WO2020081408A1 - Formulations of anti-rsv antibodies and methods of use thereof - Google Patents

Formulations of anti-rsv antibodies and methods of use thereof Download PDF

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Publication number
WO2020081408A1
WO2020081408A1 PCT/US2019/056027 US2019056027W WO2020081408A1 WO 2020081408 A1 WO2020081408 A1 WO 2020081408A1 US 2019056027 W US2019056027 W US 2019056027W WO 2020081408 A1 WO2020081408 A1 WO 2020081408A1
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WIPO (PCT)
Prior art keywords
rsv antibody
rsv
formulation
antigen
arginine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2019/056027
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English (en)
French (fr)
Inventor
Venus HASHEMI
Arnab De
Chakravarthy Nachu NARASIMHAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Publication date
Application filed by Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Priority to US17/285,156 priority Critical patent/US12565526B2/en
Priority to MYPI2021002095A priority patent/MY209127A/en
Priority to CA3115708A priority patent/CA3115708C/en
Priority to CN201980076016.1A priority patent/CN113056482A/zh
Priority to JP2021520925A priority patent/JP7467438B2/ja
Priority to SG11202103907PA priority patent/SG11202103907PA/en
Priority to EP19872495.7A priority patent/EP3867271A4/en
Priority to MX2021004356A priority patent/MX2021004356A/es
Priority to KR1020217014420A priority patent/KR102885113B1/ko
Publication of WO2020081408A1 publication Critical patent/WO2020081408A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/11—Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the invention relates to stable formulations comprising antibodies or antigen-binding fragments thereof that bind to respiratory syncytial virus (RSV). Also provided are methods of preventing and/or treating RSV-related diseases with the formulations of the invention.
  • RSV respiratory syncytial virus
  • sequence listing of the present application is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name“2464lWOPCT-SEQLIST.TXT”, creation date of October 9, 2019, and a size of 9.19 KB.
  • This sequence listing submitted via EFS-Web is part of the specification and is herein incorporated by reference in its entirety.
  • Para yxoviruses are enveloped negative-strand RNA viruses that are significant human and animal pathogens.
  • Human Respiratory Syncytial Virus (hRSV, RSV) belongs to the family Paramyxoviridae, subfamily Pneumovirinae . Two subtypes, type A and type B, have been identified and are a major cause of severe and sometimes even fatal respiratory infections in children less than 6 months of age.
  • Adults with underlying diseases, such as COPD, asthma, and cancer, and adults with immunocompromised status, including HIV or post transplantation, are also at risk of developing severe RSV infection. Fifteen percent of annual hospitalizations in adults over 50 years due to acute respiratory infection are caused by RSV.
  • hRSV Human Metapneumo Virus
  • hPIV Human Parainfluenza Virus
  • attachment protein which mediates virus binding to cells
  • F fusion protein
  • the attachment protein G binds cellular surface receptors and interacts with the F protein. This interaction triggers a conformational change in the F protein to induce membrane fusion, thereby releasing the viral ribonucleoprotein complex into the host cell cytoplasm.
  • Monoclonal antibodies against the F protein or the G protein have been shown to have neutralizing effects in vitro and prophylactic effects in vivo. See, e.g., Beeler and Coelingh 1989, J. Virol. 63 :2941-50; Garcia-Barreno et al., 1989, J. Virol. 63 :925-32; Taylor et al., 1984,
  • Antibodies for use in human subjects must be stored prior to use and transported to the point of administration. Reproducibly attaining a desired level of antibody drug in a subject requires that the drug be stored in a formulation that maintains the bioactivity of the drug.
  • such formulations will exhibit a long shelf-life, be stable when stored and transported, and will be amenable to administration at high concentrations, e.g. for use in subcutaneous administration, as well as low concentrations, e.g. for intravenous
  • formulations of the invention are useful for subcutaneous delivery to a patient in need thereof. In order to deliver maximum therapeutic benefits to patients, it is desirable that
  • formulations for subcutaneous (SC) delivery comprise a high antibody concentration (75-200 mg/ml).
  • a high concentration of API is often required for SC formulations due to the historical bioavailability of 50-60% for SC injections and the expected dose range of an antibody product.
  • high concentration of antibody, or antigen-binding fragment thereof may contribute to other properties of the product which would be undesirable, e.g. low injectability due to increased viscosity and higher than physiological osmolality and increased aggregation. Therefore, it is preferred that an antibody product intended for SC administration balances the effects of concentration while maintaining a level of drug that will provide the highest therapeutic benefit.
  • An ideal product comprises a high protein concentration, low viscosity, an osmolality similar to physiological conditions, and a low level of aggregation under typical storage conditions. Increased viscosity at high protein concentration may not only make it difficult to extract the product from its container with a syringe, but also to inject the necessary dose into a patient from the syringe (syringeability).
  • embodiments of the invention provide formulations that comprise a high concentration of antibody, or antigen-binding fragment thereof, and a viscosity level that is acceptable for subcutaneous delivery. Additionally, the formulations of the invention do not lead to high levels of aggregation, as shown in more detail throughout the Examples.
  • an anti-RSV antibody formulation comprising: a) about 50 mg/mL to about 250 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM buffer; c) a stabilizer selected from the group consisting of: (i) about 6% to about 8% weight/volume (w/v) non-reducing sugar; (ii) about 25 mM to about 75 mM each of L- arginine, or a pharmaceutically acceptable salt of L-arginine, L-proline, or a pharmaceutically acceptable salt of L-proline; L-lysine, or a pharmaceutically acceptable salt of L-lysine; L- glutamate, or a pharmaceutically acceptable salt of L-glutamate, or a mixture of the amino acids described herein, and (iii) about 25 mM to 75 pM of a chelator; d) about 0.01% to about 0.10% non ionic surfactant; and
  • the disclosure provides an anti-RSV antibody formulation, comprising: a) about 50 mg/mL to about 150 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 6% to about 8% weight/volume (w/v) sucrose; d) an excipient selected from about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine, about 25 mM to about 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine, a mixture of about 25 mM to about 75 mM L-arginine and about 25 to about 75 mM L-glutamate, and a mixture of about 25 mM to about 75 mM of L- arginine(HCl) and about 25 to about 75 mM L-lysine(HCl); e) about 25 pM to 75 pM of D
  • the disclosure provides an anti-RSV antibody formulation, comprising: a) about 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 10 mM histidine; c) about 7% weight/volume (w/v) sucrose; d) an excipient selected from about 50 mM L-arginine(HCl), about 50 mM L-lysine(HCl), a mixture of about 25 mM L-arginine and about 25 mM L-glutamate, and a mixture of about 25 mM L-arginine(HCl) and about 25 mM L-lysine(HCl); e) about 50 mM DTP A; f) about 0.02% polysorbate 80; and optionally g) about 1 mM to 20 mM L-methionine.
  • the disclosure provides an anti-RSV antibody formulation, comprising: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) an excipient selected from 50 mM L- arginine(HCl), 50 mM L-lysine(HCl), a mixture of 25 mM L-arginine and 25 mM L-glutamate, and a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50 pM DTP A; f) 0.02% polysorbate 80; and optionally g) 1 mM to 20 mM L-methionine.
  • the disclosure provides an anti-RSV antibody formulation, comprising: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50 pM DTP A; and f) 0.02% polysorbate 80.
  • the disclosure provides an anti-RSV antibody formulation consisting of: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50pM DTP A; and f) 0.02% polysorbate 80.
  • the disclosure provides an anti-RSV antibody formulation comprising: a) about 50 mg/mL to about 250 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) an excipient selected from the group consisting of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine, about 25 mM to about 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine, a mixture of about 25 mM to about 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-glutamate or a pharmaceutically acceptable salt of L-glutamate, and a mixture of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to 8% (w/v) sucrose; d) 25 mM to 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) about 25 mM to about 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to 8% (w/v) sucrose; d) 25 mM to 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) a mixture of about 25 mM to about 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-glutamate or a pharmaceutically acceptable salt of L-glutamate; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to about 8% (w/v) sucrose; d) a mixture of 25 mM to 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and 25 mM to 75 mM L- glutamate or a pharmaceutically acceptable salt of L-glutamate; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) a mixture of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to 8% (w/v) sucrose; d) a mixture of 25 mM to 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine and 25 mM to 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the formulation has a pH between 5.5 and 6.5.
  • the formulation has a pH of 6.0.
  • Also provided herein are methods of preventing and/or treating RSV-related diseases in a human patient in need thereof comprising: administering an effective amount of the anti-RSV antibody formulations of the invention to the patient.
  • Also provided herein are methods of treating or preventing RSV infection in a human patient in need thereof comprising: administering an effective amount of the anti-RSV antibody
  • Also provided herein are methods of treating or preventing RSV infection in a human patient in need thereof comprising: administering an effective amount of the anti-RSV antibody
  • formulations of the invention to the patient wherein the effective amount comprises a fixed dose of an anti-RSV antibody or antigen-binding fragment thereof, wherein the fixed dose ranges from about 10 to about 100 mg.
