[0239] This study demonstrates that arginine and lysine have a stronger stabilizing effect than NaCl. Furthermore, 75 mM and above appear to provide stability (anti-aggregation). Based on this study, arginine was selected as the most lyo-friendly stabilizing excipient and will be used in the next set of studies.

[0240] Drug product stability on final Lyo cycle / representative material

[0241] Stability was assessed in formulation science to complement IND-enabling stability studies, as this is the first representative material to complete the lyophilization step. Data were collected for three months for a reconstituted formulation at a concentration of 100 mg / ml in 30 mM L-histidine / L-histidine hydrochloride monohydrate, 80 mM L-arginine hydrochloride, 120 mM sucrose, and 0.04% (w / v) polysorbate 80 (pH 6.0). Results are shown in… Figure 3 The product showed almost no change when stored at 2-8°C for 3 months, confirming the suitability of the formulation and Lyo cycle for clinical use. Therefore, these data indicate that the formulation provides adequate stability and solubility and is suitable as a cycle 1 formulation.

[0242] Table 12 Summary of 3-month drug product stability data

[0243]

[0244] All documents, patents, journal articles and other materials cited in this application are incorporated herein by reference.

[0245] Although the invention has been described in its entirety with reference to the accompanying drawings and several embodiments thereof, it should be understood that various changes and modifications will be apparent to those skilled in the art. It should be understood that such changes and modifications are included within the scope of the invention as defined in the appended claims, unless they depart from that scope.

[0246] This invention can be further defined by referring to the following numbered paragraphs.

[0247] Paragraph 1. A preparation comprising:

[0248] i. Anti-RSV monoclonal antibody; and

[0249] ii. Ionic excipients;

[0250] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher (e.g., about 50 mg / ml to about 200 mg / ml, about 175 mg / ml, about 165 mg / ml, about 150 mg / ml or about 125 mg / ml), and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0251] Paragraph 2. The formulation according to paragraph 1, wherein the monoclonal antibody has a pI in the range of pH 6.4 to pH 7.5.

[0252] Paragraph 3 describes a formulation according to paragraph 1 or paragraph 2, wherein the monoclonal antibody has a pI in the range of approximately pH 6.4.

[0253] Paragraph 4. The preparation according to any of the preceding paragraphs, wherein the monoclonal antibody is an IgG1 monoclonal antibody.

[0254] Paragraph 5. The formulation according to any of the preceding paragraphs, wherein the monoclonal antibody has the following light chain CDR sequence:

[0255] CDR-L1 of SEQ ID NO:3

[0256] CDR-L2 of SEQ ID NO:4

[0257] CDR-L3 of SEQ ID NO:5

[0258] And the following heavy chain CDR sequences:

[0259] CDR-H1 of SEQ ID NO:6

[0260] CDR-H2 of SEQ ID NO:7

[0261] CDR-H3 of SEQ ID NO:8.

[0262] Paragraph 6 describes the formulation according to any of the preceding paragraphs, wherein the monoclonal antibody has the light chain variable region sequence of SEQ ID NO:9 and the heavy chain variable region sequence of SEQ ID NO:10.

[0263] Paragraph 7. The formulation according to any of the preceding paragraphs, wherein the monoclonal antibody has the light chain sequence of SEQ ID NO:1 and the heavy chain sequence of SEQ ID NO:2.

[0264] Paragraph 8. The preparation according to any of the preceding paragraphs, wherein the monoclonal antibody is present in the preparation at a concentration of about 100 mg / ml to about 165 mg / ml.

[0265] Paragraph 9. The preparation according to paragraph 8, wherein the monoclonal antibody is present in the preparation at a concentration of about 100 mg / ml.

[0266] Paragraph 10. The formulation according to any of the preceding paragraphs, wherein the formulation has a pH in the range of about pH 5.7 to about pH 6.1.

[0267] Paragraph 11. The formulation according to paragraph 10, wherein the formulation has a pH of about pH 6.0.

[0268] Paragraph 12. A formulation according to any of the preceding paragraphs, wherein the ionic excipient is a salt.

[0269] Paragraph 13. The formulation according to paragraph 12, wherein the salt is arginine hydrochloride.

