WO2023081652A1 - Pharmaceutical compositions of humanized anti-cd40 antibodies - Google Patents

Pharmaceutical compositions of humanized anti-cd40 antibodies Download PDF

Info

Publication number
WO2023081652A1
WO2023081652A1 PCT/US2022/079072 US2022079072W WO2023081652A1 WO 2023081652 A1 WO2023081652 A1 WO 2023081652A1 US 2022079072 W US2022079072 W US 2022079072W WO 2023081652 A1 WO2023081652 A1 WO 2023081652A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
polysorbate
acetate
antibody
antigen
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
Application number
PCT/US2022/079072
Other languages
English (en)
French (fr)
Inventor
James KRANZ
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.)
Kiniksa Phamaceuticals Ltd
Original Assignee
Kiniksa Phamaceuticals Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kiniksa Phamaceuticals Ltd filed Critical Kiniksa Phamaceuticals Ltd
Priority to CA3236827A priority Critical patent/CA3236827A1/en
Priority to CN202280075264.6A priority patent/CN118382640A/zh
Priority to KR1020247016673A priority patent/KR20240095255A/ko
Priority to EP22890984.2A priority patent/EP4426744A4/en
Priority to JP2024526890A priority patent/JP2024540377A/ja
Priority to MX2024005415A priority patent/MX2024005415A/es
Priority to AU2022381078A priority patent/AU2022381078A1/en
Publication of WO2023081652A1 publication Critical patent/WO2023081652A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/26—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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