  • Also provided herein are methods of treating or preventing RSV infection in a human patient in need thereof comprising: administering an effective amount of the anti-RSV antibody
  • formulations of the invention to the patient wherein the anti-RSV antibody formulations are administered by subcutaneous administration; or wherein the anti-RSV antibody formulations are administered by intravenous administration; or wherein the anti-RSV antibody formulations are administered by intramuscular administration.
  • anti-RSV antibody formulations of the invention for the treatment or prevention of RSV infection in a human patient.
  • FIGURES 1 A-1C show results of UP SEC %HMW, % mAb (monomer) and % LMW vs. Time Data of an anti-RSV antibody formulations at 5°C storage conditions.
  • FIGURES 2A-2C show results of UP SEC %HMW, % mAb (monomer) and % LMW vs. Time Data of an anti-RSV antibody formulations at 25°C storage conditions.
  • FIGURES 3A-3C show results of UPSEC %HMW, % mAb (monomer) and % LMW vs. Time Data of an anti-RSV antibody formulations at 40°C storage conditions.
  • FIGURES 4A-4B show results of HP-IEX % Total Acidic Peaks and % Main Peak vs. Time of an anti-RSV antibody formulations at 5°C storage conditions.
  • FIGURES 5A-5B show results of HP-IEX % Total Acidic Peaks and % Main Peak vs. Time of an anti-RSV antibody formulations at 25°C storage conditions.
  • FIGURES 6A-6B show results of HP-IEX % Total Acidic Peaks and % Main Peak vs. Time of an anti-RSV antibody formulations at 40°C storage conditions.
  • FIGURES 8A-8C show results of UPSEC %HMW, % mAb (monomer) and % LMW vs. Time Data of an anti-RSV antibody formulations at 5°C storage conditions.
  • FIGURES 9A-9C show results of UPSEC %HMW, % mAb (monomer) and % LMW vs. Time Data of an anti-RSV antibody formulations at 25°C storage conditions.
  • FIGURES 10A-10C show results of UPSEC %HMW, % mAb (monomer) and % LMW vs. Time Data of an anti-RSV antibody formulations at 40°C storage conditions.
  • FIGURES 11 A-l 1B show results of HP-IEX % Total Acidic Peaks and % Main Peak vs. Time of an anti-RSV antibody formulations at 5 °C storage conditions.
  • FIGURES 12A-12B show results of HP-IEX % Total Acidic Peaks and % Main Peak vs. Time of an anti-RSV antibody formulations at 25°C storage conditions.
  • FIGURES 13A-13B show results of HP-IEX % Total Acidic Peaks and % Main Peak vs. Time of an anti-RSV antibody formulations at 40°C storage conditions.
  • FIGURE 14 shows results of the percentage degradation of PS80 at 40°C.
  • FIGURE 15 shows a bar graph comparing viscosity of formulations using excipients of 80mM histidine, 70mM lysine or 70mM arginine.
  • the invention provides stable formulations comprising an anti-RSV antibody, or antigen binding fragment thereof that binds to RSV.
  • the invention provides stable formulations comprising an anti-RSV antibody, or anti gen -binding fragment thereof that binds to human RSV F-protein, which are useful for methods of treating or preventing human RSV infection.
  • This exemplary antibody comprises complementarity-determining regions (CDRs) having the amino acid sequences: SEQ ID NO: 1 (heavy chain CDR 1), SEQ ID NO: 2 (heavy chain CDR 2), SEQ ID NO: 3 (heavy chain CDR 3), SEQ ID NO: 4 (light chain CDR 1), SEQ ID NO: 5 (light chain CDR 2), and SEQ ID NO: 6 (light chain CDR 3).
  • CDRs complementarity-determining regions
  • SEQ ID NO: 1 dasheavy chain CDR 1
  • SEQ ID NO: 2 (heavy chain CDR 2)
  • SEQ ID NO: 3 heavy chain CDR 3
  • SEQ ID NO: 4 light chain CDR 1
  • SEQ ID NO: 5 light chain CDR 2
  • SEQ ID NO: 6 light chain CDR 3
  • this exemplary antibody comprises heavy and light chain variable regions having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO:8.
  • this exemplary antibody comprises a heavy and light chain immunoglobulin consisting of the
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administering and “treatment” also means in vitro and ex vivo treatments, e.g. , of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • RSV-related disease means any disease caused, directly or indirectly, by an infection with Respiratory Syncytial Virus (RSV) as well as diseases or conditions which predispose a patient to infection by RSV.
  • diseases falling into the former category include pneumonia and bronchiolitis.
  • Diseases and conditions in the latter category include cystic fibrosis, congenital heart disease, cancer, age related immunosuppression, transplant recipients and, generally, any condition that causes a state of immunosuppression or decreased function of the immune system such as post-operative organ transplantation regimens or premature birth.
  • Treating means to administer a therapeutic agent, such as a formulation containing any of the antibodies or antigen-binding fragments of the present invention, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity.
  • the agent is administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting the progression of such symptom(s) by any clinically measurable degree.
  • the amount of a therapeutic agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject.
  • Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom.
  • Treatment with anti-RSV antibodies could also be combined with other interventions (antibodies, nucleic acids, vaccines and small molecule compounds) to treat other respiratory pathogens.
  • Prevent means to administer a prophylactic agent, such as a formulation containing any of the antibodies or antigen-binding fragments of the present invention, internally or externally to a subject or patient at risk of becoming infected by RSV, for which the agent has prophylactic activity.
  • Preventing includes reducing the likelihood or severity of a subsequent RSV infection, ameliorating symptoms associated with lower respiratory tract infection (LRI) upon RSV infection, and inducing immunity to protect against RSV infection.
  • the agent is administered in an amount effective to neutralize RSV in the lungs and/or the nose in order block infection.
  • the amount of a prophylactic agent that is effective to ameliorate any particular disease symptom may vary according to factors such as the age, and weight of the patient, and the ability of the agent to elicit a desired response in the subject. Whether a disease symptom has been ameliorated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom or in certain instances will ameliorate the need for hospitalization.
  • patient refers to a mammal (e.g ., rat, mouse, dog, cat, rabbit) capable of being treated with the formulations of the invention, most preferably a human.
  • the patient is an adult patient.
  • the patient is a pediatric patient.
  • Those“in need of treatment” include those patients that may benefit from treatment with the formulations of the invention.
  • pharmaceutically effective amount means an amount whereby a sufficient therapeutic formulation is introduced to a patient to treat a disease or condition.
  • this level may vary according the patient’s characteristics such as age, weight, etc.
  • fixed dose refers to an amount (e.g. in milligrams) of active ingredient that is administered to a patient.
  • solution/formulation or the value of a parameter characterizing a step in a method, or the like, refers to variation in the numerical quantity of plus or minus 5%.
  • variation in the numerical quantity can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and/or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the
  • a binding compound that consists essentially of a recited amino acid sequence may also include one or more amino acids, including substitutions of one or more amino acid residues, that do not materially affect the properties of the binding compound.
  • pharmaceutical formulation refers to preparations which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the formulation would be administered.
  • formulation and“pharmaceutical formulation” are used interchangeably throughout.
  • “Pharmaceutically acceptable” refers to excipients (vehicles, additives) and compositions that can reasonably be administered to a subject to provide an effective dose of the active ingredient employed and that are "generally regarded as safe” e.g ., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human.
  • this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • the term "effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the effective amount is a "therapeutically effective amount” for the alleviation of the symptoms of the disease or condition being treated.
  • the effective amount is a “prophylactically effective amount” for prophylaxis of the symptoms of the disease or condition being prevented.
  • a “stable” formulation is one in which the protein therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage.
  • Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993).
  • Stability can be measured at a selected temperature for a selected time period.
  • a stable formulation is a formulation with no significant changes observed at a refrigerated temperature (2- 8°C) for at least 12 months.
  • a stable formulation is a formulation with no significant changes observed at a refrigerated temperature (2-8°C) for at least 18 months.
  • stable formulation is a formulation with no significant changes observed at room temperature (23-27°C) for at least 3 months.
  • stable formulation is a formulation with no significant changes observed at room temperature (23-27°C) for at least 6 months.
  • stable formulation is a formulation with no significant changes observed at room temperature (23-27°C) for at least 12 months.
  • stable formulation is a formulation with no significant changes observed at room temperature (23-27°C) for at least 18 months.
  • the criteria for stability for an antibody formulation are as
  • the formulation is colorless, or clear to slightly opalescent by visual analysis.
  • the concentration, pH and osmolality of the formulation have no more than +/-l0% change. Potency is typically within 60-140%, preferably 80-120%, of the control or reference.
  • no more than 10%, preferably 5%, of clipping of the antibody is observed, i.e., % low molecular weight species as determined, for example, by HP-SEC.
  • no more than 10%, preferably no more than 5%, of aggregation of the antibody is observed, i.e. % high molecular weight species as determined, for example, by HP-SEC.
  • anti-RSV antibody refers to a monoclonal antibody directed against the F protein or the G protein of RSV.