[0270] Paragraph 14. The formulation according to any of the preceding paragraphs, wherein the ionic excipient is present at a concentration of about 75 mM to about 100 mM.

[0271] Paragraph 15. The formulation according to paragraph 14, wherein the ionic excipient is present at a concentration of about 80 mM.

[0272] Paragraph 16. The preparation according to any of the preceding paragraphs, wherein the preparation further comprises sugar.

[0273] Paragraph 17. The preparation according to paragraph 16, wherein the sugar is sucrose.

[0274] Paragraph 18. The formulation according to any one of paragraphs 16 to 17, wherein the sugar is present at a concentration of about 100 mM to about 140 mM.

[0275] Paragraph 19. The formulation according to paragraph 18, wherein the sugar is present at a concentration of about 120 mM.

[0276] Paragraph 20. The formulation according to any of the preceding paragraphs, wherein the formulation further comprises one or more buffers.

[0277] Paragraph 21. The formulation according to paragraph 20, wherein such buffer or these buffers are selected from histidine, histidine hydrochloride and histidine / histidine hydrochloride.

[0278] Paragraph 22. The formulation according to paragraph 21, wherein such buffer or these buffers are L-histidine / L-histidine hydrochloride monohydrate.

[0279] The formulation according to any one of paragraphs 20 to 23, wherein such buffer or these buffers are present at a concentration of about 10 mM to about 50 mM.

[0280] Paragraph 23. The formulation according to paragraph 23, wherein the buffer or these buffers are present at a concentration of about 30 mM.

[0281] Paragraph 24. The formulation according to any of the preceding paragraphs, wherein the formulation further comprises a surfactant.

[0282] Paragraph 25. The formulation according to paragraph 25, wherein the surfactant is polysorbate.

[0283] Paragraph 26. The formulation according to paragraph 26, wherein the surfactant is polysorbate-80.

[0284] Paragraph 27. The formulation according to any one of paragraphs 25 to 27, wherein the surfactant is present in the formulation at a concentration of about 0.001% (w / v) to about 0.07% (w / v).

[0285] Paragraph 28. The formulation according to paragraph 28, wherein the surfactant is present in the formulation at a concentration of about 0.02% (w / v).

[0286] Paragraph 29. A formulation according to any of the preceding paragraphs, wherein the formulation further comprises one or more additional excipients, such excipients including, for example, one or more sugars, salts, amino acids, polyols, chelating agents, emulsifiers and / or preservatives.

[0287] Paragraph 30. The preparation described in any of paragraphs 1 to 29 is a pharmaceutical preparation.

[0288] Paragraph 31. The pharmaceutical preparations described in paragraph 30 are intended for use as medicines.

[0289] Paragraph 32. The pharmaceutical preparations described in paragraph 31 are intended for use in the treatment of diseases.

[0290] Paragraph 33. A method of treating or preventing a disease in a subject, the method comprising administering to the subject a pharmaceutical preparation as described in paragraph 31.

[0291] Paragraph 34. An isolated monoclonal antibody having the following light chain CDR sequence:

[0292] CDR-L1 of SEQ ID NO:3

[0293] CDR-L2 of SEQ ID NO:4

[0294] CDR-L3 of SEQ ID NO:5

[0295] And the following heavy chain CDR sequences:

[0296] CDR-H1 of SEQ ID NO:6

[0297] CDR-H2 of SEQ ID NO:7

[0298] CDR-H3 of SEQ ID NO:8.

[0299] Paragraph 35. The monoclonal antibody isolated according to paragraph 35, wherein the monoclonal antibody has the light chain variable region sequence of SEQ ID NO:9 and the heavy chain variable region sequence of SEQ ID NO:10.

[0300] Paragraph 36. The monoclonal antibody isolated according to paragraph 35 or paragraph 36, wherein the monoclonal antibody has the light chain sequence of SEQ ID NO:1 and the heavy chain sequence of SEQ ID NO:2.

[0301] Paragraph 37. The monoclonal antibody isolated according to any one of paragraphs 35 to 37, wherein the antibody is an IgG1 antibody.

