Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
  • C07K16/2842—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • 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
  • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • 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
  • C07K2317/52—Constant or Fc region; Isotype
  • C07K2317/524—CH2 domain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/52—Constant or Fc region; Isotype
  • C07K2317/526—CH3 domain
• • 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]

Definitions

• the present application relates generally to pharmaceutical compositions and dosage regimens for clinical use comprising anti- ⁇ v 6 antibodies and uses thereof.
• Integrins are a superfamily of cell surface glycoprotein receptors, which bind extracellular matrix proteins and mediate cell-cell and cell-extracellular matrix interactions (generally referred to as cell adhesion events). These receptors are composed of
• Integrins regulate a variety of cellular processes including cellular adhesion, migration, invasion, differentiation, proliferation, apoptosis and gene expression.
• the ⁇ 6 receptor is one member of a family of integrins that are expressed as cell surface heterodimeric proteins. While the ⁇ v subunit can form a heterodimer with a variety of ⁇ subunits ( ⁇ 1 , ⁇ 3, ⁇ 5, ⁇ 6, and ⁇ 8), the ⁇ 6 subunit can only be expressed as a heterodimer with the ⁇ v subunit.
• the ⁇ 6 integrin is known to be a fibronectin-, vitronectin-, latency associated peptide (LAP)-, and tenascin C-binding cell surface receptor, interacting with the extracellular matrix through the RGD tripeptide binding sites thereon.
• LAP latency associated peptide
• tenascin C-binding cell surface receptor interacting with the extracellular matrix through the RGD tripeptide binding sites thereon.
• the expression of ⁇ 6 is restricted to epithelial cells where it is expressed at relatively low levels in healthy tissue and significantly upregulated during development, injury, and wound healing
• compositions containing an anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof and their use in the treatment of, inter alia, fibrosis, acute lung injury, and acute kidney injury.
• the disclosure features a pharmaceutical composition
• a pharmaceutical composition comprising an anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof, and arginine hydrochloride (Arg.HCl).
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL).
• the VH comprises VH complementarity determining regions (VH- CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:1 or 11; VH-CDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO:3; and the VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO:6.
• the composition has a pH of 5.2 to 5.7.
• the composition comprises the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6- binding fragment thereof at a concentration of 50 mg/ml to 200 mg/ml.
• the composition comprises the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof at a concentration of 100 mg/ml to 175 mg/ml. In other embodiments, the
• composition comprises the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml. In yet other embodiments, the composition comprises the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof at a concentration of 150 mg/ml.
• the composition comprises Arg.HCl at a concentration of 50 mM to 250 mM. In another embodiment, the composition comprises Arg.HCl at a concentration of 100 mM to 200 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 125 mM to 175 mM. In yet another embodiment, wherein the composition comprises Arg.HCl at a concentration of 150 mM.
• the composition comprises methionine. In some instances, the composition comprises methionine at a concentration of 0.5 mM to 30 mM. In other instances, wherein the composition comprises methionine at a concentration of 1 mM to 10 mM. In yet other instances, the composition comprises methionine at a concentration of 5 mM. In certain embodiment, the composition comprises Polysorbate-80 (PS80). In some instances, the composition comprises PS80 at a concentration of 0.01% to 0.1%. In other instances, the composition comprises PS80 at a concentration of 0.03% to 0.08%. In yet other instances, the composition comprises PS80 at a concentration of 0.05%.
• PS80 Polysorbate-80
• the composition comprises sodium citrate and citric acid. In certain instances, the composition comprises sodium citrate and citric acid at a concentration of 5 mM to 30 mM. In other instances, the composition comprises sodium citrate and citric acid at a concentration of 15 mM to 25 mM. In other instances, the composition comprises sodium citrate and citric acid at a concentration of 20 mM.
• the composition has a pH of 5.3 to 5.6. In one embodiment, the composition has a pH of 5.5.
• the composition comprises a thiol-containing antioxidant.
• the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine.
• the thiol-containing antioxidant is GSH.
• the thiol-containing antioxidant is GSSG.
• the thiol-containing antioxidant is GSH and GSSG.
• the thiol-containing antioxidant is cysteine.
• the thiol-containing antioxidant is cystine.
• the thiol-containing antioxidant is cysteine and cystine.
• the thiol-containing antioxidant is present in the composition at a concentration of 0.02 mM to 2 mM. In some cases, the thiol-containing antioxidant is present in the composition at a concentration of 0.2 mM. In other cases, the thiol-containing antioxidant is present in the composition at a concentration of 0.4 mM. In yet other cases, the thiol-containing antioxidant is present in the composition at a concentration of 1.0 mM. In cases where the thiol-containing antioxidant is GSH and GSSG, the former is present at a concentration of 0.4 mM and the latter at a concentration of 0.2 mM. In cases where the thiol-containing antioxidant is cysteine and cystine, the former is present at a concentration of 0.4 mM and the latter at a concentration of 0.2 mM.
• the pharmaceutical composition comprises the anti- ⁇ v ⁇ 6 antibody or the ⁇ v ⁇ 6-binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml; Arg.HCl at a concentration of 125 mM to 175 mM; methionine at a concentration of 1 mM to 10 mM; sodium citrate and citric acid at a concentration of 15 mM to 25 mM; and PS80 at a concentration of 0.03% to 0.08%.
• the composition has a pH of 5.3 to 5.7.
• the pharmaceutical composition comprises the anti- ⁇ v ⁇ 6 antibody or the ⁇ v ⁇ 6-binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml; Arg.HCl at a concentration of 125 mM to 175 mM; methionine at a concentration of 1 mM to 10 mM; sodium citrate and citric acid at a concentration of 15 mM to 25 mM; a thiol-containing antioxidant at a concentration of 0.02 mM to 2 mM; and PS80 at a concentration of 0.03% to 0.08%.
• the composition has a pH of 5.3 to 5.7.
• the pharmaceutical composition comprises the anti- ⁇ v ⁇ 6 antibody or the ⁇ v ⁇ 6-binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml; Arg.HCl at a concentration of 125 mM to 175 mM; sodium citrate buffer (sodium citrate and citric acid) at a concentration of 15 mM to 25 mM; a thiol-containing antioxidant at a concentration of 0.02 mM to 2 mM; and PS80 at a concentration of 0.03% to 0.08%.
• the composition has a pH of 5.3 to 5.7.
• the pharmaceutical composition comprises the anti- ⁇ v ⁇ 6 antibody or the ⁇ v ⁇ 6-binding fragment thereof at a concentration of 150 mg/ml; Arg.HCl at a concentration of 150 mM; methionine at a concentration of 5 mM; sodium citrate and citric acid at a concentration of 20 mM; and PS80 at a concentration of 0.03% to 0.08%.
• the composition has a pH of 5.5.