  • Anti-RSV antibodies are disclosed and described in LT.S. Pat. No. 9,963,500.
  • a particular anti-RSV antibody is disclosed and described in LT.S. Pat. No. 9,963,500 and comprises complementarity-determining regions (CDRs) having the amino acid sequences:
  • an anti-RSV antibody is disclosed and described in ET.S. Pat. No. 9,963,500 and comprises heavy and light chain variable regions having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively.
  • a particular anti-RSV antibody is disclosed and described in U.S. Pat. No. 9,963,500 and comprises a heavy and light chain immunoglobulin consisting of the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10, respectively.
  • An antibody "retains its physical stability" in a pharmaceutical formulation if it shows no significant increase of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering, size exclusion chromatography (SEC) and dynamic light scattering.
  • SEC size exclusion chromatography
  • the changes of protein conformation can be evaluated by fluorescence spectroscopy, which determines the protein tertiary structure, and by FTIR spectroscopy, which determines the protein secondary structure.
  • An antibody "retains its chemical stability" in a pharmaceutical formulation, if it shows no significant chemical alteration. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often alter the protein chemical structure include hydrolysis or clipping (evaluated by methods such as size exclusion
  • an antibody "retains its biological activity" in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared.
  • the biological activity of an antibody can be determined, for example, by an antigen-binding assay.
  • Formulations of the invention include antibodies and fragments thereof that are biologically active when reconstituted or in liquid form. II. Formulations of the Invention
  • the formulations of the invention minimize the formation of antibody aggregates, increase stability and reduce viscosity.
  • the invention includes various formulations of an anti-RSV antibody, or antigen-binding fragment thereof, as described in more detail below.
  • the invention includes formulations comprising (i) an anti-RSV antibody or antigen-binding fragment thereof, (ii) a buffer (e.g ., histidine), (iii) a stabilizer (e.g, a non-reducing sugar such as sucrose); (iv) a non-ionic surfactant (e.g, polysorbate 80); and (v) an antioxidant (e.g, methionine).
  • the formulations of the invention comprise a viscosity-reducer (e.g.
  • arginine, or a pharmaceutically acceptable salt thereof lysine, or a pharmaceutically acceptable salt thereof; a mixture of arginine and lysine or pharmaceutically acceptable salts thereof, a mixture of arginine and glutamate or pharmaceutically acceptable salts thereof, and/or histidine or pharmaceutically acceptable salts thereof) and/or a metal chelator (e.g. DTP A).
  • a metal chelator e.g. DTP A
  • the invention provides stable biological formulations comprising an anti-RSV antibody which comprises complementarity-determining regions (CDRs) having the amino acid sequences: SEQ ID NO: 1 (heavy chain CDR 1), SEQ ID NO: 2 (heavy chain CDR 2), SEQ ID NO: 3 (heavy chain CDR 3), SEQ ID NO: 4 (light chain CDR 1), SEQ ID NO: 5 (light chain CDR 2), and SEQ ID NO: 6 (light chain CDR 3).
  • CDRs complementarity-determining regions
  • the invention also provides stable biological formulations comprising an anti-RSV antibody which comprises heavy and light chain variable regions having the amino acid sequences of SEQ ID NO: 7 and SEQ ID NO: 8, respectively and/or comprises a heavy and light chain immunoglobulin consisting of the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 10 respectively.
  • the methods of making the anti-RSV antibody are disclosed and described in U.S. Pat. No. 9,963,500 and are hereby incorporated by reference in its entirety.
  • SEQ ID NOs: 1-10 are set forth in Table A below:
  • the API (“active pharmaceutical ingredient”, i.e. the anti-RSV antibody or antigen-binding fragment thereof) is present in a concentration of about 50 mg/mL to about 250 mg/mL. In some embodiments of the formulations, the API ⁇ i.e. the anti-RSV antibody or antigen-binding fragment thereof) is present in a
  • the API is present in a concentration of about 75 mg/mL to about 200 mg/mL. In some embodiments, the API is present in a concentration of about 90 mg/mL to about 110 mg/mL. In another embodiment, the API is present in a concentration of about 100 mg/mL. In another embodiment, the API is present in a concentration of 90 mg/mL to 110 mg/mL. In another embodiment, the API is present in a concentration of 100 mg/mL. In another embodiment, the API is present in a concentration of 75 mg/mL. In another embodiment, the API is present in a concentration of 50 mg/mL.
  • the API is present in a concentration of about 125 mg/mL to about 175 mg/mL. In some embodiments, the API is present in a concentration of about 140 mg/mL to about 160 mg/mL. In another embodiment, the API is present in a concentration of about 150 mg/mL. In some embodiments, the API is present in a concentration of 125 mg/mL to 175 mg/mL. In some embodiments, the API is present in a concentration of 140 mg/mL to 160 mg/mL. In another embodiment, the API is present in a concentration of 150 mg/mL.
  • the API is present in a concentration of about 150 mg/mL to about 200 mg/mL. In some embodiments, the API is present in a concentration of about 165 mg/mL to about 185 mg/mL. In another embodiment, the API is present in a concentration of about 175 mg/mL. In some embodiments, the API is present in a concentration of 150 mg/mL to 200 mg/mL. In some embodiments, the API is present in a concentration of 165 mg/mL to 185 mg/mL. In another embodiment, the API is present in a concentration of 175 mg/mL.
  • the API is present in a concentration of about 175 mg/mL to about 225 mg/mL. In some embodiments, the API is present in a concentration of about 190 mg/mL to about 210 mg/mL. In another embodiment, the API is present in a concentration of about 200 mg/mL. In some embodiments, the API is present in a concentration of 175 mg/mL to 225 mg/mL. In some embodiments, the API is present in a concentration of 190 mg/mL to 210 mg/mL. In another embodiment, the API is present in a concentration of 200 mg/mL.
  • the API is present in a concentration of about 200 mg/mL to about
  • the API is present in a concentration of about 215 mg/mL to about 235 mg/mL. In another embodiment, the API is present in a concentration of about 225 mg/mL. In some embodiments, the API is present in a concentration of 200 mg/mL to 250 mg/mL. In some embodiments, the API is present in a concentration of 215 mg/mL to 235 mg/mL. In another embodiment, the API is present in a concentration of 225 mg/mL.
  • the API i.e. the anti-RSV antibody or antigen-binding fragment thereof
  • a fixed dose e.g. an amount in milligrams.
  • the API is present in a fixed dose of about 10 mg to about 150 mg.
  • the API is present in a fixed dose of 10 mg to 150 mg.
  • the API is present in a fixed dose of about 25 mg to about 125 mg.
  • the API is present in a fixed dose of 25 mg to 125 mg.
  • the API is present in a fixed dose of about 50 mg to about 100 mg.
  • the API is present in a fixed dose of 50 mg to 100 mg.
  • the formulations of the invention comprise at least one excipient that stabilizes the formulation.
  • the stabilizer is a non-reducing sugar.
  • the non-reducing sugar is sucrose.
  • the non-reducing sugar is glucose. In additional embodiments, the non-reducing sugar is trehalose. In still further embodiments, the non-reducing sugar is lactose. In other embodiments, the non-reducing sugar is raffmose.
  • the anti-RSV antibody formulations of the invention comprise a stabilizer selected from the group consisting of: about 4% to about 8% weight/volume (w/v) sucrose, glucose, trehalose, lactose or raffmose.
  • the stabilizer is about 4% to about 8% w/v sucrose. In some embodiments, the stabilizer is 4% to 8% w/v sucrose.
  • the stabilizer is about 6% to about 8% w/v sucrose.
  • the stabilizer is 4% to 8% w/v sucrose.
  • the stabilizer is about 4% to about 8% w/v trehalose. In some embodiments, the stabilizer is 4% to 8% w/v trehalose.
  • the stabilizer is about 6% to about 8% w/v trehalose. In some embodiments, the stabilizer is 6% to 8% w/v trehalose.
  • the stabilizer is about 6.5% to about 7.5% w/v sucrose. In some embodiments, the stabilizer is 6.5% to 7.5% w/v sucrose.
  • the stabilizer is 6% to 8% sucrose.
  • the stabilizer is 6.5% to 7.5% w/v sucrose.
  • the stabilizer is 7% sucrose.
  • the formulations of the invention comprise arginine, e.g ., L-arginine, or a pharmaceutically acceptable salt thereof, e.g. , HC1; lysine, e.g. , L-lysine, or a pharmaceutically acceptable salt thereof, e.g.
  • HC1 or a combination of arginine (L-arginine), or a pharmaceutically acceptable salt (HC1) thereof and lysine (L-lysine), or a pharmaceutically acceptable salt (HC1) thereof; or a combination of arginine (L-arginine), or a pharmaceutically acceptable salt (HC1) thereof and glutamate (L-glutamate), or a pharmaceutically acceptable salt thereof; all of which may provide additional stability to the formulation, as well as control viscosity, which allows formulation at high API concentration.
  • the formulations of the invention also comprise a buffer.