[0302] Paragraph 38. A pharmaceutical composition comprising isolated antibodies as defined in any one of paragraphs 35 to 38.

[0303] Paragraph 39. An isolated monoclonal antibody as described in any one of paragraphs 35 to 38 or a pharmaceutical composition as described in paragraph 39, for use as a medicine.

[0304] Paragraph 40. An isolated monoclonal antibody as described in any one of paragraphs 35 to 38 or a pharmaceutical composition as described in paragraph 39, for use in the treatment of a disease.

[0305] Paragraph 41. A method of treating or preventing a disease in a subject, the method comprising administering to the subject an isolated monoclonal antibody as described in any one of paragraphs 35 to 38 or a pharmaceutical composition as described in paragraph 39.

[0306] Paragraph 42. A freeze-dried pellet that can be reconstituted using only sterile water as defined in any of paragraphs 1 to 31.

[0307] Paragraph 43. A composition capable of being freeze-dried to form freeze-dried clumps, wherein the freeze-dried clumps are capable of being reconstituted using only sterile water as defined in any of paragraphs 1 to 31.

[0308] In summary, this application includes, but is not limited to, the following:

[0309] 1. A formulation comprising:

[0310] i. Anti-RSV monoclonal antibody; and

[0311] ii. Ionic excipients;

[0312] The monoclonal antibody is present at a concentration of about 50 mg / ml or higher, and the ionic excipient is present at a concentration of about 50 to about 150 mM, and the formulation has a pH of about 5.5 to about 7.5.

[0313] 2. The formulation according to item 1, wherein the monoclonal antibody has a pI in the range of pH 6.4 to pH 7.5.

[0314] 3. The formulation according to item 1 or item 2, wherein the monoclonal antibody has a pI in the range of about pH 6.4.

[0315] 4. The preparation according to any one of the preceding items, wherein the monoclonal antibody is an IgG1 monoclonal antibody.

[0316] 5. The formulation according to any one of the preceding claims, wherein the monoclonal antibody has the following light chain CDR sequence:

[0317] CDR-L1 of SEQ ID NO:3

[0318] CDR-L2 of SEQ ID NO:4

[0319] CDR-L3 of SEQ ID NO:5

[0320] And the following heavy chain CDR sequences:

[0321] CDR-H1 of SEQ ID NO:6

[0322] CDR-H2 of SEQ ID NO:7

[0323] CDR-H3 of SEQ ID NO:8.

[0324] 6. The preparation according to any one of the preceding items, wherein the monoclonal antibody has the light chain variable region sequence of SEQ ID NO:9 and the heavy chain variable region sequence of SEQ ID NO:10.

[0325] 7. The preparation according to any one of the preceding items, wherein the monoclonal antibody has the light chain sequence of SEQ ID NO:1 and the heavy chain sequence of SEQ ID NO:2.

[0326] 8. The preparation according to any one of the preceding items, wherein the monoclonal antibody is present in the preparation at a concentration of about 100 mg / ml to about 165 mg / ml.

[0327] 9. The preparation according to item 8, wherein the monoclonal antibody is present in the preparation at a concentration of about 100 mg / ml.

[0328] 10. The formulation according to any one of the preceding items, wherein the formulation has a pH in the range of about pH 5.7 to about pH 6.1.

[0329] 11. The formulation according to item 10, wherein the formulation has a pH of about pH 6.0.

[0330] 12. The formulation according to any one of the preceding items, wherein the ionic excipient is a salt.

[0331] 13. The formulation according to item 12, wherein the salt is arginine hydrochloride.

[0332] 14. The formulation according to any one of the preceding items, wherein the ionic excipient is present at a concentration of about 75 mM to about 100 mM.

[0333] 15. The formulation according to item 14, wherein the ionic excipient is present at a concentration of about 80 mM.

[0334] 16. The preparation according to any one of the preceding items, wherein the preparation further comprises sugar.

[0335] 17. The preparation according to item 16, wherein the sugar is sucrose.

[0336] 18. The preparation according to any one of items 16 to 17, wherein the sugar is present at a concentration of about 100 mM to about 140 mM.