• the pharmaceutical composition comprises the anti- ⁇ v ⁇ 6 antibody or the ⁇ v ⁇ 6-binding fragment thereof at a concentration of 150 mg/ml; Arg.HCl at a concentration of 150 mM; methionine at a concentration of 5 mM; sodium citrate and citric acid at a concentration of 20 mM; GSH or cysteine at a concentration of 0.4 mM; and PS80 at a concentration of 0.03% to 0.08%.
• the composition has a pH of 5.5.
• the VH consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:7 and the VL consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:8.
• the heavy chain consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:9 and the light chain consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:10;
• the disclosure also features methods of treating an ⁇ v ⁇ 6-mediated condition in a human subject in need thereof.
• the method comprises administering to the human subject a pharmaceutical composition described herein.
• the ⁇ v ⁇ 6-mediated condition is fibrosis.
• the fibrosis is lung fibrosis, kidney fibrosis, liver fibrosis, or cardiac fibrosis.
• the fibrosis is idiopathic pulmonary fibrosis.
• the ⁇ v ⁇ 6-mediated condition is acute lung injury.
• the ⁇ v ⁇ 6-mediated condition is acute kidney injury.
• the pharmaceutical composition is administered subcutaneously to the human subject.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 40 mg to 64 mg once weekly.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 40 mg once weekly.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 48 mg once weekly.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 56 mg once weekly.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 64 mg once weekly. In some instances, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 0.5 mg/kg to 0.8 mg/kg once weekly. In certain cases, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 0.5 mg/kg once weekly. In certain cases, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 0.6 mg/kg once weekly.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 0.7 mg/kg once weekly. In other cases, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof of the pharmaceutical composition is administered to the human subject at a dose of 0.8 mg/kg once weekly.
• the disclosure provides a method of treating an ⁇ v ⁇ 6-mediated condition selected from the group consisting of fibrosis, acute lung injury, and acute kidney injury in a human subject in need thereof.
• the method comprises administering
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a VH and a VL.
• the VH comprises VH-CDRs, wherein VH- CDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:1 or 11; VH-CDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO:3; and VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO:6.
• the dose is 40 mg once every week.
• the dose is 48 mg once every week. In certain instances, the dose is 56 mg once every week. In certain instances, the dose is 64 mg once every week. In certain instances, the human subject is administered at least 4 doses of the anti- ⁇ v ⁇ 6 antibody or antigen-binding fragment thereof. In other instances, the human subject is administered at least 7 doses of the anti- ⁇ v ⁇ 6 antibody or antigen-binding fragment thereof. In yet other instances, the human subject is administered at least 10 doses of the anti- ⁇ v ⁇ 6 antibody or antigen-binding fragment thereof.
• the VH consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:7 and the VL consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:8.
• the anti- ⁇ v ⁇ 6 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:9 and the light chain consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:10.
• the condition is fibrosis.
• the fibrosis is lung fibrosis, kidney fibrosis, liver fibrosis, or cardiac fibrosis.
• the fibrosis is idiopathic pulmonary fibrosis.
• the condition is acute lung injury. In another instance, the condition is acute kidney injury.
• the disclosure features a syringe or pump comprising a sterile preparation of a pharmaceutical composition described herein, wherein the syringe or pump is adapted for subcutaneous administration of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof at a fixed dose of 40 mg, 48 mg, 56 mg, or 64 mg.
• the syringe or pump comprises 0.5 to 5.0 mL of a sterile preparation of a pharmaceutical composition described herein.
• the syringe or pump comprises 0.5 to 1.0 mL of a sterile preparation of a pharmaceutical composition described herein.
• the disclosure features a syringe or pump comprising 0.8 ml of a 70 mg/ml formulation comprising the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof.
• the disclosure features a syringe or pump comprising 0.8 ml of formulation comprising the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof at a fixed dose of 56 mg.
• the pump is an LVSC pump.
• the disclosure features a syringe or pump comprising a sterile preparation of an anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof.
• the syringe or pump is adapted for subcutaneous administration of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof at a fixed dose of 40 mg, 48 mg, 56 mg, or 64 mg.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a VH and a VL.
• the VH-CDRs comprise VH- CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:1 or 11; VH-CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:3.
• the VL-CDRs comprise VL-CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:6.
• the VH consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:7 and the VL consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:8.
• the anti- ⁇ v ⁇ 6 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:9 and the light chain consists of a sequence at least 80%, at least 90%, or 100% identical to SEQ ID NO:10.
• the disclosure features a combination treatment regimen comprising a pharmaceutical composition described herein and prifenidone.
• the disclosure features a combination treatment regimen comprising a pharmaceutical composition described herein and nintedanib.
• FIG.1A is a graph depicting the % total aggregation as determined by size exclusion chromatography (SEC) of 150 g/L STX-100 formulations with different excipients.
• FIG.1C is a bar graph showing the viscosity at ambient temperature of 150 g/L STX- 100 formulations with different excipients.
• FIG.3 is a graph showing the effect of GSH on the aggregation of STX-100 formulations at 25 o C (top) and 40 o C (bottom).
• the STX-100 formulations contain 150 mg/ml of STX-100, 20 mM citrate/citric acid, 150 mM arginine hydrochloride, 5 mM methionine, 0.05%PS80 and a pH of 5.5, and either no GSH or 0.4 mM GSH.
• FIG.4 provides graphs depicting the percentage of HMW species of SB4
• FIG.5 provides graphs depicting the percentage of HMW species of an anti- ⁇ v ⁇ 5 integrin antibody (STX200) formulation (50 mg/ml antibody; 20 mM histidine; 5% sorbitol; 0.05% PS80, pH 6.5) with or without GSH (0.4mM) at 25 0 C and 40 0 C.
• STX200 anti- ⁇ v ⁇ 5 integrin antibody
• This application provides pharmaceutical compositions and dosage regimens of anti- ⁇ v ⁇ 6 antibodies and ⁇ v ⁇ 6-binding fragments thereof and their use in the treatment of diseases such as, but not limited to, fibrosis, acute lung injury, acute kidney injury, and cancer.
• diseases such as, but not limited to, fibrosis, acute lung injury, acute kidney injury, and cancer.
• ⁇ v ⁇ 6 is an integrin that is expressed on epithelial cells. It can bind to several ligands including fibronectin, vitronectin, cytotactin, tenascin, and the latency associated peptide- 1 and -3 (LAP1 and LAP3)– the N-terminal 278 amino acids of the latent precursor form of TGF- ⁇ l - through a direct interaction with an arginine-glycine-aspartate (“RGD”) motif.
• the TGF- ⁇ cytokine is synthesized as a latent complex which has the N-terminal LAP non- covalently associated with the mature active C-terminal TGF- ⁇ cytokine.
• the latent TGF- ⁇ complex cannot bind to its cognate receptor and thus is not biologically active until converted to an active form.
• ⁇ v ⁇ 6 binding to LAP1 or LAP3 leads to activation of the latent precursor form of TGF- ⁇ l and TGF- ⁇ 3 as a result of a conformational change in the latent complex allowing TGF- ⁇ to bind to its receptor.