  • CD40 is expressed primarily on the surface of B lymphocytes and other antigen-presenting cells (APCs) such as dendritic cells and macrophages.
  • CD154 is expressed primarily on the surface of T cells. The interaction between these two proteins is associated with B cell activation, which triggers cytokine expression as well as expression of cell surface markers including CD23, CD80, and CD86.
  • Antibodies e.g., humanized antibodies
  • CD40/CD154 interaction have been developed. However, formulating these antibodies or antigen-binding fragments thereof into suitable pharmaceutical compositions for administration in vivo is necessary for effective treatment.
  • a pharmaceutical composition containing a humanized anti-CD40 antibody or antigen-binding fragment thereof with a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.
  • the humanized anti-CD40 antibody is KPL- 404.
  • the pharmaceutical composition includes polysorbate 20, acetate, and one or more polar excipients.
  • the polar excipient may be or may include, for example, a sugar, a polyol, or an amino acid.
  • the sugar is, for example, sucrose, trehalose, fructose, lactose, dextrose, or mannitol.
  • the polyol is, for example, polyethylene glycol or sorbitol.
  • the amino acid is one or more of alanine, arginine, aspartic acid, asparagine, carnitine, citrulline, ornithine, glycine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 45 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate. In some embodiments, the pharmaceutical composition includes about 50 mM acetate.
  • the pharmaceutical composition includes from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) of the polar excipient.
  • mM to about 200 mM e.g., about 50 m
  • the pharmaceutical composition includes about 50 mM of the polar excipient. In some embodiments, the pharmaceutical composition includes about 100 mM of the polar excipient. In some embodiments, the pharmaceutical composition includes about 150 mM of the polar excipient. In some embodiments, the pharmaceutical composition includes about 200 mM of the polar excipient.
  • the pharmaceutical composition includes from about 1% (w/v) to about 10% (w/v) (e.g., about 2% (w/v) to about 8% (w/v), e.g., about 1% (w/v), 1.5 % (w/v), 2% (w/v), 2.5% (w/v), 3% (w/v), 3.5% (w/v), 4% (w/v), 4.5% (w/v), 5% (w/v), 5.5% (w/v), 6% (w/v), 6.5% (w/v), 7% (w/v), 7.5% (w/v), 8% (w/v), 8.5% (w/v), 9% (w/v), 9.5% (w/v), 10% (w/v)) of the polar excipient.
  • the pharmaceutical composition includes about 2.5% (w/v) of the polar excipient. In some embodiments, the pharmaceutical composition includes about 7% (w/v) of the polar excipient. In some embodiments, the pharmaceutical composition includes from about 0.001% to about 0.1% (e.g., about 0.005% to 0.05%, e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.01% polysorbate 20.
  • the pharmaceutical composition includes about 0.02% polysorbate 20.
  • the composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0, e.g., about 5.4.
  • a pharmaceutical composition containing a humanized anti-CD40 antibody or antigen-binding fragment thereof with a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.
  • the humanized anti-CD40 antibody is KPL-404.
  • the pharmaceutical composition includes polysorbate 20, acetate, and a polar excipient.
  • the polar excipient may include arginine and glutamate.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 45 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate.
  • the pharmaceutical composition includes about 50 mM acetate. In some embodiments, the pharmaceutical composition includes from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) arginine.
  • arginine
  • the pharmaceutical composition includes about 50 mM arginine. In some embodiments, the pharmaceutical composition includes about 100 mM arginine. In some embodiments, the pharmaceutical composition includes from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 50 mM to about 100 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150
  • the pharmaceutical composition includes about 50 mM glutamate. In some embodiments, the pharmaceutical composition includes about 100 mM glutamate. In some embodiments, the pharmaceutical composition includes from about 0.001% to about 0.1% (e.g., about 0.005% to 0.05%, e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.01% polysorbate 20.
  • the pharmaceutical composition includes about 0.02% polysorbate 20.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM acetate; from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM
  • the composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0, e.g., about 5.4.
  • the pharmaceutical composition includes about 50 mM acetate, about 100 mM arginine, 100 mM glutamate, and about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 50 mM acetate, about 100 mM arginine, 100 mM glutamate, and about 0.02% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 50 mM acetate, about 50 mM arginine, 50 mM glutamate, and about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 50 mM acetate, about 50 mM arginine, 50 mM glutamate, and about 0.02% polysorbate 20.
  • the pharmaceutical composition includes about 50 mM acetate, about 100 mM arginine, 50 mM glutamate, and about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 50 mM acetate, about 100 mM arginine, 50 mM glutamate, and about 0.02% polysorbate 20. The composition may have a pH of about 5.4.
  • a pharmaceutical composition including a humanized anti-CD40 antibody or antigen-binding fragment thereof having a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.
  • the pharmaceutical composition includes polysorbate 20, acetate, and a polar excipient.
  • the polar excipient may be or may include sucrose.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate. In some embodiments, the pharmaceutical composition includes about 50 mM acetate.
  • the pharmaceutical composition includes from about 1% (w/v) to about 10% (w/v), e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w/v), sucrose. In some embodiments, the pharmaceutical composition includes about 7% (w/v) sucrose.
  • the pharmaceutical composition includes from about 0.001% to about 0.1% (e.g., about 0.005% to 0.05%, e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20.
  • the pharmaceutical composition includes about 0.01% polysorbate 20.
  • the pharmaceutical composition includes about 0.02% polysorbate 20.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM) acetate, from about 1% (w/v) to about 10% (w/v), e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w/v), e.g., about 7%, sucrose, and from about 0.001% to about 0.1% (e.
  • the composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0, e.g., about 5.4.
  • the pharmaceutical composition includes about 50 mM acetate, about 7% (w/v) sucrose, and about 0.01% polysorbate 20.
  • the composition may have a pH of about 5.4.
  • the pharmaceutical composition includes about 50 mM acetate, about 7% (w/v) sucrose, and about 0.02% polysorbate 20.
  • the composition may have a pH of about 5.4.
  • a pharmaceutical composition including a humanized anti-CD40 antibody or antigen-binding fragment thereof having a heavy chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region having an amino acid sequence with at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%,or 100%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.
  • the pharmaceutical composition includes polysorbate 20, acetate, and a polar excipient.
  • the polar excipient may be or may include sorbitol.
  • the pharamcetuical composition may further include sodium chloride.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate.
  • the pharmaceutical composition includes about 50 mM acetate. In some embodiments, the pharmaceutical composition includes from about 0.1% (w/v) sorbitol to about 5% (w/v), e.g., about 1mM to about 5mM, e.g., about 2mM to about 3mM, e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% (w/v), sorbitol. In some embodiments, the pharmaceutical composition includes about 2.5% (w/v) sorbitol.
  • the pharmaceutical composition includes from about 1 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 50 mM to about 90 mM, e.g., about 60 mM to about 80 mM, e.g., about 65 mM to about 75 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) sodium chloride.
  • mM to about 100 mM e.g., about 10 mM to about 90 mM, e.g., about 50 mM to about 90 mM, e.g., about 60 mM to about 80 mM, e.g., about 65 mM to about 75
  • the pharmaceutical composition includes about 70 mM sodium chloride. In some embodiments, the pharmaceutical composition includes from about 0.001% to about 0.1% (e.g., about 0.005% to 0.05%, e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.02% polysorbate 20.
  • the pharmaceutical composition includes from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM) acetate, from about 0.1% (w/v) sorbitol to about 5% (w/v), e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% (w/v), e.g., about 2.5%,
  • the composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0, e.g., about 5.4.
  • the pharmaceutical composition includes about 50 mM acetate, about 2.5% (w/v) sorbitol, about 70 mM NaCl, and about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 50 mM acetate, about 2.5% (w/v) sorbitol, about 70 mM NaCl, and about 0.02% polysorbate 20. The composition may have pH of about 5.4.
  • the pharmaceutical composition of any one of the first, second, and third aspects has a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0.
  • the pH may be about 5.4.
  • the anti-CD40 antibody or antigen-binding fragment thereof is at a concentration of from about 0.01 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, or about 100 mg/mL to about 200 mg/mL (e.g., 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL
  • the anti-CD40 antibody or antigen-binding fragment thereof is at a concentration of about 200 mg/mL.
  • the composition is formulated in a volume of about 0.1 mL to about 2.0 mL (e.g., about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, or 2.0 mL, 2.5 mL, 3.0 mL, 3.5 mL, 4.0 mL 4.5 mL, 5.5 mL or 5.5 mL).
  • the composition is formulated in a volume of about 2.0 mL. In some embodiments of any one of the first, second, and third aspects, the composition is formulated in a volume of about 0.1 mL to about 2.0 mL (e.g., about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, or 2.0 mL, 2.5 mL, 3.0 mL, 3.5 mL, 4.0 mL 4.5 mL, 5.5 mL or 5.5 mL, e.g., about 2.0 mL, and the antibody or antigen-binding fragment thereof is at a concentration of
  • At least 95% (e.g., at least 98%) of the humanized anti-CD40 antibody or antigen-binding fragment thereof in the composition is in a monomeric form. In some embodiments, less than 5% (e.g., less than 2%) of the humanized anti-CD40 antibody or antigen-binding fragment is present in the composition as a high molecular weight (HMW) species (e.g., in an aggregated form). In some embodiments, an amount of monomeric species of the humanized anti-CD40 antibody or antigen-binding fragment in the composition decreases to no less than 95% (e.g., no less than 98%) following storage at 2-8 °C for 12 months.