  • the buffer is present in an amount of about 5 mM to about 20 mM, which provides for a pH in the range of about 5 to about 7. In some embodiments, the buffer is present in an amount of 5 mM to 20 mM, which provides for a pH in the range of 5 to 7.
  • the buffer provides the formulation a pH in the range from about 5.5 to about 6.5. In some embodiments of the invention, the buffer provides the formulation a pH in the range from 5.5 to 6.5. In some embodiments, the buffer has a pH in a range of about 6.0. In still further embodiments, the pH is 6.0.
  • the buffer has a pH of about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, or about 6.3. In particular embodiments, the buffer has a pH of 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, or 6.3.
  • buffers that will control the pH in this range include succinate (sodium or potassium), histidine, sodium acetate, phosphate (sodium or potassium), Tris (tris (hydroxymethyl) aminomethane), diethanolamine, citrate (sodium) and other organic acid buffers.
  • the buffer is histidine or acetate at a pH of about 5.5 to about 6.5. In some embodiments of the invention, the buffer is histidine or acetate at a pH of 5.5 to 6.5. In some embodiments, the buffer is an L-histidine buffer. In embodiments where the formulation is lyophilized, it is preferred that the buffer is not acetate because acetate buffer systems are not compatible with the lyophilization process.
  • pH refers to the pH after reconstitution of the lyophilized formulations of the invention.
  • the pH is typically measured at 25°C using standard glass bulb pH meter.
  • a solution comprising“histidine buffer at pH X” refers to a solution at pH X and comprising the histidine buffer, i.e. the pH is intended to refer to the pH of the solution.
  • the formulations of the invention also comprise an anti-oxidant.
  • the anti-oxidant is methionine.
  • the anti -oxidant is L-methionine, or a pharmaceutically acceptable salt thereof.
  • the methionine is L-methionine.
  • the anti-oxidant is L-methionine HC1.
  • the anti-oxidant is histidine.
  • the anti-oxidant e.g . L-methionine
  • the anti-oxidant is present in the formulations of the invention in an amount of about 1 mM to about 20 mM. In some embodiments, the anti-oxidant is present in an amount of about 5 mM to about 20 mM, about 5 mM to about 15 mM, about 5 mM to about 10 mM.
  • the anti-oxidant is present in an amount of about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM or about 20 mM. In some embodiments, the anti-oxidant is present in an amount of 5 mM to 20 mM, 5 mM to 15 mM, 5 mM to 10 mM.
  • the anti -oxidant is present in an amount of 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM or 20 mM.
  • the histidine can be present in amounts up to 100 mM.
  • histidine can serve as a buffer, an anti-oxidant, and/or to reduce viscosity in the formulations described herein.
  • histidine may be present in a concentration of about 10-20 mM, about 20-30 mM, about 30-40 mM, about 40-50 mM, about 50-60 mM, about 60-70 mM, about 70-80 mM, about 80-90 mM, or about 90-100 mM.
  • histidine may be present in a concentration of 10-20 mM, 20-30 mM, 30-40 mM, 40-50 mM, 50-60 mM, 60-70 mM, 70-80 mM, 80-90 mM, or 90-100 mM. In some embodiments, histidine may be present in a concentration of about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, or about 100 mM.
  • histidine may be present in a concentration of 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, or 100 mM.
  • the formulations of the invention also comprise a surfactant.
  • Surfactants are typically added to formulations to provide stability, reduce and/or prevent aggregation or to prevent and/or inhibit protein damage during processing conditions such as purification, filtration, freeze-drying, transportation, storage, and delivery.
  • a surfactant is useful for providing additional stability to the active ingredient(s), i.e. the anti-RSV antibody or antigen-binding fragment thereof.
  • Surfactants that may be useful in the formulations of the invention include, but are not limited to: nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters (Polysorbates, sold under the trade name TWEEN (ETniquema Americas LLC, Wilmington, DE)) including Polysorbate-20 (polyoxyethylene sorbitan monolaurate), Polysorbate-40 (polyoxyethylene sorbitan monopalmitate), Polysorbate-60 (polyoxyethylene sorbitan monostearate), and Polysorbate-80 (polyoxyethylene sorbitan monooleate); polyoxyethylene alkyl ethers such as BRIJ 58 (Uniquema Americas LLC, Wilmington, DE) and BRIJ 35; poloxamers ( e.g ., poloxamer 188); TRITON X-100 (Union Carbide Corp., Houston, TX) and TRITON X-l 14; NP40; Span 20, Span 40, Span 60, Span 65, Span 80 and Span
  • the amount of surfactant to be included in the formulations of the invention is an amount sufficient to perform the desired function, i.e. a minimal amount necessary to stabilize the active pharmaceutical ingredient (i.e. the anti-RSV antibody or antigen-binding fragment thereof) in the formulation.
  • the surfactant is present in a concentration of from about 0.008% to about 0.1% w/v.
  • the surfactant is present in the formulation in an amount from about 0.01% to about 0.04% w/v; from about 0.01% to about 0.03% w/v, from about 0.01% to about 0.02% w/v, from about 0.015% to about 0.04% w/v; from about 0.015% to about 0.03% w/v, from about 0.015% to about 0.02% w/v, from about 0.02% to about 0.04% w/v, from about 0.02% to about 0.035% w/v, or from about 0.02% to about 0.03% w/v.
  • the surfactant is present in an amount of about 0.02% w/v.
  • the surfactant is present in an amount of about 0.01%, about 0.015%, about 0.025%, about 0.03%, about 0.035%, or about 0.04% w/v.
  • the surfactant is a nonionic surfactant selected from the group consisting of: Polysorbate 20, Polysorbate 80 and F127. In preferred embodiments, the surfactant is Polysorbate 80.
  • the anti-RSV antibody formulations comprise about 0.01% to about 0.04% w/v PS80.
  • the anti-RSV antibody formulations comprise PS80 in an amount of about 0.008%, about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04% or about 0.045% w/v.
  • the anti-RSV antibody formulations comprise about 0.02% w/v PS80.
  • the anti- RSV antibody formulations comprise 0.01% to 0.04% w/v PS80.
  • the anti- RSV antibody formulations comprise PS80 in an amount of 0.008%, 0.01%, 0.015%, 0.02%,
  • the anti-RSV antibody formulations comprise 0.02% w/v PS80.
  • the anti-RSV antibody formulations of the invention comprise a chelator selected from DTPA and EDTA.
  • the chelator is DTPA.
  • the amount of DTPA is about 10 mM to about 90 pM, about 25 pM to about 75 pM, or about 50 pM.
  • the chelator is DTPA.
  • the amount of DTPA is 10 pM to 90 pM, 25 pM to 75 pM, or 50 pM.
  • embodiments of the formulation can contain a stabilizer, a buffer, an anti-oxidant, a surfactant, and a chelator, in the amounts/concentrations specified above.
  • the disclosure also provides an anti-RSV antibody formulation as described herein, wherein the formulation is contained in a glass vial or injection device ( e.g . a syringe).
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 2-8°C for 12 months, the percent of heavy chain and light chain measured by reducing CE-SDS is > 96%.
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 2-8°C for 12 months the percent of intact IgG in the formulation measured by non-reducing CE-SDS is > 97%.
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 2-8°C for 12 months, the percent of monomer as measured by HP-SEC is > 98.5%.
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 2-8°C for 12 months, the percent of high molecular weight species as measured by HP-SEC is ⁇ 1.5%. In further embodiments, the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 25°C for 12 months, the percent of monomer as measured by HP-SEC is > 98.0%.
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 25°C for 6 months, the percent of high molecular weight species as measured by HP-SEC is ⁇ 2%.
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 40°C for 3 months, the percent of monomer as measured by HP-SEC is > 94.0%, > 94.5% or > 95.0%.
  • the disclosure provides anti-RSV antibody formulations as described herein, wherein after storage of the formulation at 40°C for 3 months, the percent of high molecular weight species as measured by HP-SEC is ⁇ 5.5%, ⁇ 5.0%, or ⁇ 4.4%.
  • an anti-RSV antibody formulation comprising: a) about 50 mg/mL to about 250 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM buffer; c) a stabilizer selected from the group consisting of: (i) about 6% to about 8% weight/volume (w/v) non-reducing sugar; (ii) about 25 mM to about 75 mM of L-arginine, or a pharmaceutically acceptable salt of L-arginine; about 25 mM to about 75 mM L-proline, or a pharmaceutically acceptable salt of L-proline; about 25 mM to about 75 mM L- glutamate, or a pharmaceutically acceptable salt of L-glutamate; about 25 mM to about 75 mM L- lysine, or a pharmaceutically acceptable salt of L-lysine, or a mixture of such amino acids, and (iii) about 25 mM to
  • an anti-RSV antibody formulation comprising: a) about 50 mg/mL to about 150 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 6% to about 8% weight/volume (w/v) sucrose; d) an excipient selected from about 25 mM to about 75 mM of L-arginine or a
  • L-arginine about 25 mM to about 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine, about 25 mM to about 75 mM of a mixture of L- arginine(HCl) and L-glutamate, and about 25 mM to about 75 mM of a mixture of L-arginine(HCl) and L-lysine(HCl); e) about 25 to 75 mM of DTP A; f) about 0.01% to about 0.10% polysorbate 80; and optionally g) about 1 mM to about 20 mM L-methionine.
