WO2022026699A1 - Formulations d'anticorps anti-intégrine bêta7 et dispositifs - Google Patents

Formulations d'anticorps anti-intégrine bêta7 et dispositifs Download PDF

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Publication number
WO2022026699A1
WO2022026699A1 PCT/US2021/043690 US2021043690W WO2022026699A1 WO 2022026699 A1 WO2022026699 A1 WO 2022026699A1 US 2021043690 W US2021043690 W US 2021043690W WO 2022026699 A1 WO2022026699 A1 WO 2022026699A1
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Prior art keywords
formulation
hvr
seq
amino acid
acid sequence
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PCT/US2021/043690
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English (en)
Inventor
Jennifer PULLEY
Meina Tao TANG
Swati TOLE
Helen TYRRELL
Mariam ABOUHOSSEIN
Hemanth AMARCHINTA
Audrey BORUVKA
Han Ting DING
Heather L. FLORES
Glen Scott GIESE
Renato Ravanello
Wenhui Zhang
Original Assignee
Genentech, Inc.
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Application filed by Genentech, Inc., F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical Genentech, Inc.
Priority to KR1020237006223A priority Critical patent/KR20230041071A/ko
Priority to MX2023001157A priority patent/MX2023001157A/es
Priority to EP21766732.8A priority patent/EP4188958A1/fr
Priority to AU2021316017A priority patent/AU2021316017A1/en
Priority to BR112023001734A priority patent/BR112023001734A2/pt
Priority to CA3190109A priority patent/CA3190109A1/fr
Priority to IL300133A priority patent/IL300133A/en
Priority to JP2023506189A priority patent/JP2023536158A/ja
Publication of WO2022026699A1 publication Critical patent/WO2022026699A1/fr

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    • 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
    • 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
    • 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
    • C07K2317/90—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

  • Formulations comprising an anti-integrin beta7 antibody or an antigen-binding fragment thereof are provided, including pharmaceutical formulations and devices comprising such formulations and methods of using such formulations and devices.
  • integrins are ab heterodimeric cell surface receptors involved in numerous cellular processes from cell adhesion to gene regulation (Hynes Cell (1992);69: 11-25; and Hemler, Annu. Rev. Immunol. (1990), 8:365-368).
  • Several integrins have been implicated in disease processes and have generated widespread interest as potential targets for drug discovery (Sharar etal, Springer Semin. Immunopathol . (1995); 16:359- 378).
  • integrins are involved in leukocyte trafficking, adhesion and infiltration during inflammatory processes (Nakajima etal, J. Exp. Med.
  • integrins regulates the adhesive properties of cells and different integrins are involved in different inflammatory responses (Butcher etal, Science (1996);272:60-66.
  • the beta7 integrins i.e., a4b7 and h1rHhEb7 are expressed primarily on monocytes, lymphocytes, eosinophils, basophils, and macrophages but not on neutrophils (Elices et al, Cell (1990);60:577-584).
  • the primary ligands for a4b7 integrin are the endothelial surface proteins mucosal address in cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM-1) (Makarem et al, J. Biol. Chem. (1994);269:4005-4011).
  • MAdCAM cell adhesion molecule
  • VCAM-1 vascular cell adhesion molecule
  • HEVs high endothelial venules
  • Monoclonal antibodies directed against a4b7, MAdCAM or VCAM have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Laberge etal, Am. ./. Respir. Crit. Care Med. (1995); 151 :822- 829.), rheumatoid arthritis (Barbadillo e/a/., Springer Semin. Immunopathol. (1995);16:375-379), colitis (Viney, J. Immunol. (1996);157: 2488-2497) and inflammatory bowel diseases (Podalski, N. Eng. J. Med. (1991);325:928-937; Powrie et al, Ther. Immunol. (1995);2: 115-123).
  • chronic inflammatory diseases such as asthma (Laberge etal, Am. ./. Respir. Crit. Care Med. (1995); 151 :822- 829.), rheumatoid arthritis (Barbadillo e/a/
  • etrolizumab was administered by a health care provider in a clinical setting either intravenously or subcutaneously.
  • a vial and syringe with a vial concentration of 150 mg/ml was used for subcutaneous administration.
  • inflammatory bowel diseases such as ulcerative colitis and Crohn’s Disease are chronic diseases, long-term therapeutic treatment with etrolizumab may be needed.