  • HMW high molecular weight
  • an amount of HMW species of the humanized anti-CD40 antibody or antigen-binding fragment in the composition increases to no more than 5% (e.g., no more than 2%) following storage at 2-8 ° C for 12 months.
  • a kit that includes a pharmaceutical composition of any one of the first second, and third aspects, as described herein, and instructions for use thereof.
  • featured is the use of a pharmaceutical composition of any one of the first second, and third aspects, as described herein, in the manufacture of a medicament for suppressing the immune system in a human subject.
  • a pharmaceutical composition of any one of the first second, and third aspects, as described herein, for use in suppressing the immune system in a human subject for use in suppressing the immune system in a human subject.
  • the invention features a method of suppressing the immune system in a human subject by administering a pharmaceutical composition of any one of the first second, and third aspects, as described herein, to a subject (e.g., a subject in need thereof, such as a human subject).
  • a subject e.g., a subject in need thereof, such as a human subject.
  • FIG.1 is a set of graphs showing SEC results presented graphically for %Main, %HMW and %LMW species of KPL-404 for Formulations A, 1, and 2.
  • FIGS.2A and 2B are graphs showing comparison of particle concentrations from biophysical characterization studies.
  • FIG.2A shows 200 mg/mL KPL-404 Formulations A-C (no PS20 in Formulation C), and
  • FIG.2B shows high concentrations of KPL-404 in Formulations A-C.
  • FIG.3 is a graph showing viscosity vs. shear rate for high concentration KPL-404 formulations.
  • FIG.4 is a graph showing Total KPL-404 species Population by CG-MALS for formulation A.
  • FIG.5 is a graph showing Total KPL-404 species Population by CG-MALS for formulation B.
  • FIG.6 is a graph showing Total KPL-404 species Population by CG-MALS for formulation C.
  • FIG.7 is a graph showing Exponential depe ndence of measured viscosity vs protein concentration for formulation A (circles), B (squares), and C (triangles).
  • FIG.8 is a graph showing Instron Force Profiles, KPL-404 in Formulation A, with Injection times from a Standard Ypsomate Autoinjector (2.25 mL).
  • FIG.9 is a graph showing Instron Force Profiles, KPL-404 in Formulation B, with Injection times from a Standard Ypsomate Autoinjector (2.25 mL).
  • FIGS.10A and 10B are graphs showing Instron Force Profiles, KPL-404 in Formulation C, with Injection times from a Standard Ypsomate (FIG.10A) or Ypsomate Pro (FIG.10B) Autoinjector (2.25 mL).
  • FIG.13 is a graph showing SEC %Main as a function of time, 5°C storage.
  • FIG.14 is a graph showing SEC %Main as a function of time, 25°C storage.
  • FIG.15 is a graph showing SEC %Main as a function of time, 40°C storage.
  • FIG.16 is a graph showing SEC %Main as a function of time, -70°C storage.
  • the present disclosure relates to pharmaceutical compositions containing anti-CD40 antibodies and antigen-binding fragments of the antibody that may be used in various therapeutic, prophylactic, diagnostic, and other methods.
  • the pharmaceutical compositions contain antibodies or antigen-binding fragments thereof that can block the ability of CD40 to bind CD154 and do so without activating the cell expressing CD40 (e.g., a B cell).
  • compositions described herein may be used to treat autoimmune diseases and disorders.
  • the antibody or antigen-binding fragment thereof is derived from the murine 2C10 antibody and humanized variants thereof, e.g., as described in PCT Pub. Nos. WO 2012/125569 and WO 2017/040932, which are herein incorporated by reference in their entirety, including the sequences described therein.
  • the pharmaceutical compositions contain combinations of specific carriers and excipients that impart surprisingly beneficial properties to the compositions, including the ability to formulate the drug (the anti-CD40 antibodies and antigen-binding fragments thereof) at a high concentration (as described herein), to enhance stability of the composition (e.g., extended shelf-life), to reduce aggregation of the drug, and to improve viscosity parameters of the composition.
  • the components of the pharmaceutical composition are described in more detail below.
  • the pharmaceutical compositions described herein include an antibody or antigen-binding fragment thereof, e.g., derived from the murine 2C10 antibody, including, without limitation, the humanized anti-CD40 antibody identified as KPL-404.
  • the antibody or antigen-binding fragment thereof includes a heavy chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 9.
  • the antibody includes the heavy chain amino acid sequence as set forth in SEQ ID NO: 11.
  • the antibody or antigen-binding fragment thereof includes a light chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to a light chain variable region amino acid sequence as set forth in SEQ ID NO: 10.
  • the antibody includes the light chain amino acid sequence as set forth in SEQ ID NO: 12.
  • the antibodies or antigen-binding fragments thereof each include both a heavy chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to a heavy chain variable region amino acid sequence as set forth in SEQ ID NO: 9, and a light chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 7
  • the antibody includes the heavy chain amino acid sequence as set forth in SEQ ID NO: 11 and the light chain amino acid sequence as set forth in SEQ ID NO: 12.
  • the anti-CD40 antibody is KPL-404.
  • the antibodies or antigen-binding fragments thereof used to produce a pharmaceutical composition described herein include a heavy chain variable region including an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% sequence identity to a heavy chain variable region amino acid sequence set forth in any one of SEQ ID NOs: 13, 14, 16, 17,
  • a heavy chain variable region of the antibody or antigen-binding fragment thereof includes complementarity determining regions (CDRs) that are at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the CDRs of a heavy chain variable region of the KPL-404 antibody (CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 3, 4, 5, respectively).
  • CDRs complementarity determining regions
  • the light chain variable region of the antibody or antigen-binding fragment thereof includes CDRs that are at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the CDRs of a light chain variable region of the KPL-404 antibody (CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 6, 7, 8, respectively).
  • the heavy chain includes the CDRs as set forth in SEQ ID NOs: 3-5, respectively, and the light chain includes the CDRs as set forth in SEQ ID NOs: 6-8, respectively.
  • the heavy chain has at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 9 and the CDRs set forth in SEQ ID NOs: 3-5, respectively, and the light chain has at least 80% (e.g., at least 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 10 and the CDRs set forth in SEQ ID NOs: 6-8, respectively.
  • antibodies or antigen-binding fragments thereof in which specific amino acids have been substituted, deleted, or added are also within the scope of the disclosure. These alternations do not have a substantial effect on the peptide’s biological properties such as binding activity.
  • antibodies may have amino acid substitutions in the framework region, such as to improve binding to the antigen.
  • a selected, small number of acceptor framework residues can be replaced by the corresponding donor amino acids.
  • the donor framework can be a mature or germline human antibody framework sequence or a consensus sequence.
  • Guidance concerning how to make phenotypically silent amino acid substitutions is provided in, e.g., Bowie et al. (Science, 247: 1306-1310, 1990), Cunningham et al.
  • the peptides described herein may be a functionally active variant of the antibodies or antigen- binding fragments thereof disclosed herein, e.g., with less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5% or about 1% amino acid residues substituted or deleted but that retain essentially the same immunological properties including, but not limited to, binding to CD40.
  • the antibodies or antigen-binding fragments thereof may also include variants, analogs, orthologs, homologs and derivatives of peptides, that exhibit a biological activity, e.g., binding of an antigen such as CD40.
  • the peptides may contain one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), peptides with substituted linkages, as well as other modifications known in the art.
  • the antibody or antigen-binding fragment thereof can be derivatized or linked to another functional molecule.
  • an antibody can be functionally linked (by chemical coupling, genetic fusion, noncovalent interaction, etc.) to one or more other molecular entities, such as another antibody, a detectable agent, an immunosuppressant, a cytotoxic agent, a pharmaceutical agent, a protein or peptide that can mediate association with another molecule (such as a streptavidin core region or a polyhistidine tag), amino acid linkers, signal sequences, immunogenic carriers, or ligands useful in protein purification, such as glutathione-S-transferase, histidine tag, and staphylococcal protein A.
  • another antibody such as another antibody, a detectable agent, an immunosuppressant, a cytotoxic agent, a pharmaceutical agent, a protein or peptide that can mediate association with another molecule (such as a streptavidin core region or a polyhistidine tag), amino acid linkers, signal sequences, immunogenic carriers, or ligands useful in protein purification, such as gluta
  • Cytotoxic agents may include radioactive isotopes, chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant, or animal origin, and fragments thereof. Such cytotoxic agents can be coupled to the humanized antibodies of the present disclosure using standard procedures, and used, for example, to treat a patient indicated for therapy with the antibody.
  • One type of derivatized protein is produced by crosslinking two or more proteins (of the same type or of different types).
  • Suitable crosslinkers include those that are heterobifunctional, having two distinct reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N- hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate).
  • Useful detectable agents with which a protein can be derivatized (or labeled) include fluorescent agents, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, and radioactive materials.
  • Non- limiting, exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, and phycoerythrin.
  • a protein or antibody can also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, beta-galactosidase, acetylcholinesterase, glucose oxidase and the like.
  • detectable enzymes such as alkaline phosphatase, horseradish peroxidase, beta-galactosidase, acetylcholinesterase, glucose oxidase and the like.