• upregulated expression of ⁇ v ⁇ 6 can lead to local activation of TGF- ⁇ , which in turn can activate a cascade of events downstream events.
• the TGF- ⁇ l cytokine is a pleiotropic growth factor that regulates cell proliferation, differentiation, and immune responses.
• the amino acid sequence of human integrin ⁇ v (UniProtKB - P06756 (ITAV_HUMAN) is shown below (the 30 aa signal peptide sequence is underlined):
• VLAGLLLLAV LVFVMYRMGF FKRVRPPQEE QEREQLQPHE NGEGNSET (SEQ ID NO:12)
• the mature ⁇ v protein corresponds to amino acids 31-1048 of SEQ ID NO:12.
• the mature ⁇ 6 protein corresponds to amino acids 22-788 of SEQ ID NO:13.
• the antibodies described herein can bind specifically to the ⁇ v ⁇ 6 protein having the amino acid sequence set forth in positions 31-1048 of SEQ ID NO:12 and the amino acid sequence set forth in positions 22-788 of SEQ ID NO:13. In some embodiments, the antibodies described herein can bind specifically to the ⁇ 6 protein having the amino acid sequence set forth in positions 22-788 of SEQ ID NO:13.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof used in the compositions and methods described herein comprises the three heavy chain variable domain complementarity determining regions (CDRs) of an antibody referred to as“STX- 100”.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises the three light chain variable domain CDRs of STX-100.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises the three heavy chain variable domain CDRs and the three light chain variable domain CDRs of STX- 100.
• the CDRs can be based on any CDR definition known in the art, e.g., the definitions of Kabat, Chothia, Chothia from Abysis, enhanced Chothia/AbM, or based on the contact definition. Exemplary CDR sequences of STX-100 (according to Kabat) are provided in Table 1 below.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises of a VH CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:1 or GFTFSRYVMS (SEQ ID NO:11), a VH CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:2; and a VH CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:3.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a VL CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:4, a VL CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5; and a VL CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:6.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises the CDRs comprising the amino acid sequences set forth in SEQ ID NOs:1 to 6. In certain aspects, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises the CDRs comprising the amino acid sequences set forth in SEQ ID NOs:11, 2, 3, 4, 5, and 6. In certain aspects, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises the CDRs consisting of the amino acid sequences set forth in SEQ ID NOs:1 to 6. In certain aspects, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises the CDRs consisting of the amino acid sequences set forth in SEQ ID NOs:11, 2, 3, 4, 5, and 6.
• STX-100 is a humanized humanIgG1/human kappa monoclonal antibody that specifically binds to the integrin ⁇ v ⁇ 6.
• VH heavy chain variable domain
• the light chain variable domain (VL) of STX-100 comprises or consists of the following amino acid sequence (VL CDRs (Kabat definition) bolded):
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a VH comprising or consisting of the amino acid sequence set forth in SEQ ID NO:7.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof selectively binds to ⁇ v ⁇ 6 and comprises a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VH domain of STX-100 (SEQ ID NO:7), or differs at least at 1 to 5 amino acid residues, but at fewer than 40, 30, 20, 15, or 10, residues, from SEQ ID NO:7.
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof blocks the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to ⁇ 6-expressing cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as immunostaining of paraffin-embedded tissues.
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a VL comprising or consisting of the amino acid sequence set forth in SEQ ID NO:8.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof selectively binds to ⁇ v ⁇ 6 and comprises a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VL domain of STX-100 (SEQ ID NO:8), or differs at least at 1 to 5 amino acid residues, but at fewer than 40, 30, 20, 15, or 10, residues, from SEQ ID NO:8.
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof blocks the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as immunostaining of paraffin-embedded tissues.
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a VH having the amino acid sequence set forth in SEQ ID NO:7 and a VL having the amino acid sequence set forth in SEQ ID NO:8.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof selectively binds to ⁇ v ⁇ 6 and comprises (i) a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VH domain of STX-100 (SEQ ID NO:7), and (ii) a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of the VL domain of STX-100 (SEQ ID NO:8)
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof blocks the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as immunostaining of paraffin-embedded tissues.
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to
• STX-100 is an IgG1/kappa antibody.
• HC Mature STX-100 Heavy Chain [H-CDR1, H-CDR2, and H-CDR3 are bolded;
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a HC having the amino acid sequence set forth in SEQ ID NO:9.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof selectively binds to ⁇ v ⁇ 6 and comprises a HC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO:9, or differs at least at 1 to 5 amino acid residues, but at fewer than 40, 30, 20, 15, or 10, residues, from SEQ ID NO:9.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6- binding fragment thereof comprises a heavy chain set forth in SEQ ID NO:9, except for 1 to 5 amino acid substitutions in the heavy chain constant region.
• these anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof block the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to ⁇ 6-expressing cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a LC having the amino acid sequence set forth in SEQ ID NO:10.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof selectively binds to ⁇ v ⁇ 6 and comprises a LC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO:10, or differs at least at 1 to 5 amino acid residues, but at fewer than 40, 30, 20, 15, or 10, residues, from SEQ ID NO:10.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6- binding fragment thereof comprises a light chain set forth in SEQ ID NO:10, except for 1 to 5 amino acid substitutions in the light chain constant region.
• these anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof block the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprises a HC having the amino acid sequence set forth in SEQ ID NO:9 and a LC having the amino acid sequence set forth in SEQ ID NO:10.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof selectively binds to human ⁇ v ⁇ 6 and comprises (i) a HC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of SEQ ID NO:9, or differs at least at 1 to 5 amino acid residues, but at fewer than 40, 30, 20, 15, or 10, residues, from SEQ ID NO:9; and (ii) a LC that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%
• these anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof block the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to ⁇ 6-expressing cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as immunostaining of paraffin-embedded tissues.
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP
• the anti- ⁇ v ⁇ 6 antibody is an IgG antibody.
• the anti- ⁇ v ⁇ 6 antibody has heavy chain constant region chosen from, e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE.
• the anti- ⁇ v ⁇ 6 antibody is of the human IgG1 isotype.
• the anti- ⁇ v ⁇ 6 antibody is of the human IgG2 isotype.
• the anti- ⁇ v ⁇ 6 antibody is of the human IgG3 isotype.
• the anti- ⁇ v ⁇ 6 antibody is of the human IgG4 isotype.
• the antibody has a light chain constant region chosen from, e.g., a human kappa or human lambda light chain.
• the anti- ⁇ v ⁇ 6 antibody is a human IgG1/human kappa antibody.
• the heavy chain constant region is human or a modified form of a human constant region.
• the human constant region may include at least 1 and up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitutions.
• the modified human Fc region is a modified human IgG1 Fc region.
• the constant region of an anti- ⁇ v ⁇ 6 antibody is modified by mutation of one or more amino acid residues to impart a desired functional property (e.g., altered effector function or half-life, reduced glycosylation).
• the N-linked glycosylation site may be substituted to prevent or reduce N- linked glycosylation of Fc region (e.g., human IgG1 Fc region).