  • an anti-RSV antibody formulation comprising: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) an excipient selected from 50 mM L-arginine(HCl), 50 mM L- lysine(HCl), a mixture of 25 mM L-arginine and 25 mM L-glutamate, and a mixture of 25 mM L- arginine(HCl) and 25 mM L-lysine(HCl); e) 50 mM DTP A; f) 0.02% polysorbate 80; and optionally g) 1 mM to 20 mM L-methionine.
  • an anti-RSV antibody formulation comprising: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) a mixture of 25 mM L-arginine(HCl) and 25 mM L- lysine(HCl); e) 50 mM DTP A; and f) 0.02% polysorbate 80.
  • the concentration of the anti-RSV antibody, or antigen-binding fragment thereof is about 50 mg/mL to about 150 mg/mL. In another aspect, the concentration of the anti- RSV antibody, or antigen-binding fragment thereof, is about 75 mg/mL to about 125 mg/mL. In another aspect, the concentration of the anti-RSV antibody, or antigen-binding fragment thereof, is 50 mg/mL to 150 mg/mL. In another aspect, the concentration of the anti-RSV antibody, or antigen binding fragment thereof, is 75 mg/mL to 125 mg/mL. In another aspect, the concentration of the anti-RSV antibody, or antigen-binding fragment thereof, is 100 mg/mL. In another aspect, the concentration of the anti-RSV antibody, or antigen-binding fragment thereof, is 75 mg/mL. In another aspect, the concentration of the anti-RSV antibody, or antigen-binding fragment thereof, is 50 mg/mL.
  • the formulation has a pH between about 5.5 and about 6.5. In another aspect, the formulation has a pH between 5.5 and 6.5. In another aspect, the formulation has a pH of 6.0.
  • the buffer is histidine.
  • the concentration of histidine is from about 1 mM to about 20 mM. In another aspect, the concentration of histidine is from about 5 mM to about 15 mM. In another aspect, the concentration of histidine is 1 mM to 20 mM. In another aspect, the concentration of histidine is 5 mM to 15 mM. In another aspect, the
  • the instant formulation comprises a stabilizer selected from a non reducing sugar; L-arginine, or a pharmaceutically acceptable salt of L-arginine; L-proline, or a pharmaceutically acceptable salt of L-proline; L-glutamate, or a pharmaceutically acceptable salt of L-glutamate; L-lysine, or a pharmaceutically acceptable salt of L-lysine; or a mixture of such amino acids.
  • the instant formulation comprises an excipient selected from about 50 mM L-arginine(HCl), about 50 mM L-lysine(HCl), a mixture of about 25 mM L-arginine and about 25 mM L-glutamate, and a mixture of about 25 mM L-arginine(HCl) and about 25 mM L- lysine(HCl).
  • the instant formulation comprises a chelator which is DTPA at a concentration of about 25 mM to about 75 mM. In another aspect, the instant formulation comprises a chelator which is DTPA at a concentration of about 50 pM. In another aspect, the instant formulation comprises a chelator which is DTPA at a concentration of 50 pM.
  • the formulation comprises a non-ionic surfactant which is PS80 at a concentration of about 0.01% to about 0.10% w/v. In another aspect, the formulation comprises a non-ionic surfactant which is PS80 at a concentration of about 0.02% w/v. In another aspect, the formulation comprises a non-ionic surfactant which is PS80 at a concentration of 0.02% w/v.
  • the formulation comprises an antioxidant which is L-methionine at a concentration of about 1 mM to about 20 mM. In another aspect, the formulation comprises an antioxidant which is L-methionine at a concentration of about 10 mM. In another aspect, the formulation comprises an antioxidant which is L-methionine at a concentration of 10 mM.
  • an anti-RSV antibody formulation comprising: a) about 50 mg/mL to about 250 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) an excipient selected from the group consisting of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine, about 25 mM to about 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine, a mixture of about 25 mM to about 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-glutamate or a pharmaceutically acceptable salt of L-glutamate, and a mixture of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to 8% (w/v) sucrose; d) 25 mM to 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) about 25 mM to about 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to 8% (w/v) sucrose; d) 25 mM to 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) a mixture of about 25 mM to about 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-glutamate or a pharmaceutically acceptable salt of L-glutamate; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to about 8% (w/v) sucrose; d) a mixture of 25 mM to 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and 25 mM to 75 mM L- glutamate or a pharmaceutically acceptable salt of L-glutamate; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) a mixture of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 20 mM histidine; c) 4% to 8% (w/v) sucrose; d) a mixture of 25 mM to 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine and 25 mM to 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the disclosure provides an anti-RSV antibody formulation
  • the disclosure provides an anti-RSV antibody formulation comprising: a) 50 mg/mL to 250 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 100 mM histidine; c) 4% to 8% (w/v) sucrose; and d) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 100 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) about 25 mM to about 75 mM of L- arginine or a pharmaceutically acceptable salt of L-arginine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 100 mM histidine; c) 4% to 8% (w/v) sucrose; d) 25 mM to 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 100 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) about 25 mM to about 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 100 mM histidine; c) 4% to 8% (w/v) sucrose; d) 25 mM to 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 100 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) a mixture of about 25 mM to about 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-glutamate or a pharmaceutically acceptable salt of L-glutamate; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 100 mM histidine; c) 4% to about 8% (w/v) sucrose; d) a mixture of 25 mM to 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and 25 mM to 75 mM L-glutamate or a
  • the anti-RSV antibody formulation comprises: a) about 50 mg/ml to about 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 100 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) a mixture of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) about 0.01% to about 0.10% (w/v) polysorbate 80.
  • the anti-RSV antibody formulation comprises: a) 50 mg/ml to 250 mg/ml of an anti-RSV antibody, or antigen-binding fragment thereof; b) 5 mM to 100 mM histidine; c) 4% to 8% (w/v) sucrose; d) a mixture of 25 mM to 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine and 25 mM to 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine; and e) 0.01% to 0.10% (w/v) polysorbate 80.
  • the histidine concentration is between about 70 mM and about 90 mM. In some embodiments, the histidine concentration is between 70 mM and 90 mM. In some embodiments, the histidine concentration is about 80 mM. In some embodiments, the histidine concentration is 80 mM.
  • the anti-RSV antibody formulation comprises about 125 mg/mL to about 175 mg/mL of the anti-RSV antibody, or antigen binding fragment thereof. In one embodiment, the anti-RSV antibody formulation comprises 125 mg/mL to 175 mg/mL of the anti-RSV antibody, or antigen -binding fragment thereof. In one embodiment, the anti-RSV antibody formulation comprises about 150 mg/ml of the anti-RSV antibody, or antigen-binding fragment thereof. In one embodiment, the anti-RSV antibody formulation comprises 150 mg/ml of the anti-RSV antibody, or antigen-binding fragment thereof.
  • the anti-RSV antibody formulation comprises about 150 mg/mL to about 200 mg/mL of the anti-RSV antibody, or antigen- binding fragment thereof. In some embodiments, the anti-RSV antibody formulation comprises 150 mg/mL to 200 mg/mL of the anti-RSV antibody, or antigen-binding fragment thereof. In some embodiments, the anti-RSV antibody formulation comprises about 175 mg/ml of the anti-RSV antibody, or antigen-binding fragment thereof. In some embodiments, the anti-RSV antibody formulation comprises 175 mg/ml of the anti-RSV antibody, or antigen-binding fragment thereof.
  • the anti-RSV antibody formulation comprises about 175 mg/mL to about 225 mg/mL of the anti-RSV antibody, or antigen binding fragment thereof. In some embodiments, the anti-RSV antibody formulation comprises 175 mg/mL to 225 mg/mL of the anti-RSV antibody, or antigen-binding fragment thereof. In some embodiments, the anti-RSV antibody formulation comprises about 200 mg/ml of the anti-RSV antibody, or antigen-binding fragment thereof. In some embodiments, the anti-RSV antibody formulation comprises 200 mg/ml of the anti-RSV antibody, or antigen-binding fragment thereof.
  • the anti-RSV antibody formulation further comprises about 25 to about 75 mM diethylenetriamine pentaaeetate (DTP A). In some embodiments, the anti-RSV antibody formulation further comprises 25 to 75 pM
  • DTP A diethylenetriamine pentaaeetate
  • the anti-RSV antibody formulation further comprises about 1 mM to about 20 mM L-methionine. In some embodiments, the anti-RSV antibody formulation further comprises 1 mM to 20 mM L-methionine.
  • the pH of the anti-RSV antibody formulation is 5.5 to 6.5. In some embodiments, the pH of the anti-RSV antibody formulation is about 6.0. In some embodiments, the pH of the anti-RSV antibody formulation is 6.0.