  • a protein can also be derivatized with a prosthetic group (e.g., streptavidin/biotin and avidin/biotin).
  • the humanized anti-CD40 antibody or its fragment is used unlabeled and detected with a labeled antibody that binds the humanized anti-CD40 antibody or its fragment.
  • compositions containing an antibody or antigen- binding fragment thereof as described herein (e.g., an antibody or antigen-binding fragment thereof containing a heavy chain variable region having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 9 and a light chain variable region having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 10, formulated together with a pharmaceutically acceptable carrier).
  • an antibody or antigen-binding fragment thereof containing a heavy chain variable region having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 9 and a light chain variable region having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 10, formulated together with a pharmaceutically acceptable carrier).
  • the present disclosure also features pharmaceutical compositions containing an antibody or antigen-binding fragment thereof as described herein (e.g., an antibody or antigen-binding fragment thereof containing a heavy chain having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 11 and a light chain having at least 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to SEQ ID NO: 12, formulated together with a pharmaceutically acceptable carrier).
  • the pharmaceutical composition containing the antibody or antigen-binding fragment thereof can be used, e.g., for the treatment of a disease or disorder, as described herein.
  • the pharmaceutical compositions include polysorbate 20, acetate, and one or more polar excipients.
  • the polar excipient may be or may include, for example, a sugar, a polyol, or an amino acid.
  • the sugar is, for example, sucrose, trehalose, fructose, lactose, dextrose, or mannitol.
  • the polyol is, for example, polyethylene glycol or sorbitol.
  • the amino acid is one or more of alanine, arginine, aspartic acid, asparagine, carnitine, citrulline, ornithine, glycine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine, and valine.
  • the acetate may include, for example, sodium acetate (e.g., in salt form) or acetate in its ionic form.
  • the polar excipient is, for example sucrose, arginine, glutamate, sorbitol, or a combination thereof.
  • the polar excipient is sucrose. In some embodiments the polar excipient is arginine. In some embodiments the polar excipient is glutamate. In some embodiments, the polar excipient is a mixture of arginine and glutamate. In some embodiments, the polar excipient is sorbitol.
  • the pharmaceutical composition includes from about 5 mM to about 100 (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 45 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate. In some embodiments, the pharmaceutical composition includes about 50 mM acetate.
  • the pharmaceutical composition includes from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM, e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) of the polar excipient.
  • mM to about 200 mM e.g., about 50 m
  • the pharmaceutical composition includes about 50 mM of the polar excipient. In some embodiments, the pharmaceutical composition includes about 100 mM of the polar excipient. In some embodiments, the pharmaceutical composition includes about 150 mM of the polar excipient. In some embodiments, the pharmaceutical composition includes about 200 mM of the polar excipient.
  • the pharmaceutical composition includes from about 1% (w/v) to about 10% (w/v) (e.g., about 2% (w/v) to about 8% (w/v), e.g., about 1% (w/v), 1.5 % (w/v), 2% (w/v), 2.5% (w/v), 3% (w/v), 3.5% (w/v), 4% (w/v), 4.5% (w/v), 5% (w/v), 5.5% (w/v), 6% (w/v), 6.5% (w/v), 7% (w/v), 7.5% (w/v), 8% (w/v), 8.5% (w/v), 9% (w/v), 9.5% (w/v), 10% (w/v)) of the polar excipient.
  • the pharmaceutical composition includes about 2.5% (w/v) of the polar excipient. In some embodiments, the pharmaceutical composition includes about 7% (w/v) of the polar excipient. In some embodiments, the pharmaceutical composition includes from about 0.001% to about 0.1% (e.g., about 0.005% to 0.05%, e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.01% polysorbate 20.
  • the pharmaceutical composition includes about 0.02% polysorbate 20.
  • the composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0, e.g., about 5.4.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM) acetate, from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM,
  • the pharmaceutical composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0.
  • the pH may be about 5.4.
  • the pharmaceutical composition can include, e.g., an amount of an anti-CD40 antibody or antigen-binding fragment thereof described herein (e.g., KPL-404), such as, e.g., about 100 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, or about 100 mg/mL to about 200 mg/mL (e.g., about 100 mg/mL, 105 mg/mL, 110 mg/mL, 115 mg/mL, 120 mg/mL, 125 mg/mL, 130 mg/mL, 135 mg/mL, 140 mg/mL, 145 mg/mL, 150 mg/mL, 155 mg/mL, 160 mg/mL, 165 mg/mL, 170 mg/mL, 175 mg/mL, 180 mg/mL, 185 mg/mL, 190 mg/mL, 195 mg/mL, 200
  • At least 95% (e.g., at least 98%) of the humanized anti-CD40 antibody or antigen-binding fragment thereof in the composition is in a monomeric form. In some embodiments, less than 5% (e.g., less than 2%) of the humanized anti-CD40 antibody or antigen-binding fragment is present in the composition as a high molecular weight (HMW) species (e.g., in an aggregated form). In some embodiments, an amount of monomeric species of the humanized anti-CD40 antibody or antigen-binding fragment in the composition decreases to no less than 95% (e.g., no less than 98%) following storage at 2-8 °C for 12 months.
  • HMW high molecular weight
  • an amount of HMW species of the humanized anti-CD40 antibody or antigen-binding fragment in the composition increases to no more than 5% (e.g., no more than 2%) following storage at 2-8 ° C for 12 months.
  • Formulation C Formulation C: 200 mg/mL KPL-404 in 50 mM acetate, 100 mM arginine, 100 mM glutamate, 0.02% polysorbate 20, pH 5.4.
  • a pharmaceutical composition of the disclosure may also include modifications relative to Formulation C.
  • the pharmaceutical composition can include polysorbate 20, acetate, arginine, and glutamate in amounts that differ from Formulation C.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate, such as about 50 mM acetate.
  • the pharmaceutical composition can include from about 1 mM to about 200 mM (e.g., about 1 mM, 2 mM, 3 mM, 4 mM.5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) arginine, such as about 50 mM or about 100 mM arginine.
  • arginine such as about 50 mM or about 100 mM arginine.
  • the pharmaceutical composition can include from about 1 mM to about 200 mM (e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM) glutamate, such as about 50 mM or about 100 mM glutamate.
  • mM e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM
  • the pharmaceutical composition includes from about 0.001% to about 0.1% (e.g., about 0.005% to 0.05%, e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20, such as about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 0.02% polysorbate 20.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM) acetate, from about 1 mM to about 200 mM (e.g., about 50 mM to about 150 mM, e.g., about 75 mM to about 125 mM, e.g., about 90 mM to about 110 mM, e.g., about 95 mM to about 105 mM,
  • the pharmaceutical composition can include about 50 mM acetate, about 100 mM arginine, about 100 mM glutamate, and about 0.01% polysorbate 20.
  • the pharmaceutical composition can include about 50 mM acetate, about 100 mM arginine, about 100 mM glutamate, and about 0.02% polysorbate 20.
  • the pharmaceutical composition includes about 50 mM acetate, about 50 mM arginine, 50 mM glutamate, and about 0.01% polysorbate 20.
  • the pharmaceutical composition includes about 50 mM acetate, about 50 mM arginine, 50 mM glutamate, and about 0.02% polysorbate 20.
  • the pharmaceutical composition includes about 50 mM acetate, about 100 mM arginine, 50 mM glutamate, and about 0.01% polysorbate 20. In some embodiments, the pharmaceutical composition includes about 50 mM acetate, about 100 mM arginine, 50 mM glutamate, and about 0.02% polysorbate 20.
  • the pharmaceutical composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0.
  • the pH may be about 5.4.
  • the pharmaceutical composition can include, e.g., an amount of an anti-CD40 antibody or antigen-binding fragment thereof described herein (e.g., KPL-404), such as, e.g., about 100 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, or about 100 mg/mL to about 200 mg/mL (e.g., about 100 mg/mL, 105 mg/mL, 110 mg/mL, 115 mg/mL, 120 mg/mL, 125 mg/mL, 130 mg/mL, 135 mg/mL, 140 mg/mL, 145 mg/mL, 150 mg/mL, 155 mg/mL, 160 mg/mL, 165 mg/mL, 170 mg/mL, 175 mg/mL, 180 mg/mL, 185 mg/mL, 190 mg/mL, 195 mg/mL, 200
  • Formulation A 200 mg/mL KPL-404 in 50 mM acetate, 7% (w/v) sucrose, 0.01% polysorbate 20, pH 5.4.
  • a pharmaceutical composition of the disclosure may also include modifications relative to Formulation A.
  • the pharmaceutical composition can include polysorbate 20, acetate, and sucrose.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate, such as about 50 mM acetate.
  • the pharmaceutical composition can include from about 1% (w/v) to about 10% (w/v), e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w/v), sucrose, such as about 7% (w/v) sucrose.
  • the pharmaceutical composition can include from about 0.001% to about 0.1% (e.g., 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20, such as about 0.01% or about 0.02% polysorbate 20.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM) acetate, from about 1% (w/v) to about 10% (w/v), e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (w/v), e.g., about 7%, sucrose, and from about 0.001% to about 0.1% (e.g.,
  • the pharmaceutical composition can include about 50 mM acetate, about 7% (w/v) sucrose, and about 0.01% polysorbate 20.
  • the pharmaceutical composition can include about 50 mM acetate, about 7% (w/v) sucrose, and about 0.02% polysorbate 20.
  • the pharmaceutical composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0.
  • the pH may be about 5.4.
  • the pharmaceutical composition can include, e.g., an amount of an anti-CD40 antibody or antigen-binding fragment thereof described herein (e.g., KPL-404), such as, e.g., about 100 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, or about 100 mg/mL to about 200 mg/mL (e.g., about 100 mg/mL, 105 mg/mL, 110 mg/mL, 115 mg/mL, 120 mg/mL, 125 mg/mL, 130 mg/mL, 135 mg/mL, 140 mg/mL, 145 mg/mL, 150 mg/mL, 155 mg/mL, 160 mg/mL, 165 mg/mL, 170 mg/mL, 175 mg/mL, 180 mg/mL, 185 mg/mL, 190 mg/mL, 195 mg/mL, 200
  • Formulation B 200 mg/mL KPL-404 in 50 mM acetate, 2.5% (w/v) sorbitol, 70 mM NaCl, 0.01% polysorbate 20, pH 5.4.
  • a pharmaceutical composition of the disclosure may also include modifications relative to Formulation B.