• the anti- ⁇ v ⁇ 6 antibody is a full-length (whole) antibody or substantially full-length.
• the protein can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains.
• the anti- ⁇ v ⁇ 6 antibody is an ⁇ v ⁇ 6-binding fragment.
• the ⁇ v ⁇ 6-binding fragment is a Fab, a Fab’, an F(ab')2, a Facb, an Fv, a single chain Fv (scFv), a sc(Fv)2, or a diabody.
• Antibodies such as STX-100, or ⁇ v ⁇ 6-binding fragments thereof can be made, for example, by preparing and expressing synthetic genes that encode the recited amino acid sequences or by mutating human germline genes to provide a gene that encodes the recited amino acid sequences. Moreover, this antibody and other anti- ⁇ v ⁇ 6 antibodies can be produced, e.g., using one or more of the following methods. Methods of Producing Antibodies
• Anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments can be produced in bacterial or eukaryotic cells. Some antibodies, e.g., Fab’s, can be produced in bacterial cells, e.g., E. coli cells. Antibodies can also be produced in eukaryotic cells such as transformed cell lines (e.g., CHO, 293E, COS). In addition, antibodies (e.g., scFv’s) can be expressed in a yeast cell such as Pichia (see, e.g., Powers et al., J Immunol Methods.251:123-35 (2001)), Hanseula, or Saccharomyces.
• a yeast cell such as Pichia (see, e.g., Powers et al., J Immunol Methods.251:123-35 (2001)), Hanseula, or Saccharomyces.
• a polynucleotide encoding the antibody is constructed, introduced into an expression vector, and then expressed in suitable host cells.
• Polynucleotides encoding an anti- ⁇ v ⁇ 6 antibody comprising the VH and/or VL, HC and/or LC of the ⁇ v ⁇ 6 antibodies described herein would be readily envisioned by the ordinarily skilled artisan. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the antibody.
• the expression vector should have characteristics that permit amplification of the vector in the bacterial cells. Additionally, when E. coli such as JM109, DH5 ⁇ , HB101, or XL1-Blue is used as a host, the vector must have a promoter, for example, a lacZ promoter (Ward et al., 341:544-546 (1989), araB promoter (Better et al., Science, 240:1041-1043 (1988)), or T7 promoter that can allow efficient expression in E. coli.
• a promoter for example, a lacZ promoter (Ward et al., 341:544-546 (1989), araB promoter (Better et al., Science, 240:1041-1043 (1988)
• T7 promoter that can allow efficient expression in E. coli.
• Such vectors include, for example, M13-series vectors, pUC-series vectors, pBR322, pBluescript, pCR-Script, pGEX-5X-1 (Pharmacia),“QIAexpress system” (QIAGEN), pEGFP, and pET (when this expression vector is used, the host is preferably BL21 expressing T7 RNA polymerase).
• the expression vector may contain a signal sequence for antibody secretion.
• the pelB signal sequence Lei et al., J. Bacteriol., 169:4379 (1987)
• calcium chloride methods or electroporation methods may be used to introduce the expression vector into the bacterial cell.
• the expression vector includes a promoter necessary for expression in these cells, for example, an SV40 promoter (Mulligan et al., Nature, 277:108 (1979)), MMLV-LTR promoter, EF1 ⁇ promoter (Mizushima et al., Nucleic Acids Res., 18:5322 (1990)), or CMV promoter.
• SV40 promoter Mulligan et al., Nature, 277:108 (1979)
• MMLV-LTR promoter MMLV-LTR promoter
• EF1 ⁇ promoter EF1 ⁇ promoter
• the recombinant expression vectors may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
• the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Pat. Nos.4,399,216, 4,634,665 and 5,179,017).
• typically the selectable marker gene confers resistance to drugs, such as G418, hygromycin, or methotrexate, on a host cell into which the vector has been introduced.
• examples of vectors with selectable markers include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.
• antibodies are produced in mammalian cells.
• exemplary mammalian host cells for expressing an antibody include Chinese Hamster Ovary (CHO cells) (including dhfr – CHO cells, described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in Kaufman and Sharp (1982) Mol.
• Biol.159:601-621 human embryonic kidney 293 cells (e.g., 293, 293E, 293T), COS cells, NIH3T3 cells, lymphocytic cell lines, e.g., NS0 myeloma cells and SP2 cells, and a cell from a transgenic animal, e.g., a transgenic mammal.
• the cell is a mammary epithelial cell.
• a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain of an anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) is introduced into dhfr – CHO cells by calcium phosphate-mediated transfection.
• the antibody heavy and light chain genes are each operatively linked to enhancer/promoter regulatory elements (e.g., derived from SV40, CMV, adenovirus and the like, such as a CMV enhancer/AdMLP promoter regulatory element or an SV40 enhancer/AdMLP promoter regulatory element) to drive high levels of transcription of the genes.
• enhancer/promoter regulatory elements e.g., derived from SV40, CMV, adenovirus and the like, such as a CMV enhancer/AdMLP promoter regulatory element or an SV40 enhancer/AdMLP promoter regulatory element
• the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
• the selected transformant host cells are cultured to allow for expression of the antibody heavy and light chains and the antibody is recovered from the culture medium.
• Antibodies can also be produced by a transgenic animal.
• U.S. Pat. No. 5,849,992 describes a method of expressing an antibody in the mammary gland of a transgenic mammal.
• a transgene is constructed that includes a milk-specific promoter and nucleic acids encoding the antibody of interest and a signal sequence for secretion.
• the milk produced by females of such transgenic mammals includes, secreted-therein, the antibody of interest.
• the antibody can be purified from the milk, or for some applications, used directly. Animals are also provided comprising one or more of the nucleic acids described herein.
• the antibodies of the present disclosure can be isolated from inside or outside (such as medium) of the host cell and purified as substantially pure and homogenous antibodies. Methods for isolation and purification commonly used for antibody purification may be used for the isolation and purification of antibodies, and are not limited to any particular method. Antibodies may be isolated and purified by appropriately selecting and combining, for example, column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel
• Chromatography includes, for example, affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reverse-phase chromatography, and adsorption
• compositions comprising the anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof described herein.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise an anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6- binding fragment thereof comprising an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH comprises the H- CDRs and the VL comprises the L-CDRs of STX-100.
• VH immunoglobulin heavy chain variable domain
• VL immunoglobulin light chain variable domain
• the heavy chain CDRs comprise or consist of the amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; and the light chain CDRs (L-CDRs) comprise or consist of the amino acid sequences set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
• the heavy chain CDRs (H-CDRs) comprise or consist of the amino acid sequences set forth in SEQ ID NO:11, SEQ ID NO:2, and SEQ ID NO:3; and the light chain CDRs (L-CDRs) comprise or consist of the amino acid sequences set forth in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
• the anti- ⁇ v ⁇ 6 antibody compositions comprises an anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof comprising (i) a VH comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:7; and (ii) a VL comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:8.