  • the anti-RSV antibody comprises CDRs having the amino acid sequences of SEQ ID NOs: 1-6. In some embodiments, the anti-RSV antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-RSV antibody comprises a heavy chain immunoglobulin consisting of the amino acid sequence set forth in SEQ ID NO: 9 and a light chain immunoglobulin consisting of the amino acid sequence set forth in SEQ ID NO: 10. In one aspect, the disclosure provides a method of treating or preventing RSV infection in a human patient in need thereof comprising: administering an effective amount of the anti-RSV antibody formulation of any one of the above aspects and embodiments to the patient.
  • the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof, of about 10 mg to about 150 mg. In some embodiments, the effective amount of the anti- RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof of 10 mg to 150 mg. In some embodiments, the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof between about 25 mg and about 125 mg. In some embodiments, the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof between 25 mg and 125 mg.
  • the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof between about 50 mg and about 100 mg. In some embodiments, the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof between 50 mg and 100 mg. In some embodiments, the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof of about 100 mg. In some embodiments, the effective amount of the anti-RSV antibody formulation comprises a fixed dose of anti-RSV antibody or antigen-binding fragment thereof of about 100 mg.
  • the anti-RSV antibody formulation is administered by intramuscular administration.
  • the disclosure provides an anti-RSV antibody formulation of any one of the foregoing aspects or embodiments for use in a method for treating or preventing RSV infection in a human patient.
  • the disclosure provides for use of the anti-RSV antibody formulation of any one of the foregoing aspects or embodiments in the manufacture of a medicament for treating or preventing RSV infection in a human patient.
  • any of the formulations described herein is in an aqueous solution.
  • the invention provides lyophilized formulations made by lyophilizing an aqueous formulation to provide a reconstituted formulation of the invention, as discussed more fully, infra.
  • Lyophilized formulations of therapeutic proteins provide several advantages. Lyophilized formulations in general offer better chemical stability than solution formulations, and thus increased half-life. A lyophilized formulation may also be reconstituted at different concentrations depending on clinical factors, such as route of administration or dosing. For example, a lyophilized formulation may be reconstituted at a high concentration (i.e . in a small volume) if necessary for subcutaneous administration, or at a lower concentration if administered intravenously. High concentrations may also be necessary if high dosing is required for a particular subject, particularly if administered subcutaneously where injection volume must be minimized.
  • therapeutic proteins e.g ., anti-RSV antibody, or an antigen binding fragment thereof
  • lyophilized antibody formulation is disclosed at U.S. Pat. No. 6,267,958, which is hereby incorporated by reference in its entirety.
  • Lyophilized formulations of another therapeutic protein are disclosed at U.S. Pat. No. 7,247,707, which is hereby incorporated by reference in its entirety.
  • the lyophilized formulation is prepared in anticipation of reconstitution at high concentration of drug product (DP, in an exemplary embodiment an anti-RSV antibody, or antigen binding fragment thereof), i.e. in anticipation of reconstitution in a low volume of water.
  • drug product in an exemplary embodiment an anti-RSV antibody, or antigen binding fragment thereof
  • Subsequent dilution with water or isotonic buffer can then readily be used to dilute the DP to a lower concentration.
  • excipients are included in a lyophilized formulation of the invention at levels that will result in a roughly isotonic formulation when reconstituted at high DP concentration, e.g. for subcutaneous administration. Reconstitution in a larger volume of water to give a lower DP concentration will necessarily reduce the tonicity of the reconstituted solution, but such reduction may be of little significance in non-subcutaneous, e.g. intravenous, administration.
  • the lyophilized powder may be reconstituted in the standard low volume of water and then further diluted with isotonic diluent, such as 0.9% sodium chloride.
  • an anti-RSV antibody (or antigen-binding fragment thereof) is formulated as a lyophilized powder for reconstituting and utilizing for intravenous, subcutaneous, or intramuscular administration.
  • the antibody or antigen- binding fragment thereof
  • the antibody is provided at about 50 mg/vial, and is reconstituted with sterile water for injection prior to use. If desired, the reconstituted antibody may be aseptically diluted with 0.9% sodium chloride Injection USP in a sterile IV container.
  • the target pH of the reconstituted formulation is 5.5 ⁇ 0.5.
  • the lyophilized formulation of the invention enables reconstitution of the anti-RSV antibody to high concentrations, such as about 20, 25, 30, 40, 50, 60, 75, 100, 125, 150, 175 or more mg/mL.
  • Lyophilized formulations are by definition essentially dry, and thus the concept of concentration is not useful in describing them. Describing a lyophilized formulation in the terms of the weight of the components in a unit dose vial is more useful, but is problematic because it varies for different doses or vial sizes. In describing the lyophilized formulations of the invention, it is useful to express the amount of a component as the ratio of the weight of the component compared to the weight of the drug substance (DS) in the same sample (e.g . a vial). This ratio may be expressed as a percentage. Such ratios reflect an intrinsic property of the lyophilized formulations of the invention, independent of vial size, dosing, and reconstitution protocol.
  • the lyophilized formulation of anti-RSV antibody, or antigen-binding fragment is defined in terms of the pre-lyophilization solution used to make the lyophilized formulation, such as the pre-lyophilization solution.
  • the pre-lyophilization solution comprises antibody, or antigen-binding fragment thereof, at a concentration of about 10 mg/mL, about 25 mg/mL, or about 50 mg/mL.
  • Such pre-lyophilization solutions may be at pH 4.4 - 5.2 (including about 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1. and 5.2), e.g. preferably about pH 4.8, or about pH 5.5.
  • the lyophilized formulation of anti-RSV antibody, or antigen binding fragment is defined in terms of the reconstituted solution generated from the lyophilized formulation.
  • Reconstituted solutions may comprise antibody, or antigen-binding fragment thereof, at concentrations of about 50, 60, 75, 80, 90 or 100 mg/mL or higher concentrations such as 150 mg/mL, 167 mg/mL, 200 mg/mL, or up to about 250 mg/mL.
  • Such reconstituted solutions may be at about pH 5.5, or range from about pH 5.0 to about 6.0.
  • the lyophilized formulations of the invention are formed by lyophilization (freeze-drying) of a pre-lyophilization solution. Freeze-drying is accomplished by freezing the formulation and subsequently subliming water at a temperature suitable for primary drying. Under this condition, the product temperature is below the eutectic point or the collapse temperature of the formulation. Typically, the shelf temperature for the primary drying will range from about -30 to 25°C (provided the product remains frozen during primary drying) at a suitable pressure, ranging typically from about 50 to 250 mTorr.
  • the formulation, size and type of the container holding the sample (e.g, glass vial) and the volume of liquid will dictate the time required for drying, which can range from a few hours to several days (e.g. 40-60 hrs).
  • a secondary drying stage may be carried out at about 0- 40°C, depending primarily on the type and size of container and the type of protein employed.
  • the secondary drying time is dictated by the desired residual moisture level in the product and typically takes at least about 5 hours.
  • the moisture content of a lyophilized formulation is less than about 5%, and preferably less than about 3%.
  • the pressure may be the same as that employed during the primary drying step. Freeze-drying conditions can be varied depending on the formulation and vial size.
  • the container in which reconstitution of the protein is to be carried out may, for example, be a 3, 5, 10, 20, 50 or 100 cc vial.
  • the lyophilized formulations of the invention are reconstituted prior to administration.
  • the protein may be reconstituted at a concentration of about 10, 15, 20, 25, 30, 40, 50, 60, 75, 80, 90 or 100 mg/mL or higher concentrations such as 150 mg/mL, 200 mg/mL, 250 mg/mL, or 300 mg/mL up to about 500 mg/mL.
  • High protein concentrations are particularly useful where subcutaneous delivery of the reconstituted formulation is intended.
  • lower concentrations of the protein may be desired (e.g. from about 5-50 mg/mL).
  • Reconstitution generally takes place at a temperature of about 25°C to ensure complete hydration, although other temperatures may be employed as desired.
  • the time required for reconstitution will depend, e.g., on the type of diluent, amount of excipient(s) and protein.
  • Exemplary diluents include sterile water, bacteriostatic water for injection (BWFI), a pH buffered solution (e.g. phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.
  • BWFI bacteriostatic water for injection
  • a pH buffered solution e.g. phosphate-buffered saline
  • sterile saline solution e.g. sterile saline solution
  • Ringer's solution sterile saline solution
  • dextrose solution e.g., Ringer's solution, Ringer's solution or dextrose solution.
  • the disclosure provides a liquid anti-RSV antibody formulation that is reconstituted from a lyophilized formulation wherein the reconstituted solution comprises: a) about 50 mg/mL to about 150 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 6% to about 8% weight/volume (w/v) sucrose; d) an excipient selected from about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L- arginine, about 25 mM to about 75 mM of L-proline or a pharmaceutically acceptable salt of L- proline, about 25 mM to about 75 mM of L-glutamate or a pharmaceutically acceptable salt of L- glutamate, about 25 mM to about 75 mM L-lysine or a pharmaceutically acceptable salt of L-lysine, about 25 mM to about 75 mM of a mixture of L
  • the disclosure provides a liquid anti-RSV antibody formulation that is reconstituted from a lyophilized formulation wherein the reconstituted solution comprises: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) an excipient selected from 50 mM L-arginine(HCl), 50 mM L-lysine(HCl), a mixture of 25 mM L-arginine and 25 mM L-glutamate, and a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50 pM DTP A; f) 0.02% polysorbate 80; and optionally g) 1 mM to 20 mM L- methionine.