[0337] 19. The preparation according to item 18, wherein the sugar is present at a concentration of about 120 mM.

[0338] 20. The preparation according to any one of the preceding items, wherein the preparation further comprises one or more buffers.

[0339] 21. The formulation according to item 20, wherein such buffer or these buffers are selected from histidine, histidine hydrochloride and histidine / histidine hydrochloride.

[0340] 22. The formulation according to item 21, wherein the buffer or these buffers are L-histidine / L-histidine hydrochloride monohydrate.

[0341] 23. The formulation according to any one of items 20 to 22, wherein the buffer or these buffers are present at a concentration of about 10 mM to about 50 mM.

[0342] 24. The formulation according to item 23, wherein the buffer or these buffers are present at a concentration of about 30 mM.

[0343] 25. The formulation according to any one of the preceding items, wherein the formulation further comprises a surfactant.

[0344] 26. The formulation according to item 25, wherein the surfactant is polysorbate.

[0345] 27. The formulation according to item 26, wherein the surfactant is polysorbate-80.

[0346] 28. The formulation according to any one of claims 25 to 27, wherein the surfactant is present in the formulation at a concentration of about 0.001% (w / v) to about 0.07% (w / v).

[0347] 29. The formulation according to claim 28, wherein the surfactant is present in the formulation at a concentration of about 0.02% (w / v).

[0348] 30. The formulation according to any one of the preceding items, wherein the formulation further comprises one or more additional excipients, such excipients including, for example, one or more sugars, salts, amino acids, polyols, chelating agents, emulsifiers and / or preservatives.

[0349] 31. The preparation according to any one of items 1 to 30, wherein the preparation is a pharmaceutical preparation.

[0350] 32. The pharmaceutical preparation according to item 31, for use as a medicine.

[0351] 33. The pharmaceutical preparation according to item 31, for use in the treatment of a disease.

[0352] 34. A method for treating or preventing a disease in a subject, the method comprising administering to the subject the pharmaceutical preparation according to claim 31.

[0353] 35. A freeze-dried pellet capable of being reconstituted using only sterile water as defined in any one of items 1 to 31.

[0354] 36. A composition capable of being freeze-dried to form freeze-dried clumps, wherein the freeze-dried clumps are reconstituted using only sterile water as defined in any one of items 1 to 31.

Claims

1. A formulation comprising: A 100 mg / ml anti-RSV monoclonal antibody, wherein the antibody comprises the light chain sequence of SEQ ID NO: 1 and the heavy chain sequence of SEQ ID NO: 2; 30 mM of L-histidine, L-histidine hydrochloride, or a combination thereof; 80 mM L-arginine hydrochloride; 120 mM sucrose; and 0.02% (w / v) of polysorbate 80; The formulation has a pH of 5.7 to 6.

3.

2. The formulation according to claim 1, wherein the L-histidine hydrochloride is L-histidine hydrochloride monohydrate.

3. The formulation according to claim 1, wherein the formulation has a pH of 5.7 to 6.

1.

4. The formulation according to claim 1, wherein the formulation has a pH of 6.

0.

5. The formulation according to claim 1, wherein the formulation is a liquid.

6. Use of a pharmaceutical preparation in the manufacture of a medicament for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in human subjects, wherein the pharmaceutical preparation comprises: A 100 mg / mL anti-RSV monoclonal antibody, wherein the antibody comprises the light chain sequence of SEQ ID NO: 1 and the heavy chain sequence of SEQ ID NO: 2; 30 mM of L-histidine, L-histidine hydrochloride, or a combination thereof; 80 mM L-arginine hydrochloride; 120 mM sucrose; and 0.02% (w / v) polysorbate 80, The drug formulation has a pH of 5.7 to 6.

3.

7. The use according to claim 6, wherein the L-histidine hydrochloride is L-histidine hydrochloride monohydrate.

8. The use according to claim 6, wherein the pharmaceutical formulation has a pH of 5.7 to 6.

1.

9. The use according to claim 6, wherein the pharmaceutical formulation has a pH of 6.

0.

10. The use according to claim 6, wherein the pharmaceutical preparation is a liquid.

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