• the anti- ⁇ v ⁇ 6 antibody compositions comprises an anti- ⁇ v ⁇ 6 antibody comprising (i) a heavy chain comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:9; and (ii) a light chain comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:10.
• a heavy chain comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:9
• a light chain comprising or consisting of an amino acid sequence that is at least
• the anti- ⁇ v ⁇ 6 antibodies selectively bind to ⁇ v ⁇ 6.
• these anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof block the binding of ⁇ v ⁇ 6 to its ligand, latency associated peptide (LAP), as determined by blocking of ligand binding either to purified hs ⁇ v ⁇ 6 or to ⁇ 6-expressing cells.
• LAP latency associated peptide
• these anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragments thereof have one or more (e.g., one, two, three, four) of these properties: (i) specifically bind with high affinity to ⁇ v ⁇ 6; (ii) inhibit the binding of ⁇ v ⁇ 6 to LAP, fibronectin, vitronectin, or tenascin with an IC50 value lower than that of the 10D5 antibody (WO 99/07405); (iii) block or inhibit activation of TGF- ⁇ ; (iv) specifically bind to the ⁇ 6 subunit; and (v) recognize ⁇ v ⁇ 6 in immunostaining procedures such as
• these compositions are high concentration anti- ⁇ v ⁇ 6 antibody compositions.
• “high concentration anti- ⁇ v ⁇ 6 antibody composition” is meant a composition comprising anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of greater than 100 mg/ml and less than 300 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 50 mg/ml to 250 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 50 mg/ml to 225 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 75 mg/ml to 225 mg/ml. In certain instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 50 mg/ml to 200 mg/ml. In other instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 75 mg/ml to 165 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 100 mg/ml to 225 mg/ml. In yet other instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 125 mg/ml to 225 mg/ml. In other instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 125 mg/ml to 175 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 240 mg/ml. In certain instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 225 mg/ml. In certain instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 200 mg/ml. In certain instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6- binding fragments thereof at a concentration of 175 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 150 mg/ml. In other instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 125 mg/ml. In some instances, the anti- ⁇ v ⁇ 6 antibody composition comprises anti- ⁇ v ⁇ 6 antibodies or ⁇ v ⁇ 6-binding fragments thereof at a concentration of 100 mg/ml.
• a composition comprising an anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof described herein may be in any one of a variety of forms. These include, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions, or suspensions. The preferred form can depend on the intended mode of administration and therapeutic application.
• a pharmaceutical composition described herein is in the form of a sterile injectable or infusible solution. Sterile injectable solutions can be prepared by incorporating an antibody described herein in the required amount with one or a combination of ingredients, followed by filtered sterilization.
• dispersions are prepared by incorporating an antibody described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients.
• a sterile powders for the preparation of sterile injectable solutions an exemplary method of preparation is vacuum drying and freeze drying that yields a powder of an antibody described herein plus any additional desired ingredient from a previously sterile-filtered solution thereof.
• the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
• the anti- ⁇ v ⁇ 6 antibody compositions may additionally comprise one or more excipients.
• the excipient lowers/reduces the aggregation and/or viscosity of the antibody in the composition compared to aggregation and/or viscosity of the antibody in the pharmaceutical composition without that excipient.
• such an excipient is arginine.
• the excipient is L-arginine hydrochloride.
• Arginine e.g., L-arginine hydrochloride
• Arginine hydrochloride can be included in the composition at a concentration of 40 mM to 260 mM, 50 mM to 250 mM, 50 mM to 200 mM, 50 mM to 150 mM, 50 mM to 125 mM, 50 mM to 100 mM, 75 mM to 250 mM, 75 mM to 200 mM, 75 mM to 150 mM, or 75 mM to 100 mM.
• arginine e.g., Arg.HCl
• arginine e.g., Arg.HCl
• arginine e.g., Arg.HCl
• arginine hydrochloride can be included in the composition at a concentration of 80 mM, 100 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 220 mM, or 260 mM.
• arginine e.g., arginine hydrochloride
• arginine e.g., arginine hydrochloride
• arginine hydrochloride can be included in the composition at a concentration of 100 mM.
• arginine e.g., arginine hydrochloride
• 150 mM e.g., 150 mM.
• the anti- ⁇ v ⁇ 6 antibody composition comprises sucrose at a concentration of 0.05% to 5%, 0.05% to 4%, 0.05% to 3%, 1% to 5 %, 1% to 4%, 1% to 3%, 2% to 5%, 2% to 4%, or 2% to 3%.
• the anti- ⁇ v ⁇ 6 antibody composition comprises sucrose at a concentration of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%. In a particular embodiment, the anti- ⁇ v ⁇ 6 antibody composition comprises sucrose at a concentration of 3%. In another particular embodiment, the anti- ⁇ v ⁇ 6 antibody composition comprises sucrose at a concentration of 1%.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise methionine.
• methionine is included in the composition at a concentration from 0.5 mM to 25 mM.
• methionine is included in the composition at a concentration from 1 mM to 10 mM.
• methionine is included in the composition at a concentration from 3 mM to 8 mM.
• methionine is included in the
• composition at a concentration of 1 mM, 2 mM, 5 mM, 10 mM, 15 mM, 20 mM or 25 mM.
• methionine is included in the composition at a concentration of 10 mM.
• methionine is included in the composition at a concentration of 5 mM.
• Antibody product manufacturing is a complex process that can involve several steps such as, e.g., drug substance and bulk formulation, filtration, shipping, pooling, filling, lyophilization, inspections, packaging, and storage. During these steps, antibodies may be subjected to many different forms of stresses, e.g., agitation, temperature, light exposure, and oxidation. These types of stresses can lead to denaturation and aggregation of the antibody, which compromise the product quality and can even lead to loss of a production batch.
• the composition may include a polysorbate.
• the composition comprises polysorbate-80 at a concentration of 0.01% to 0.5%, 0.01% to 0.1%, 0.01% to 0.09%, 0.01% to 0.08%, 0.01% to 0.07%, 0.01% to 0.06%, 0.01% to 0.05%, 0.01% to 0.04%, or 0.01% to 0.03%.
• the composition comprises polysorbate-80 at a concentration of 0.02% to 0.08%. In some embodiments, the composition comprises polysorbate-80 at a concentration of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%. In a particular embodiment, the composition comprises polysorbate-80 at a concentration of 0.05%.
• the antibody composition comprises sodium citrate and citric acid as the buffering agent.
• the composition comprises sodium citrate and citric acid at a concentration of 5 mM to 50 mM, 5 mM to 40 mM, 5 mM to 35 mM, 5 mM to 30 mM, 5 mM to 25 mM, 10 mM to 50 mM, 10 mM to 40 mM, 10 mM to 30 mM, 10 mM to 25 mM, 15 mM to 50 mM, 15 mM to 40 mM, 15 mM to 30 mM, or 15 mM to 25 mM.