  • the pharmaceutical composition can include polysorbate 20, acetate, sorbitol, and sodium chloride.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) acetate, such as about 50 mM acetate.
  • the pharmaceutical composition can include from about 0.1% (w/v) sorbitol to about 5% (w/v), e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% (w/v), sorbitol, such as about 2.5% (w/v) sorbitol.
  • the pharmaceutical composition can include from about 1 mM to about 100 mM (e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM) sodium chloride, such as about 70 mM sodium chloride.
  • mM e.g., about 1 mM, 2 mM, 3 mM, 4 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM
  • sodium chloride such as about 70 mM sodium chloride.
  • the pharmaceutical composition can include from about 0.001% to about 0.1% (e.g., 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%) polysorbate 20, such as about 0.01% polysorbate 20 and 0.02% polysorbate 20.
  • the pharmaceutical composition can include from about 5 mM to about 100 mM (e.g., about 10 mM to about 90 mM, e.g., about 25 mM to about 75 mM, e.g., about 40 mM to about 60 mM, e.g., about 45 mM to about 55 mM, e.g., about 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM, e.g., about 50 mM) acetate, from about 0.1% (w/v) sorbitol to about 5% (w/v) ( e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% (w/v), e.g., about 2.5%) sorbi
  • the pharmaceutical composition can include about 50 mM acetate, about 2.5% (w/v) sorbitol, about 70 mM NaCl, and about 0.01% polysorbate 20.
  • the pharmaceutical composition can include about 50 mM acetate, about 2.5% (w/v) sorbitol, about 70 mM NaCl, and about 0.02% polysorbate 20.
  • the pharmaceutical composition may have a pH of from about 5.0 to about 8.0, e.g., about 5.4 to about 6.5; e.g., about 5.4 to about 5.75; e.g., 5.4 to about 5.6; e.g, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 and 8.0.
  • the pH may be about 5.4.
  • the pharmaceutical composition can include, e.g., an amount of an anti-CD40 antibody or antigen-binding fragment thereof described herein (e.g., KPL-404), such as, e.g., about 100 mg/mL to about 300 mg/mL, e.g., about 100 mg/mL to about 250 mg/mL, about 150 mg/mL to about 250 mg/mL, or about 100 mg/mL to about 200 mg/mL (e.g., about 100 mg/mL, 105 mg/mL, 110 mg/mL, 115 mg/mL, 120 mg/mL, 125 mg/mL, 130 mg/mL, 135 mg/mL, 140 mg/mL, 145 mg/mL, 150 mg/mL, 155 mg/mL, 160 mg/mL, 165 mg/mL, 170 mg/mL, 175 mg/mL, 180 mg/mL, 185 mg/mL, 190 mg/mL, 195 mg/mL, 200
  • a composition of the present disclosure can be formulated for administration by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. Administration may be parenteral, intravenous, intrathecal, subcutaneous, oral, topical, local, intramuscular, intradermal, transdermal, subdermal, transbuccal, rectal, spinal, or epidermal. Intravenous delivery by continuous infusion is one exemplary method for administering the present antibodies or antigen-binding fragments thereof. To administer the present agent by certain routes of administration, it may be necessary to coat the agent with, or co-administer the agent with, a material to prevent its inactivation.
  • the agent may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Parenteral administration can include modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
  • compositions containing an antibody or antigen-binding fragment as described herein have in vitro and in vivo therapeutic, prophylactic, and/or diagnostic utilities.
  • the antibodies or antigen-binding fragments thereof can be administered in a subject, as part of an in vivo (e.g., therapeutic or prophylactic) protocol.
  • the contacting step includes administering an anti-CD40 antibody or portion thereof to the subject under conditions effective to permit binding of the antibody or antigen-binding fragment thereof to CD40 in the subject.
  • the antibodies or antigen-binding fragments thereof can be administered to reduce the likelihood of, or increase the duration prior to, transplant rejection, to induce immunosuppression, or to treat an immune (e.g., an autoimmune) disorder.
  • the pharmaceutical compositions described herein can be uses in suppressing the immune system in a human subject, or for use in the manufacture of a medicament for suppressing the immune system in a human subject.
  • the pharmaceutical compositions described herein may be used in any situation in which immunosuppression is desired (e.g., transplant rejection or autoimmune disorders). These antibodies are particularly useful for treating transplant rejection, e.g., reducing the likelihood that a particular transplant is rejected by the host or increasing the time before rejection takes place.
  • the pharmaceutical compositions described herein can also be used to treat autoimmune disorders.
  • the autoimmune disorder may be associated with or caused by the presence of an autoantibody.
  • the pharmaceutical composition can be used in the treatment of various disorders associated with the expression of CD40.
  • a disorder may be any condition that would benefit from treatment with the present antibody or its fragment. This includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question.
  • disorders to be treated herein include autoimmune diseases, immunologic disorders, inflammatory disorders, and cancer Compositions and Kits
  • the disclosure also features compositions and kits containing materials useful for the treatment of a condition or disorder described herein.
  • the composition or kit may include a container including a pharmaceutical composition as described herein (e.g., one of Formulation C, A, or B containing an amount of an anti-CD40 antibody or antigen-binding fragment thereof, such as, e.g., about 100 mg/mL to about 300 mg/mL), and optionally, a label.
  • Suitable containers include, for example, bottles, vials, syringes, prefilled syringes, autoinjectors and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a pharmaceutical composition as described herein, e.g., that is effective for treating the condition, and may have a sterile access port.
  • the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle.
  • the label on or associated with the container indicates that the composition is used for treating the condition of choice.
  • the kit may further include a second container with a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a pharmaceutically acceptable buffer such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • the kit or composition can contain an antibody or antigen-binding fragment thereof as described herein formulated to about 100 mg/mL to about 300 mg/mL. In one embodiment, the composition is formulated to about 200 mg/mL of the antibody or antigen-binding fragment thereof.
  • the antibody or antigen-binding fragment thereof may be at a concentration of from about 0.01 mg/mL to about 300 mg/mL (e.g., 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, or 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL,
  • the composition may be formulated in a single use vial with about 0.5 mL to about 2.0 mL (e.g., 1.0 mL or 2.0 mL) extractable volume.
  • the composition may also be formulated in a prefilled syringe with about 0.5 mL to about 2.0 mL (e.g., 1.0 mL or 2.0 mL) injectable volume.
  • the composition may also be formulated in an autoinjector with about 0.5 mL to about 2.0 mL (e.g., 1.0 mL or 2.0 mL) injectable volume.
  • the composition can be formulated in a volume of about 0.1 mL to about 10.0 mL (e.g., about 0.5 to about 5 mL, e.g., about 1.0mL to about 2.0 mL, e.g., 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, 2.0 mL, 3.0 mL, 4.0 mL, 5.0 mL, 6.0 mL, 7.0 mL, 8.0 mL, 9.0 mL or 10.0 mL), such as a volume of about 2.0 mL.
  • kits for example, instructions for use; other reagents, a therapeutic agent, or an agent useful for coupling an antibody to a label or therapeutic agent, or other materials for preparing the antibody for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.
  • Examples The following examples of specific aspects for carrying out the present disclosure are offered for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.
  • Example 1 Described herein are studies that were performed to assess formulations that would allow for an increase in the concentration of KPL-404 to at least 100 mg/mL.
  • the candidate formulations described herein include KPL-404 and the following excipients: Formulation 1: 20 mM sodium phosphate, 200 mM glycine, 0.01% polysorbate 20 (PS20), pH 6.5 Formulation 2: 50 mM sodium Acetate/NaAcetate, 200 mM glycine 0.01% PS20, pH 5.5 Formulation A: 50 mM Acetate/NaAcetate, 7%(w/v) sucrose, 0.01% PS20, pH 5.4 Formulation B: 50 mM Acetate/NaAcetate, 2.5%(w/v) sorbitol, 70 mM NaCl, 0.01% PS20, pH 5.4 Formulation C: 50 mM Acetate/NaAcetate, 100 mM Arginine, 100 mM Glutamate, 0.01% PS20, pH 5.4 Formulation C was selected as the planned formulation for 200 mg/mL KPL-404 formulation for drug substance (DS) and drug product (DP) with 0.02% PS
  • KPL-404 was exchanged into 12 different buffers, including Formulations A (pH 5.6), 1 and 2. Freeze/Thaw (F/T) stress was assessed, cycling samples between -70C and ambient temperature three times. Agitation stress was also assessed by shaking at 200 rpm for 48 hours in the upright position. A short-term stability study was conducted, with samples stored at 2-8°C, 25°C, or at 40°C for up to 3 weeks. The SEC results show that the excipient does play an important role in ensuring KPL-404 stability following F/T and agitation stress, with glycine Formulations 1 and 2 being most susceptible to degradation, i.e.
  • KPL-404 was stable in Formulation A, which included sucrose as a stabilizing agent. SEC results for screened formuations A, 1 and 2 are presented graphically in FIG 1. There are clear differences among the formulations, with Formulation 2 being the least stable showing loss of main and increase of both HMW and LMW species. Formulation 1 showed increases in HMW species at 40°C and was unstable during F/T stress and agitation tests. Formulation A was the lead candidate in these screening studies and was selected for further development studies.
  • KPL-404 was formulated at 200 mg/mL in each of the three candidate formulations (Formulations A-C) by UF/DF and set on stability in a vial presentation. KPL-404 was highly concentrated by UF/DF until the flux went to zero.
  • the concentrations that were achieved were: 272 mg/mL KPL-404 in the Formulation A: (50 mM Acetate, 7%(w/v) sucrose, 0.001% PS20, pH 5.4) 274 mg/mL KPL-404 in Formulation B: 50 mM Acetate, 2.5%(w/v) sorbitol, 70 mM NaCl, 0.001% PS20, pH 5.4 291 mg/mL KPL-404 in Formulation C: 50 mM Acetate, 100 mM Arg/100 mM Glu, 0.001% PS20, pH 5.4 Samples of each of these were characterized externally using biophysical techniques to characterize self-association as a function of protein concentrations.