  • self- administration of etrolizumab or administration in the home by a caregiver or healthcare professional is desirable. Accordingly, development of self-administration devices and formulations of etrolizumab compatible with such devices would be advantageous.
  • proteins including antibodies such as etrolizumab
  • a formulation must preserve intact the conformational integrity of at least a core sequence of the protein’s amino acids while at the same time protecting the protein’s multiple functional groups from degradation.
  • Degradation pathways for proteins can involve chemical instability (e.g., any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity) or physical instability (e.g., changes in the higher order structure of the protein).
  • Chemical instability can result from deamidation, racemization, hydrolysis, oxidation, beta elimination or disulfide exchange. Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example.
  • the three most common protein degradation pathways are protein aggregation, deamidation and oxidation. Cleland et al Critical Reviews in Therapeutic Drug Carrier Systems 10(4): 307-377 (1993).
  • High concentration (e.g., > 100 mg/mL) liquid antibody formulations are desirable, for example, for routes of therapeutic administration or for therapeutic applications where small volumes of drug product are advisable, for example, for subcutaneous injection including, for example, using a prefilled syringe or self- administration device.
  • High concentration antibody formulations pose numerous challenges and problems including challenges and problems associated with use of prefilled syringes or self-administration devices.
  • One problem is instability due to the formation of particulates. With reconstituted liquid formulations, this problem has been addressed through the use of surfactants (e.g., a polysorbate), but surfactants are sometimes thought unsuitable for liquid formulations, because they render further processing difficult.
  • surfactants further do not reduce the increased viscosity caused as a result of numerous intermolecular interactions from the macromolecular nature of antibodies.
  • Selection of pH and optimal excipients is important for preventing particle formation resulting from polysorbate-induced degradation, preventing isomerization of certain amino acids and formation of undersirable intermediates and for extending shelf- life in addition to providing advantages for manufacturing. Selection of pH and optimal excipients is also important for development of formulations, e.g., for compatibility with storage conditions, for administration by prefilled syringe, including prefilled syringe containing devices such as a prefilled syringe with a needle safety device or an autoinjector or self-administration devices, for example, to ensure compatibility with device components and to provide low injection forces.
  • formulations comprising an anti-beta7 antibody, including etrolizumab, having extended stability and low viscosity at high antibody concentrations.
  • High antibody concentration formulations having such properties would be highly advantageous for certain routes of administration, e.g., for subcutaneous administration, including use with prefilled syringes and self administration devices.
  • the formulations provided herein address these needs and provide other useful benefits.
  • formulations comprising an anti-beta7 antibody having extended stability and low viscosity at high antibody concentrations.
  • High antibody concentration formulations having such properties would be highly advantageous for certain routes of administration, e.g., for subcutaneous administration.
  • the formulations provided herein address these needs and provide other useful benefits.
  • the formulations of the present disclosure are based, at least in part, on the discovery that an anti-integrin beta7 antibody described herein, etrolizumab, can be formulated at a high concentration (about > 100 mg/mL) in a histidine buffer, and arginine succinate, and a surfactant and that such high antibody concentration formulation is of low viscosity, has extended physical and chemical stability and maintains potency.
  • the presently disclosed formulations are optimally compatible for self-administration devices such as a prefilled syringe with a needle safety device (PFS- NSD).
  • the prefilled syringe is assembled into an autoinjector.
  • Formulations of the present disclosure are useful for, e.g., the treatment of a gastrointestinal inflammatory disorder, e.g., an inflammatory bowel disease, e.g., ulcerative colitis and Crohn's disease.
  • a gastrointestinal inflammatory disorder e.g., an inflammatory bowel disease, e.g., ulcerative colitis and Crohn's disease.
  • a formulation comprising an anti-integrin beta7 antibody or an antigen-binding fragment thereof.
  • concentration of the antibody or antigen-binding fragment thereof in the formulation is at least about 100 mg/mL and the viscosity of the formulation is less than about 20 centipoise (cP) at 25°C. In certain embodiments, the viscosity of the formulation is less than about 7 cP at 25°C.