• the composition comprises sodium citrate and citric acid at a concentration of 5 mM to 35 mM. In certain embodiments, the composition comprises sodium citrate and citric acid at a concentration of 10 mM to 30 mM. In some embodiments, the composition comprises sodium citrate and citric acid at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30mM, or 35 mM. In a particular embodiment, the composition comprises sodium citrate and citric acid at a concentration of 20 mM.
• the pH of the antibody composition can be from 5.0 to 6.5. In certain cases, the pH of the antibody composition can be 5.2 to 6.2. In certain instances, the pH of the antibody composition is 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5. In a particular embodiment, the pH of the antibody composition is 5.5.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM) and methionine (e.g., 5 mM). In certain cases, these compositions have a pH of 5.5.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM) and a buffer (e.g., sodium citrate and citric acid at 20 mM). In certain cases, these compositions have a pH of 5.5.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), and PS80 (e.g., 0.05%). In certain cases, these compositions have a pH of 5.5.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), sodium citrate and citric acid (e.g., 20 mM), and PS80 (e.g., 0.05%), and has a pH of 5.2 to 6.2.
• the anti- ⁇ v ⁇ 6 compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), sodium citrate and citric acid (e.g., 20 mM), and PS80 (e.g., 0.05%), and has a pH of 5.5.
• the anti- ⁇ v ⁇ 6 compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), sodium citrate and citric acid (e.g., 20 mM), PS80 (e.g., 0.05%), and sucrose (up to 3%), and has a pH of 5.2 to 6.2.
• the anti- ⁇ v ⁇ 6 compositions comprise L-arginine hydrochloride, methionine, sodium citrate and citric acid, PS80, and has a pH of 5.5.
• the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 100 mg/ml to 165 mg/ml. In one instance, the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 150 mg/ml. In one instance, the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 100 mg/ml.
• the anti- ⁇ v ⁇ 6 composition comprises a thiol-containing antioxidant (e.g., reduced glutathione (GSH), oxidized glutathione (GSSG), GSH + GSSG, cysteine, cystine, cysteine + cystine) at a concentration of 0.02 mM to 2 mM (e.g., 0.02, 0.03, 0.05, 0.06, 0.08, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mM).
• a thiol-containing antioxidant e.g., reduced glutathione (GSH), oxidized glutathione (GSSG), GSH + GSSG, cysteine, cystine, cysteine + cystine
• the composition comprises GSH at a concentration of 0.4 mM. In some cases, the composition comprises GSSG at a concentration of 0.2 mM. In some cases, the composition comprises GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In some cases, the composition comprises cysteine at a concentration of 0.4 mM. In some cases, the composition comprises cystine at a concentration of 0.2 mM. In some cases, the composition comprises cysteine at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), sodium citrate and citric acid (e.g., 20 mM), a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM), and PS80 (e.g., 0.05%), and has a pH of 5.2 to 6.2.
• L-arginine hydrochloride e.g., 150 mM
• methionine e.g., 5 mM
• sodium citrate and citric acid e.g., 20 mM
• a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L- arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), sodium citrate and citric acid (e.g., 20 mM), a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM), and PS80 (e.g., 0.05%), and has a pH of 5.5.
• L- arginine hydrochloride e.g., 150 mM
• methionine e.g., 5 mM
• sodium citrate and citric acid e.g., 20 mM
• a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), methionine (e.g., 5 mM), sodium citrate and citric acid (e.g., 20 mM), PS80 (e.g., 0.05%), a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM), and sucrose (up to 3%), and has a pH of 5.2 to 6.2.
• L-arginine hydrochloride e.g., 150 mM
• methionine e.g., 5 mM
• sodium citrate and citric acid e.g., 20 mM
• PS80 e.g., 0.05%
• a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cyst
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride, methionine, histidine, PS80, and a thiol- containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine, and has a pH of 5.5.
• the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 100 mg/ml to 165 mg/ml. In one instance, the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 150 mg/ml. In one instance, the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 100 mg/ml.
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), sodium citrate buffer (sodium citrate and citric acid) (e.g., 20 mM), a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM), and PS80 (e.g., 0.05%), and has a pH of 5.2 to 6.2.
• L-arginine hydrochloride e.g., 150 mM
• sodium citrate buffer sodium citrate and citric acid
• a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine
• PS80 e.g., 0.05%)
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), sodium citrate and citric acid (e.g., 20 mM), a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM), and PS80 (e.g., 0.05%), and has a pH of 5.5.
• L-arginine hydrochloride e.g., 150 mM
• sodium citrate and citric acid e.g., 20 mM
• a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine
• PS80 e.g. 0.02 mM to 2 mM
• PS80 e.g. 0.02 mM to 2 mM
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride (e.g., 150 mM), sodium citrate and citric acid (e.g., 20 mM), PS80 (e.g., 0.05%), a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM), and sucrose (up to 3%), and has a pH of 5.2 to 6.2.
• L-arginine hydrochloride e.g., 150 mM
• sodium citrate and citric acid e.g., 20 mM
• PS80 e.g., 0.05%
• a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine (e.g., 0.02 mM to 2 mM)
• sucrose up
• the anti- ⁇ v ⁇ 6 antibody compositions comprise L-arginine hydrochloride, histidine, PS80, and a thiol-containing antioxidant such as GSH, GSSG, GSH and GSSG, cysteine, cystine, or cysteine and cystine, and has a pH of 5.5.
• the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 100 mg/ml to 165 mg/ml. In one instance, the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 150 mg/ml. In one instance, the anti- ⁇ v ⁇ 6 antibody is present at a concentration of 100 mg/ml.
• the composition (e.g., a pharmaceutical composition) comprises an anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6-binding fragment thereof at a concentration of 75 mg/ml to 250 mg/ml, arginine (e.g., L-arginine hydrochloride) at a concentration of 50 mM to 200 mM, methionine at a concentration of 1 mM to 10 mM; polysorbate-80 at a concentration of 0.01% to 0.1%, sodium citrate and citric acid at a concentration of 10 mM to 30 mM, and sucrose at a concentration of 0% to 3%.
• the composition has a pH of 5.2 to 6.0.
• the anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6-binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of STX-100 (e.g., SEQ ID NOs: 1 or 11, 2, 3, 4, 5, and 6).
• the anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6- binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively.
• the anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6- binding fragment thereof of the composition comprises a heavy chain and a light chain comprising SEQ ID NOs: 9 and 10, respectively.
• the composition has a pH of 5.5 and comprises STX-100 or a STX-100-binding fragment thereof at a concentration of 150 mg/ml, L-arginine hydrochloride at a concentration of 150 mM, methionine at a concentration of 5 mM, polysorbate-80 at a concentration of 0.05%, and sodium citrate and citric acid at a concentration of 20 mM.
• the composition further comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH + GSSG, cysteine, cystine, cysteine + cystine) at a concentration of 0.02 mM to 2 mM.