  • Drug substance material used to prepare these formulations was initially manufactured with PS20 at 0.001% . Separately, formulations were spiked with 10% (w/v) PS20 to achieve 0.01% PS20 and were also analyzed. In parallel, CG-MALS testing was performed on formulations with PS20 adjusted to 0.01%. Viscosity and Instron testing were performed as a function of protein concentration to assess syringeability. From these characterization studies, it was concluded that KPL-404 could achieve a concentration of up to 292 mg/mL in Formulation C. Abbreviated stability studies were performed at 220 mg/mL each of Formulations A and B, and at 235 mg/mL in Formulation C.
  • the conditioned ProA load material was 0.2 ⁇ m filtered prior to loading the column. Each Pro A eluate was neutralized to target pH 5.00, 0.2 ⁇ m filtered, and stored at ⁇ -65 °C. A total of 4 cycles were performed to generate 68 grams of UFDF load material for high concentration studies.
  • Material Generation for UFDF Confirmation To generate load material for each ProA cycle, drug substance was thawed at 2-8°C overnight and adjusted using ProA equilibration buffer to a target 10 g/L. The conditioned ProA load material was 0.2 ⁇ m filtered prior to loading the column. Each Pro A eluate was 0.2 ⁇ m filtered and stored at ⁇ -65 °C.
  • a system rinse using 1x to 1.5x the holdup volume was performed to allow for a process step mass balance calculation.
  • a PS20 stock solution of 10% w/v was prepared in each respective formulation buffer and spiked into both the target 200 g/L sample to a target 0.01% PS20.
  • Final 0.2 ⁇ m filtration was performed using 3.5 cm 2 PES filters from Sartorius.
  • Each pool was filtered separately, and the pressure monitored.
  • the remainder of the drug substance pools were handled in accordance with the DP stability study to ensure compliance with that study’s objectives.
  • RESULTS AND DISCUSSION Effect of formulations A-C on > 200 mg/mL KPL-404 Small scale UF/DF was performed to generate the following samples, which were concentrated until the tangential flow stopped.
  • KPL-404 drug substance i.e., an antibody having a heavy chain variable region with the amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region with the amino acid sequence set forth in SEQ ID NO: 10.
  • Formulations were then further concentrated up to ⁇ 250 mg/mL. To all of these, PS20 was added to a target of 0.01% and then filtered. Biophysical characterization Malvern Panalytical Studies Formulations were studied by a variety of biophysical techniques, including dynamic light scattering, static light scattering (B22 and CIMax), electrophoretic light scattering (Zeff), thermodynamic stability by differential scanning calorimetry (melting transitions), injectability by microcapillary viscometry and rheology, and nanoparticle tracking analysis. An initial set of formulations were characterized at 200 mg/mL as shown in Table 2. It was discovered that Formulation C lacked PS20 after testing had been completed.
  • Formulation C had the lowest colloidal stability based on kD value. Similarly, Formulation C had the highest concentration of subvisible particles (Cs ⁇ p) compared to Formulations A and B (FIG.2A). Thermal analysis indicated similar thermal stability for aggregation onset and for each of the three observed thermal transitions, with Formulation A being higher in stability due to sucrose, in comparison to Formulations B and C which were essentially equivalent. Biophysical characterization studies were repeated following generation of high concentration (> 200 mg/mL) KPL-404 formulations, including 0.02% PS20 in Formulation C, Table 3. When 0.02% PS20 was in the formulations, Formulation C had the highest colloidal stability based on kD value.
  • Formulation C had a lower concentration of subvisible particles (Cs ⁇ p) compared to Formulation B (FIG. 2B).
  • Rheological assessment of viscosity as a function of shear rate showed different behavior at 100 mg/mL and > 200 mg/mL (FIG.3).
  • At 100 mg/mL all formulations demonstrated Newtonian behavior with similar viscosities as a function of shear rate.
  • a static invariant viscosity vs shear rate is observed for Formulation C.
  • CG-MALS has implemented CG-MALS by merging an autosampler that generates a concentration gradient from two solutions (from a high concentration protein formulation and matched placebo) in conjunction with in-line sample analysis.
  • KPL-404 formulations and matching formulation buffers were filtered using 0.22 ⁇ m syringe filters. Fifteen concentrations were analyzed per formulation, with concentrations confirmed by UV Absorbance. Fitting of data to reversible/irreversible association models were performed using Wyatt Calypso software (144 kDa monomer). CG-MALS results for Formulation A No reversible associations could be modeled with the highest concentration points included.
  • the inability to fit reversible oligomers may be due to repulsive interactions at higher concentrations dominating and masking the underlying attractive interactions Due to strong repulsive interactions masking underlying attractive interactions, the highest concentration we could fit with the reversible associations model was ⁇ 127 mg/mL with reversible dimer. Data up to ⁇ 127 mg/mL could be modeled with reversible dimer. Concentration of reversible dimer did not exceed the monomer within the concentration range that we could fit. Reversible dimer was present even at the lowest concentration ( ⁇ 0.5 mg/mL); see FIG.4. CG-MALS results for Formulation B Similarly, no reversible associations could be modeled with the highest concentration points included.
  • CG-MALS demonstrates KPL-404 readily forms reversible dimers and higher ordered oligomer that are not detected by SEC (which dilutes to ⁇ 1 mg/mL prior to injection). Results were generally consistent with a hard sphere repulsive behavior, with underlying attractive behavior in all formulations as indicated by the need to include reversible associations in global analysis. Formulation A was more effective at inhibiting formation of reversible oligomers below 125 mg/mL, but data were not fittable at higher concentrations.
  • Formulation B was the least stable with respect to oligomerization, with reversible oligomers becoming the dominant species at ⁇ 35 mg/mL.
  • Formulation C shows oligomers become the dominant species at > 60 mg/mL, and has lower viscosity compared to formulation A, which is consistent with lower energy self-association at elevated concentrations for Formulation C.
  • the shear-thinning data reveal a notable and unexpected difference between the self- association dynamics of formulation C from the other formulations, suggesting that arginine and glutamate affect these interactions via a different mechanism.
  • the light scattering data demonstrate that KPL-404 is predominantly a monomer in Formulations A, B and C below ⁇ 100 mg/mL. At higher concentrations, however, these data suggest that Formulation C has a superior ratio of reversible dimer to non-reversible dimer compared to Formulations A and B. Syringeability characterization. Viscosity was assessed as a function of variable concentration for each of the three formulations, Table 4 and FIG.7. Viscosity varied exponentially with respect to protein concentration.
  • the inset in FIG.7 highlights the KPL-404 concentration where a given formulation crosses 25 cP, a theoretical upper limit on syringeability based on extrusion force.
  • Formulation A with sucrose exceeded 25 cP at ⁇ 200 mg/mL
  • Formulations B and C exceeded 25 cP above 220 mg/mL
  • Formulation C being slightly less viscous than B.
  • Table 4 Conditions for KPL-914 Current Formulation PFS Stability Study.
  • Each of Formulations A, B, and C were filled by hand into a 2.25 mL BD Neopak syringe. The same sample was tested five times with a new syringe for each test. Instron testing was performed, recording gliding forces as a function of protein concentration for each formulation, Table 5.
  • testing utilized the highest concentration sample of each formulation, diluting the recovered sample with buffer to generate lower concentration. The results show decreasing injection force as a function of decreasing concentration. Injection times for the lowest three concentrations were recorded using manually assembled Auto-Injectors (AI) with each of the candidate formulations in a 2.25 mL BD Neopak syringe, Table 5. The time was established by video recording, calculating time from frame rate and the number of frames from first to last drop. The standard Ypsomate AI was tested in all three candidates: • Injection times (into air) for formulation A were ⁇ 20 s at 220 mg/mL and higher and was ⁇ 15 s at 200 mg/mL.
  • AI Auto-Injectors
  • Aggregation data were also produced for Formulation C (200 mg/mL KPL-404 in 50 mM sodium acetate, 100 mM L-Arginine, 100 mM L-Glutamate, 0.02% polysorbate 20, pH 5.4) KPL-404 up to 12 months at 2-8 °C.
  • FIG.1 shows a set of graphs showing SEC results presented graphically for %Main, %HMW and %LMW species of KPL-404 for Formulations A, 1 and 2. Chromatograms of initial samples are shown in FIG.11, showing initially all three formulations are essentially the same as the reference standard.
  • KPL-404 was stable at 5°C in the current formulation at 100 mg/mL, showing slow rate of change over 12 months with a slope that projects a ⁇ 1% change after 60 months.
  • Formulation C was more stable than both Formulations A and B; the slope for Formulation C predicts a ⁇ 1% change after ⁇ 36 months, whereas A and B project twice the rate of change as Formulation C.
  • KPL-404 was stable at -70°C, with change of %Main occurring at a similar rate for Formulation A at 100 mg/mL and for Formulations A, B, and C at 200 mg/mL. Note that only Formulation A at 100 mg/mL had sufficient data for meaningful statistical analysis; analysis of higher concentration data sets are included in Table 15 for qualitative comparison. The data predict no statistically meaningful change in %Main purity while held frozen, through 12 months of data. Table 15: Summary of P-values for Slope of SEC Results as a Function of Time.
  • KPL-404 is stable in all three formulations, but Formulation C is superior to both Formulation A and B in supporting concentrations above 200 mg/mL.
  • Example 2 A 26-Week Repeat-Dose Toxicity and Toxicokinetic Study of KPL-404 Administered Once Weekly via Intravenous or Subcutaneous Injection to Cynomolgus Monkeys with an 8-Week Recovery Period
  • the objectives of this study were to evaluate the toxicity of KPL-404 prepared in Formulation C (200 mg/mL KPL-404, 50 mM Acetate, 100 mM L-Arginine, 100 mM L-Glutamate, 0.02% polysorbate 20, pH 5.4, when administered by intravenous or subcutaneous injection once weekly over a 26-week period to cynomolgus monkeys and to evaluate the potential reversibility or delayed occurrence of any effects over an 8-week recovery period.
  • KPL-404 was administered to 5 male and 5 female cynomolgus monkey per group via subcutaneous (SC) injection or intravenous bolus (IV) injection at doses of 30 or 97 mg/kg, once weekly for 26 weeks, according to the study design in In-text Table 1.
  • SC subcutaneous
  • IV intravenous bolus