  • the disclosure provides a liquid anti-RSV antibody formulation that is reconstituted from a lyophilized formulation wherein the reconstituted solution comprises: a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50 pM DTP A; and f) 0.02% polysorbate 80.
  • the disclosure also provides a liquid anti-RSV antibody formulation that is reconstituted from a lyophilized formulation wherein the reconstituted solution comprises: a) about 50 mg/mL to about 250 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) about 5 mM to about 20 mM histidine; c) about 4% to about 8% (w/v) sucrose; d) an excipient selected from the group consisting of about 25 mM to about 75 mM of L-arginine or a pharmaceutically acceptable salt of L-arginine, about 25 mM to about 75 mM of L-lysine or a pharmaceutically acceptable salt of L-lysine, a mixture of about 25 mM to about 75 mM L-arginine or a pharmaceutically acceptable salt of L-arginine and about 25 mM to about 75 mM L-glutamate or a pharmaceutically acceptable salt of L-glutamate, and a mixture of about 25 mM
  • a liquid antibody formulation can be made by taking the drug substance (e.g ., anti-RSV antibody) which is in liquid form and buffer exchanging it into the desired buffer as the last step of the purification process. There is no lyophilization step in this embodiment.
  • the drug substance in the final buffer is concentrated to a desired concentration.
  • Excipients such as sucrose, methionine and polysorbate 80 are added to the drug substance and it is diluted using the appropriate buffer to final protein concentration.
  • the final formulated drug substance is filtered, e.g. using 0.22 pm filters, and filled into a final container (e.g. glass vials or syringes).
  • Such a liquid formulation is exemplified by a final liquid formulation comprising a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50 pM DTP A; and f) 0.02% polysorbate 80.
  • a final liquid formulation comprising a) 100 mg/mL of an anti-RSV antibody, or antigen-binding fragment thereof; b) 10 mM histidine; c) 7% weight/volume (w/v) sucrose; d) a mixture of 25 mM L-arginine(HCl) and 25 mM L-lysine(HCl); e) 50 pM DTP A; and f) 0.02% polysorbate 80.
  • the invention also relates to a method of preventing or treating RSV infection in a subject, the method comprising administering an effective amount of any of the formulations of the invention; /. e. , any formulation described herein, to the subject.
  • the formulation is administered to the subject via intravenous administration.
  • the formulation is administered to the subject via subcutaneous administration.
  • the formulation is administered via intramuscular administration.
  • a mammal preferably a human
  • a prophylactic, therapeutic or pharmaceutical formulation of the present invention for the treatment, prevention or amelioration of one or more symptoms associated with a RSV infection in an amount effective for decreasing RSV titers.
  • an effective amount of an anti-RSV antibody or antibody fragment reduces the RSV titers in the lung as measured, for example, by the concentration of RSV in sputum samples or a lavage from the lungs from a mammal.
  • a mammal preferably a human
  • a prophylactic, therapeutic or pharmaceutical formulation comprising an anti-RSV antibody of the present invention or fragments thereof for the treatment, prevention or amelioration of symptoms associated with a RSV infection in an amount effective for neutralizing RSV and/or blocking RSV infection in the mammal.
  • the formulations of the instant invention can also be used immunotherapeutically for RSV disease in both humans and other animals.
  • the term,“immunotherapeutically” or“immunotherapy” as used herein in conjunction with the anti-RSV antibody or antigen-binding fragments thereof of the invention denotes both prophylactic as well as therapeutic administration and both passive immunization with substantially purified polypeptide products, as well as gene therapy by transfer of polynucleotide sequences encoding the product or part thereof.
  • Passive immunization includes transfer of active humoral immunity or providing antibodies to a subject in need thereof.
  • the present invention provides methods for transfer of active humoral immunity and methods of providing RSV antibodies or antigen-binding fragments thereof, such as IgG antibodies, to a patient at risk of RSV infection.
  • RSV antibodies or antigen-binding fragments thereof such as IgG antibodies
  • the monoclonal antibodies or antigen-binding fragments thereof can be administered to high-risk subjects in order to lessen the likelihood and/or severity of RSV disease or administered to subjects already evidencing active RSV infection.
  • the present invention also provides a method for modulating or treating at least one adult or pediatric RSV related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, lower respiratory infections, pneumonia, tracheobronchitis, bronchiolitis, bronchitis, and any related infections or inflammatory disorders, such as but not limited to at least one of, or at least one inflammation related to, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, adult respiratory distress syndrome, allergic rhinitis, perennial rhinitis, asthma, systemic anaphylaxis, receptor hypersensitivity reactions, chronic obstructive pulmonary disease (COPD), hypersensitivity pneumonitis, granulomas due to intracellular organisms, drug sensitivity, cachexia, cystic fibrosis, neonatal chronic lung disease; at least one infectious disease
  • Such a method can optionally comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one RSV antibody or antigenic fragment thereof to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
  • prophylactic, therapeutic or pharmaceutical formulation comprising an anti-RSV antibody of the invention or fragments thereof are administered to a mammal, preferably a human, to treat, prevent or ameliorate one or more symptoms associated with RSV infection.
  • prophylactic, therapeutic or pharmaceutical formulations comprising an anti- RSV antibody of the invention or fragments thereof are administered to a human with cystic fibrosis, bronchopulmonary dysplasia, congenital heart disease, congenital immunodeficiency or acquired immunodeficiency, or to a human who has had a transplant (e.g ., bone marrow, lung, or hematopoietic stem cell transplantation (HSCT)) to treat, prevent or ameliorate one or more symptoms associated with RSV infection.
  • a transplant e.g ., bone marrow, lung, or hematopoietic stem cell transplantation (HSCT)
  • prophylactic, therapeutic or pharmaceutical formulations comprising an anti-RSV antibody of the invention or fragments thereof are administered to a human infant, preferably a human infant bom prematurely or a human infant at risk of hospitalization for RSV infection to treat, prevent or ameliorate one or more symptoms associated with RSV infection.
  • prophylactic, therapeutic or pharmaceutical formulations of the instant invention are administered to the elderly or people in group homes (e.g., nursing homes or rehabilitation centers) or immunocompromised individuals.
  • the present invention provides a method of preventing respiratory infection caused by RSV. In another embodiment, the present invention provides a method of preventing lower respiratory infection caused by RSV. In another embodiment, the present invention provides a method of preventing lower respiratory infection caused by RSV A and B strains. In another embodiment, the present invention provides a method of preventing medically attended lower respiratory infection caused by RSV A and B strains in infants bom > 29 weeks of gestation and ⁇ 8 months of age at time of dosing. In another embodiment, the present invention provides a method of preventing lower respiratory tract infection caused by RSV in all infants entering their first RSV season and children with chronic lung disease or congenital heart disease entering their first and second RSV season.
  • Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g, Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et al. (2000) J Immunol. 165:6205; He, et al. (1998) J Immunol. 160: 1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al.
  • Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (see, e.g., Meyaard e/ a/. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13 :233-242; Preston et al, supra, Kaithamana et al. (1999) J. Immunol. 163 :5157-5164).
  • Antibodies can be conjugated, e.g, to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, e.g, to dyes, radioisotopes, enzymes, or metals, e.g, colloidal gold (see, e.g., Le Doussal et al. (1991) J. Immunol. 146: 169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811; Everts et al. (2002) J.
  • PEG polyethylene glycol
  • Fluorescent reagents suitable for modifying nucleic acids including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g, as diagnostic reagents, are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, OR; Sigma-Aldrich (2003) Catalogue,
  • Analytical methods suitable for evaluating the product stability include size exclusion chromatography (SEC), dynamic light scattering test (DLS), differential scanning calorimetery (DSC), iso-asp quantification, potency, LTV at 340 nm, LTV spectroscopy, and FTIR.
  • SEC size exclusion chromatography
  • DSC differential scanning calorimetery
  • iso-asp quantification potency, LTV at 340 nm, LTV spectroscopy, and FTIR.
  • SEC J. Pharm. Scien., 83 : 1645-1650, (1994); Pharm. Res., 11 :485 (1994); J. Pharm. Bio. Anal., 15: 1928 (1997); J. Pharm. Bio. Anal., 14: 1133-1140 (1986)
  • DSC Pharm. Res., 15:200 (1998); Pharm. Res., 9: 109 (1982
  • the iso-asp content in the samples is measured using the Isoquant Isoaspartate Detection System (Promega).
  • the kit uses the enzyme Protein Isoaspartyl Methyltransferase (PIMT) to specifically detect the presence of isoaspartic acid residues in a target protein.
  • PIMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to isoaspartic acid at the .alpha.-carboxyl position, generating S-adenosyl-L-homocysteine (SAH) in the process.