• a thiol-containing antioxidant e.g., GSH, GSSG, GSH + GSSG, cysteine, cystine, cysteine + cystine
• the composition further comprises sucrose at a concentration of 0.01% to 3%.
• the anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6-binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of STX-100 (e.g., SEQ ID NOs: 1 or 11, 2, 3, 4, 5, and 6).
• the anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6- binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively.
• the anti- ⁇ v ⁇ 6 antibody or an ⁇ v ⁇ 6- binding fragment thereof of the composition comprises a heavy chain and a light chain comprising SEQ ID NOs: 9 and 10, respectively.
• the composition has a pH of 5.5 and comprises STX-100 or a STX-100-binding fragment thereof at a concentration of 150 mg/ml, L-arginine
• hydrochloride at a concentration of 150 mM
• a thiol-containing antioxidant e.g., GSH, GSSG, GSH + GSSG, cysteine, cystine, cysteine + cystine
• GSH thiol-containing antioxidant
• polysorbate-80 at a concentration of 0.05%
• sodium citrate and citric acid at a concentration of 20 mM.
• the thiol-containing antioxidant is GSH at a concentration of 0.4 mM.
• the thiol-containing antioxidant is GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM.
• the thiol-containing antioxidant is cysteine at a concentration of 0.4 mM. In another embodiment, the thiol-containing antioxidant is cysteine at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM.
• the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof described above can be administered to a subject, e.g., a human subject, at different doses.
• the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof can be administered as a fixed dose (i.e., independent of the weight of the patient), or in a mg/kg dose (i.e., a dose which varies based on the weight of the subject).
• Dosage unit form or“fixed dose” as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier and optionally in association with the other agent. Single or multiple dosages may be given. The treatment can continue for days, weeks, months or even years.
• the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a fixed dose of 40 mg to 64 mg once weekly. In one embodiment, for treating an indication described herein in an adult human subject, the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a fixed dose of 40 mg once weekly. In another embodiment, the dosage of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is a fixed dose of 48 mg once weekly.
• the dosage of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is a fixed dose of 56 mg once weekly. In another embodiment, the dosage of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is a fixed dose of 64 mg once weekly.
• the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a mg/kg dose of 0.3 mg/kg to 1.0 mg/kg. In one embodiment, for treating an indication described herein in an adult human subject, the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a mg/kg dose of 0.5 mg/kg to 0.8 mg/kg.
• the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a mg/kg dose of 0.5 mg/kg.
• the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6- binding fragment thereof is a mg/kg dose of 0.6 mg/kg.
• the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a mg/kg dose of 0.7 mg/kg.
• the dosage of the anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof is a mg/kg dose of 0.8 mg/kg.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered in combination with a therapeutically effective amount of an art recognized treatment for IPF.
• Exemplary art recognized treatment options that can be used in combination with the antibody of the invention include: Corticosteroids (prednisone); Cyclophosphamide
• an antibody of the invention is combined with prifenidone or nintedanib.
• the subject is administered prifenidone as follows:
• the subject is administered a therapeutically effective amount of nintedanib at a fixed dose of 150 mg twice daily in combination with the antibody of the invention.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered in combination with an antibody that inhibits the activity of connective tissue growth factor (CTGF) such as, but not limited to, the fully-human monoclonal antibody, Pamrevlumab.
• CTGF connective tissue growth factor
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered in combination with a therapeutically effective amount of a selective autotaxin inhibitor (e.g., GLPG1690).
• a selective autotaxin inhibitor e.g., GLPG1690
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered in combination with a therapeutically effective amount of GBT-440.
• a pharmaceutical composition may include a“therapeutically effective amount” of an agent described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic, or detrimental effects, of the composition is outweighed by the therapeutically beneficial effects. In certain embodiment, the therapeutically effective amount of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is 40 mg to 64 mg.
• the therapeutically effective amount of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is 40 mg. In another embodiment, the therapeutically effective amount of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is 48 mg. In yet another embodiment, the therapeutically effective amount of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is 56 mg. In yet another embodiment, the therapeutically effective amount of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is 64 mg.
• the route and/or mode of administration of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof can be tailored for the individual subject.
• the route of administration is one of: subcutaneous injection (SC), intravenous injection or infusion (IV), intraperitoneal administration (IP), or intramuscular injection.
• SC subcutaneous injection
• IV intravenous injection or infusion
• IP intraperitoneal administration
• intramuscular injection intramuscular injection.
• the route of administration is subcutaneous.
• the route of administration is intravenous.
• compositions that comprise the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof alone or in combination with non ⁇ v ⁇ 6 antibody agent(s) can be
• the device can be designed with features such as portability, room temperature storage, and ease of use so that it can be used in emergency situations, e.g., by an untrained subject or by emergency personnel in the field, removed to medical facilities and other medical equipment.
• the device can include, e.g., one or more housings for storing pharmaceutical preparations that include the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6- binding fragment thereof, and can be configured to deliver one or more unit doses of the anti- ⁇ v ⁇ 6 antibody or other agent.
• the pharmaceutical composition can be administered with a needleless hypodermic injection device, such as the devices disclosed in US 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
• a needleless hypodermic injection device such as the devices disclosed in US 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
• implants and modules examples include: US 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; US 4,486,194, which discloses a therapeutic device for administering medicaments through the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; US 4,439,196, which discloses an osmotic drug delivery system having multi- chamber compartments; and US 4,475,196, which discloses an osmotic drug delivery system. Many other devices, implants, delivery systems, and modules are also known.
• the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered to a human subject with a syringe. In another embodiment, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered to a human subject with a pump for subcutaneous delivery. In some embodiments, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered to a human subject with an autoinjector. In other embodiments, the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof is administered to a human subject with a subcutaneous large volume injector.
• This disclosure provides a pump or syringe comprising a sterile preparation of an anti- ⁇ v ⁇ 6 antibody (e.g., STX-100) or ⁇ v ⁇ 6-binding fragment thereof.
• the syringe or pump can be adapted for subcutaneous administration of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof.
• the syringe or pump delivers a fixed doses(s) (e.g., 40 mg, 48 mg, 56 mg, 64 mg) of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof.
• the disclosure also provides a pump, syringe, or injector (e.g., autoinjector, subcutaneous large volume injector) comprising a sterile preparation of the pharmaceutical compositions described above.
• the syringe or pump can be adapted for subcutaneous administration of the pharmaceutical compositions comprising the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof.
• the syringe or pump delivers a fixed doses(s) (e.g., 40 mg, 48 mg, 56 mg, 64 mg) of the anti- ⁇ v ⁇ 6 antibody or ⁇ v ⁇ 6-binding fragment thereof.
• the antibodies of this disclosure are useful in the treatment, including prevention, of ⁇ v ⁇ 6-mediated diseases.
• these antibodies can be used to treat fibrosis (e.g., lung fibrosis, kidney fibrosis, liver fibrosis, cardiac fibrosis), acute lung injury, acute kidney injury, Alport’s Syndrome, psoriasis, scleroderma, and sclerosis of lung, liver, or kidney, by blocking the activation of TGF- ⁇ or blocking the binding of ⁇ 6 to any other ligands, such as fibronectin, vitronectin, and tenascin.