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
PCT/US2022/079072 2021-11-05 2022-11-01 Pharmaceutical compositions of humanized anti-cd40 antibodies Ceased WO2023081652A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA3236827A CA3236827A1 (en) 2021-11-05 2022-11-01 Pharmaceutical compositions of humanized anti-cd40 antibodies
CN202280075264.6A CN118382640A (zh) 2021-11-05 2022-11-01 人源化抗cd40抗体的药物组合物
KR1020247016673A KR20240095255A (ko) 2021-11-05 2022-11-01 인간화 항-cd40 항체의 약학적 조성물
EP22890984.2A EP4426744A4 (en) 2021-11-05 2022-11-01 PHARMACEUTICAL COMPOSITIONS OF HUMANIZED ANTI-CD40 ANTIBODIES
JP2024526890A JP2024540377A (ja) 2021-11-05 2022-11-01 ヒト化抗ｃｄ４０抗体の医薬組成物
MX2024005415A MX2024005415A (es) 2021-11-05 2022-11-01 Composiciones farmaceuticas de anticuerpos anti-cd40 humanizados.
AU2022381078A AU2022381078A1 (en) 2021-11-05 2022-11-01 Pharmaceutical compositions of humanized anti-cd40 antibodies

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163276363P 2021-11-05 2021-11-05
US63/276,363 2021-11-05