  • SAH S-adenosyl-L-homocysteine
  • the potency or bioidentity of an antibody can be measured by its ability to bind to its antigen.
  • the specific binding of an antibody to its antigen can be quantitated by any method known to those skilled in the art, for example, an immunoassay, such as ELISA (enzyme-linked
  • Ultra Performance - Size Exclusion Chromatography was performed by diluting the samples (anti-RSV antibody) to 1.0 mg/mL in mobile phase (100 mM sodium phosphate and 100 mM sodium chloride, pH 7.0); flow rate of 0.5 mL/min. The diluted samples were injected (5 pL) into a UPLC equipped with a Waters BEH200 column and a UV detector. Proteins in the sample were separated by size and detected by UV absorption at 214 nm.
  • Anti-RSV Antibody Formulation Excipient amino acids and mixtures thereof Screening (to reduce aggregation)
  • the first two excipients were examined to understand the effects of the positively charged lysine and arginine in the presence of the chloride counteranion.
  • the third excipient was tested to understand the effect of arginine in the presence of another counteranion (glutamate).
  • the fourth excipient was a mixture of the first two excipients to determine if the two excipients can play a complementary role. It was hypothesized that this mixture may play a better role than the individual excipients, as the mixture of excipients have different pKa and differentially shield the surface change distribution of the mAb, thereby increasing repulsive interactions, which in turn would reduce aggregation and viscosity.
  • the five formulations were filled into vials and staged on stability at 5°C (ambient humidity), 25° C (60% relative humidity), and 40°C (75% relative humidity) for eight weeks protected from light.
  • the five formulations are listed in Table 2 below.
  • Ultra Performance - Size Exclusion Chromatography was performed by diluting the samples to 1.0 mg/mL (anti-RSV antibody) in mobile phase (100 mM sodium phosphate and 100 mM sodium chloride, pH 7.0); flow rate of 0.5 mL/min.
  • the diluted samples were injected (5 pL) into a UPLC equipped with a Waters BEH200 column and a UV detector. Proteins in the sample were separated by size and detected by UV absorption at 214 nm.
  • FIGURE 1 As shown in FIGURE 1, FIGURE 2, and FIGURE 3, UP-SEC analysis of the samples to determine the percentage of HMW and percentage of monomer indicated that at 5°C, 25°C and 40°C, all the formulations showed a trend of increase in %UMW peak and %LMW peak (and a consequent decrease in % monomer peak) up to the 8-week time point. At 25°C, all the
  • formulation 1 shows a greater increase in %HMW and %LMW as compared to the other formulations. Additionally, formulation 1 showed a greater decrease of % monomer. Thus, all four sets of excipients decrease the %HMW and %LMW and thus improve the stability of the anti-RSV antibody DP.
  • Anti-RSV Antibody Formulation Excipient Screening (amino acids and mixtures thereof) to improve chemical stability of the anti-RSV antibody
  • the first two excipients were examined to understand the effects of the positively charged lysine and arginine in the presence of the chloride counteranion.
  • the third excipient was tested to understand the effect of arginine in the presence of another counteranion (glutamate).
  • the fourth excipient was a mixture of the first two excipients to determine whether the two excipients can play a complementary role. It was hypothesized that this mixture may play a better role than the individual excipients, as the mixture of excipients have different pKa and differentially shields the surface change distribution of the mAh, and this may impact chemical degradation of the mAh.
  • the five formulations were filled into vials and staged on stability at 5°C (ambient humidity), 25°C (60% relative humidity), and 40°C (75% relative humidity) for eight weeks protected from light.
  • the five formulations are as shown in Example 2.
  • Ion exchange chromatography was performed to evaluate the chemical stability and to monitor the change in the charge variant profile over time.
  • An ion exchange HPLC method was performed using a Dionex ProPac WCX-10 column and a UV detector at 280 nm. Samples were diluted in purified water, and 80 pg were injected for analysis.
  • the mobile phase used for the IEX analysis of the thermal stability samples was a gradient of the following mobile phases (mobile phase A:20 mM MOPS, pH 7.2; mobile phase B: 50 mM sodium phosphate, 60 mM sodium chloride pH 8.0).
  • the assay is performed using a mobile phase gradient from 20 mM MOPS, pH 7.2 to 50 mM sodium phosphate, 60 mM NaCl, pH 8.0. ETV detection was performed at 280 nm.
  • formulation 1 shows a greater increase in % acidic peak as compared to the other formulations. Additionally, formulation 1 showed a greater decrease of % main peak as compared to the other formulations. Thus, all the four sets of excipients decrease the % acidic peak and thus improves the chemical stability of the anti-RSV antibody DP.
  • this mixture may play a better role than the individual excipients, as the mixture of excipients have different pKa and differentially shields the surface change distribution of the mAh, thereby increasing the repulsive protein-protein interaction and decreasing viscosity of the mAh.
  • Viscosity was measured as a function of shear rate with shear rates of samples being determined by sample viscosity.
  • Ultra Performance - Size Exclusion Chromatography was performed by diluting the samples to 1.0 mg/mL in mobile phase (100 mM sodium phosphate and 100 mM sodium chloride, pH 7.0); flow rate of 0.5mL/min. The diluted samples were injected (5 pL) into a UPLC equipped with a Waters BEH200 column and a UV detector. Proteins in the sample were separated by size and detected by UV absorption at 214 nm.
  • FIGURE 8 As shown in FIGURE 8, FIGURE 9 and FIGURE 10, UP-SEC analysis of the samples to determine the percentage of HMW and percentage of monomer indicated that at 5°C, 25°C and 40°C, both formulations showed a trend towards an increase in %HMW peak and %LMW peak (and a consequent decrease in % monomer peak) up to the 8-week time point. At 25°C, both formulations showed similar trends, but smaller changes, as compared to 40°C. At 5°C, no substantial changes were observed.
  • formulation 1 showed a greater increase in %HMW and %LMW as compared to formulation 2. Additionally, formulation 1 showed a greater decrease of % monomer as compared to formulation 2. Thus, DTPA (formulation 2) decreases the %UMW and %LMW and thus improves the aggregation of the anti-RSV antibody DP.
  • the mobile phase used for the IEX analysis of the thermal stability samples was a gradient of the following mobile phases (mobile phase A:20 mM MOPS, pH 7.2; mobile phase B: 50 mM sodium phosphate, 60 mM sodium chloride pH 8.0).
  • the assay was performed using a mobile phase gradient from 20 mM MOPS, pH 7.2 to 50 mM sodium phosphate, 60 mM NaCl, pH 8.0.
  • UV detection was performed at 280 nm.
  • the two formulations were filled into vials and staged on stability at 5°C (ambient humidity), 25° C (60% relative humidity), and 40°C (75% relative humidity) for eight weeks protected from light.
  • the two formulations are as provided in Example 5.
  • FIGURE 14 shows the % degradation of PS80 at 40°C. The % degradation was slightly less for formulation 2 (in the presence of DTPA). Thus, DTPA might protect against PS80 degradation and these two excipients (DTPA and PS80) are mutually compatible.
  • anti-RSV antibody was formulated at two different concentrations (around 200 mg/ml and 154 mg/mL) into four different formulations: a first formulation of lOmM histidine, 7% sucrose and 0.02% PS80, pH6, and three formulations adding an additional high concentration of excipient: 70mM Histidine (for a total concentration of 80mM histidine), 70mM Lysine, or 70mM Arg.
  • the samples were loaded into a 500 pl syringe and viscosity was measured (four times for each sample) at room temperature with an
  • FIGURE 15 shows a bar graph comparing the four different formulations of anti-RSV antibody at their respective concentrations (around 200 mg/ml and at 154 mg/mL).
  • 70 mM lysine, or 70 mM arginine showed a significant decrease in mean viscosity compared with the first formulation.
  • Anti-RSV antibody at 213 mg/mL in the formulation of lOmM histidine, 7% sucrose and 0.02% PS80, pH6 has a mean viscosity of 64.97 centipoise (cP).
  • additional excipient of 70mM histidine total concentration of 80 mM histidine
  • 70mM lysine reduced the mean viscosity of 192 mg/mL anti-RSV antibody formulation to 19.81 cP.

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US12240917B2 (en) 2012-11-02 2025-03-04 Bioverativ Usa Inc. Anti-complement C1s antibodies and uses thereof
US12391750B2 (en) 2016-10-12 2025-08-19 Bioverativ Usa Inc. Anti-C1S antibodies and methods of use thereof
RU2807524C2 (ru) * 2018-10-18 2023-11-15 МЕРК ШАРП И ДОУМ ЭлЭлСи Составы антител к rsv и способы их применения
US11634485B2 (en) 2019-02-18 2023-04-25 Eli Lilly And Company Therapeutic antibody formulation
WO2023245048A1 (en) * 2022-06-15 2023-12-21 Bioverativ Usa Inc. Anti-complement c1s antibody formulation

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US12565526B2 (en) 2026-03-03
CA3115708A1 (en) 2020-04-23
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