• the novelty of this approach includes: (1) it blocks the activation of TGF- ⁇ rather than the binding of TGF- ⁇ to its receptor, (2) it can inhibit TGF- ⁇ locally (i.e., at sites of ⁇ v ⁇ 6 upregulation) rather than systemically, and (3) it inhibits binding of ⁇ v ⁇ 6 to a ligand.
• the antibodies of the disclosure are useful in treating cancer or cancer metastasis (including tumor growth and invasion), particularly epithelial cancers.
• cancer or cancer metastasis including tumor growth and invasion
• epithelial cancers are squamous cell carcinoma, e.g., head and neck, oral, breast, lung, prostate, cervical, pharyngeal, colon, pancreatic and ovarian cancers.
• ⁇ v ⁇ 6-binding antibodies or fragments thereof may be used in therapeutic regimens for treating humans having, or at risk of developing carcinomas.
• Such methods of the invention are useful in treating cancer and associated events, including tumor growth, metastasis and angiogenesis.
• Particularly amenable to such an approach are those diseases or cancers that are characterized by increased levels of ⁇ v ⁇ 6 expression in the tissues or cells of a mammal suffering from the disease, and which are responsive to treatments, which target the tissues or cells expressing increased levels of ⁇ v ⁇ 6 and eliminate those tissues or cells.
• metastatic cancers of epithelial tissues i.e., metastatic carcinomas and/or adenocarcinomas
• epithelial tissues i.e., metastatic carcinomas and/or adenocarcinomas
• the breast, ovary, prostate, liver, lung, pancreas, colon head and neck tissues (e.g., oral, pharyngeal, lingual and laryngeal tissues), endometrium, cervix, stomach and spleen.
• Particularly suitable for treatment by these methods of the present invention are carcinomas of the endometrium, pancreas, colon (e.g., colorectal carcinomas), cervix, lung and breast (including ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) of the breast).
• DCIS ductal carcinoma in situ
• LCIS lobular carcinoma in situ
• Accelerated stability evaluation was performed at 40°C incubation over 4 weeks for the formulations.
• the following quality attributes were monitored: visible particulates and clarity, % high molecular weight species (via SEC), total sub-visible particulates (via MFI), turbidity (via OD340), pH, fragmentation (via GXII), % total acidic isoforms (via iCIEF), and viscosity at T0.
• Maximum weightage was assigned to Critical quality attributes (CQA) like aggregate level and particle formation and were utilized in formulation selection. The formulations with least amount of aggregate level and particle formation were selected for further evaluations.
• CQA Critical quality attributes
• Example 1 Based on the pre-formulation results in Example 1, the following five liquid formulations and corresponding container-closures (CCs) were selected for pursuing a long- term (24 month) stability study:
• Lot# 18169-62 150 mg/mL STX-100 in 20 mM Na-citrate/citric acid, pH 5.3, 150 mM arginine hydrochloride (Arg.HCl), 0.05% PS-80 (1 mL fill in 3 mL Schott vial) 2) Lot# 18169-64: 150 mg/mL STX-100 in 20 mM Na-citrate/citric acid, pH 5.3, 150 mM arginine hydrochloride (Arg.HCl), 0.05% PS-80 (1 mL fill in BD Hypak pre- filled syringe, 27G needle)
• Oxidation data Forced oxidation analysis in the past on STX-100 samples had revealed oxidation propensity in Met-55 contained in the second heavy chain CDR along with two other methionines (Met-255 and Met-431) in the Fc region. Structure-activity relationship studies revealed that oxidation in these residues do not lead to any change in binding activity to the antigen. In this study, it was also investigated whether oxidation in these residues over time leads to instability due to the presence of polysorbate-80 as a likely oxidizing agent.
• the % oxidation was determined using a LCMS method after generating in Met residues contained in corresponding peptides generated (Met-55 in peptide H2, Met-255 in peptide H15, and Met-431 in peptide H30) by LysC cleavage. Overall, there was no major increase in oxidation at each site although the presence of methionine as an excipient in the formulation did suppress this oxidation reaction (Tables 9A and 9B).
• the core formulation buffer was: 20 mM Citric acid / Na-citrate, 150 mM arginine HCl, 0.05% PS80.
• the only solution parameter with a significant impact on viscosity was the protein concentration which was expected in the range examined.
• Formulation A 150 mg/mL STX-100, 20 mM Na-citrate/citric acid, pH 5.5, 150 mM Arginine-HCl, 10 mM Methionine, 0.05% polysorbate-80.
• Formulation B 150 mg/mL STX-100, 20 mM Na-citrate/citric acid, pH 5.5, 150 mM Arginine-HCl, 5 mM Methionine, 0.03% polysorbate-80.
• the different PS-80 levels selected for evaluations were 0, 0.01, 0.02, 0.05, 0.08, 0.1 % w/v in 150 mg/mL STX-100 formulation containing 20 mM Na-citrate/citric acid, pH 5.5, 150 mM Arginine-HCl, 5 mM Methionine.
• the container closure system used for the evaluations were Polycarbonate bottles (1 mL fill in 5 mL bottle), Small DS bag (30 mL capacity, 5 or 15 mL fill), PFS syringes (BD Hypak 47368319 with plungers (47165919) filled with either 0.8 mL or 0.3 mL at 150 mg/mL or 0.3 mL at 40 mg/mL).
• the product quality attributes examined were: Visible appearance (particulates), Turbidity (A340), % Total aggregates (SEC), Protein concentration (SoloVPE method), and Sub-visible particulates (MFI)
• the control STX-100 formulation had 150 mg/mL STX-100, 20mM citrate/citric acid, 150 mM L-Arginine HCl, 5 mM Methionine, 0.05% Polysorbate-80, pH 5.5.
• the control STX-100 formulation had 150 mg/mL STX-100, 20mM citrate/citric acid, 150 mM L-Arginine HCl, 5 mM Methionine, 0.05% Polysorbate-80, pH 5.5.
• the control STX-100 formulation had 150 mg/mL STX-100, 20mM citrate/citric acid, 150 mM L-Arginine HCl, 5 mM Methionine, 0.05% Polysorbate-80, pH 5.5.
• Stability study data for 50 and 100 mg/mL STX-100 formulations in 20 mM sodium citrate buffer containing 150 mM Arg.HCL, 5 mM methionine, 0.05% PS80, at pH 5.5 filled into syringes (0.8 mL /syringe) supports stability for 36 months when stored at 2-8°C. This is based on stability data at the long term storage condition of 2-8°C. See Tables 12 and 13
• formulation at 70 mg/mL (0.8 mL/syringe) selected to deliver a dose of 56 mg.
• Table 12 Stability Data for STX-100 Drug Product at 100 mg/mL in 1 mL Syringe, Stored

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