Publications (1)

Publication Number Publication Date
WO2023081652A1 true WO2023081652A1 (en) 2023-05-11

Family

ID=86242030

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/079072 Ceased WO2023081652A1 (en) 2021-11-05 2022-11-01 Pharmaceutical compositions of humanized anti-cd40 antibodies

Country Status (9)

Country Link
US (2) US20230279135A1 (https=)
EP (1) EP4426744A4 (https=)
JP (1) JP2024540377A (https=)
KR (1) KR20240095255A (https=)
CN (1) CN118382640A (https=)
AU (1) AU2022381078A1 (https=)
CA (1) CA3236827A1 (https=)
MX (1) MX2024005415A (https=)
WO (1) WO2023081652A1 (https=)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112018004296B1 (pt) 2015-09-04 2020-05-05 Primatope Therapeutics Inc anticorpos anti-cd40 humanizados e usos dos mesmos
US12234294B2 (en) 2021-11-05 2025-02-25 Kiniksa Pharmaceuticals, Gmbh Pharmaceutical composition of a humanized anti-CD40 antibody
US20250276092A1 (en) 2024-03-01 2025-09-04 Regeneron Pharmaceuticals, Inc. Methods and compositions for re-dosing aav using anti-cd40 antagonistic antibody to suppress host anti-aav antibody response
WO2025184603A2 (en) 2024-03-01 2025-09-04 Regeneron Pharmaceuticals, Inc. The use of cd40 inhibitors for inhibiting an immune response and enabling immunogen administration and re-administration

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150110783A1 (en) * 2006-04-21 2015-04-23 Xoma Technology Ltd. Antagonist anti-cd40 antibody pharmaceutical compositions
US20180078640A1 (en) * 2015-09-04 2018-03-22 Primatope Therapeutics Inc. Humanized anti-cd40 antibodies and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150110783A1 (en) * 2006-04-21 2015-04-23 Xoma Technology Ltd. Antagonist anti-cd40 antibody pharmaceutical compositions
US20180078640A1 (en) * 2015-09-04 2018-03-22 Primatope Therapeutics Inc. Humanized anti-cd40 antibodies and uses thereof

Also Published As

Publication number Publication date
KR20240095255A (ko) 2024-06-25
JP2024540377A (ja) 2024-10-31
MX2024005415A (es) 2024-07-30
EP4426744A4 (en) 2025-10-22
US20230279135A1 (en) 2023-09-07
EP4426744A1 (en) 2024-09-11
AU2022381078A1 (en) 2024-05-23
US20250282884A1 (en) 2025-09-11
CN118382640A (zh) 2024-07-23
CA3236827A1 (en) 2023-05-11

Similar Documents

Publication Publication Date Title
US20250282884A1 (en) Pharmaceutical compositions of humanized anti-cd40 antibodies
JP2020516608A (ja) 安定な抗体製剤
US12234294B2 (en) Pharmaceutical composition of a humanized anti-CD40 antibody
KR102413592B1 (ko) 약학적 제형 및 그의 제조 방법
US20250114449A1 (en) Stable anti-osmr antibody formulation
JP2022532927A (ja) 抗ａｎｇｐｔｌ３抗体を含有する安定化製剤
KR20220124208A (ko) 프로그램된 세포 사멸 수용체1 항체 제제 및 그 용도
AU2018236651A1 (en) Liquid formulation of anti-TNF alpha antibody
EP3236990A1 (en) Liquid pharmaceutical composition
JP2022546400A (ja) 高濃度の薬理学的に活性な抗体の新規製剤
KR20250025681A (ko) 항-igf-1r 항체 조성물
HK40109865A (zh) 稳定的抗osmr抗体制剂
WO2025255300A1 (en) FORMULATIONS FOR ANTI-N3pGlu AMYLOID BETA ANTIBODIES
TWI771335B (zh) 穩定藥學調配物
RU2743681C2 (ru) Состав антитела
EA048605B1 (ru) Стабилизированные составы, содержащие анти-angptl3-антитела
BR122024022996A2 (pt) Formulação estável de anticorpo anti-osmr e os usos do anticorpo anti-osmr e da formulação estável do mesmo

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22890984

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 3236827

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2024526890

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 202280075264.6

Country of ref document: CN

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024008796

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2022381078

Country of ref document: AU

Date of ref document: 20221101

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2022890984

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022890984

Country of ref document: EP

Effective date: 20240605

ENP Entry into the national phase

Ref document number: 112024008796

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20240503

WWW Wipo information: withdrawn in national office

Ref document number: 2022890984

Country of ref document: EP