  • the anti-integrin beta7 antibody is a monoclonal antibody. In certain embodiments, the anti-integrin beta7 antibody is a humanized antibody. In certain embodiments, the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein:
  • HVRs light chain hypervariable regions
  • the HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:l;
  • the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:2;
  • the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:3;
  • the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:4;
  • the HVR-H2 comprises the amino acid sequence SEQ ID NO:5;
  • the HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO:7.
  • the anti-integrin beta7 antibody or antigen binding fragment thereof comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9.
  • the anti- integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 11.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 12.
  • the anti-integrin beta7 antibody is etrolizumab.
  • the concentration of the anti-integrin beta7 antibody or antigen-binding fragment thereof in the formulation is between about 100 mg/ml and about 220 mg/ml.
  • the concentration of the anti-integrin beta7 antibody or antigen binding fragment thereof in the formulation is about 150 mg/ml.
  • the pH of the formulation is greater than 5.0 and up to 7.0. In certain embodiments, the pH of the formulation is greater than 5.5. In certain embodiments, the pH of the formulation is between 5.6 and 6.1. In certain embodiments, the pH of the formulation is 5.8, between 5.7 and 5.9, or between 5.75 and 5.85. In certain embodiments, the formulation comprises arginine-succinate. In certain embodiments, the concentration of the arginine succinate in the formulation is between about 100 mM and about 300 mM. In certain embodiments, the concentration of the arginine succinate in the formulation is between about 150 mM and about 300 mM. In certain embodiments, the concentration of the arginine succinate in the formulation is between about 150 mM and about 250 mM. In certain embodiments, the concentration of the arginine succinate in the formulation is about 200 mM.
  • the formulation further comprises a surfactant, and the concentration of the surfactant in the formulation is greater than 0.01% weight/volume (w/v) and up to about 1% w/v. In certain embodiments, the concentration of the surfactant in the formulation is between 0.03% w/v and 0.06% w/v. In certain embodiments, the concentration of the surfactant in the formulation is 0.04% w/v or about 0.04% w/v. In certain embodiments, the surfactant is polysorbate 20.
  • the formulation further comprises histidine.
  • the concentration of the histidine in the formulation is between about 5 mM and about 40 mM. In certain embodiments, the concentration of the histidine in the formulation is 20 mM or about 20 mM.
  • the formulation has extended stability.
  • the anti-integrin beta7 antibody is stable for at least about seven years at - 20°C. In certain embodiments, the anti-integrin beta7 antibody or antigen-binding fragment thereof is stable for at least about one year at 5 °C. In certain embodiments, the anti-integrin beta7 antibody or antigen-binding fragment thereof is stable for at least about five years at 5 °C. In certain embodiments, the anti-integrin beta7 antibody or antigen-binding fragment thereof is stable for about six years at 5 °C.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof is stable for at least about 1 day at room temperature. In certain embodiments, the anti-integrin beta7 antibody or antigen-binding fragment thereof is stable for up to about one month at room temperature.
  • the present disclosure provides a formulation comprising an anti-integrin beta7 antibody or an antigen-binding fragment thereof in 20 mM or about 20 mM histidine buffer, pH 5.8, 0.04% polysorbate 20, and 200 mM or about 200 mM arginine succinate, wherein the concentration of the anti-integrin beta7 antibody is about 150 mg/ml, and wherein the anti-integrin beta7 antibody comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein:
  • HVRs light chain hypervariable regions
  • the HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:l;
  • the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:2;
  • the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:3;
  • the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:4;
  • the HVR-H2 comprises the amino acid sequence SEQ ID NO:5;
  • the HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO:7.
  • the formulation has a pH of between 5.7 and 5.9 or between 5.75 and 5.85. In certain embodiments, the formulation comprises 0.04% polysorbate 20 or about 0.04% polysorbate 20.
  • the presently disclosed subject matter provides a formulation comprising an anti- integrin beta7 antibody, in 20 mM histidine buffer or about 20 mM histidine buffer, pH 5.8 or pH between 5.7 and 5.9 or pH between 5.75 and 5.85, 0.04% polysorbate 20 or about 0.04% polysorbate 20, and 200 mM arginine succinate or about 200 mM arginine succinate, and wherein the anti-integrin beta7 antibody comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-Hl, HVR-H2, and HVR-H3, wherein: (i) the HVR-Ll comprises the amino acid sequence set forth in SEQ ID NO: 1; (ii) the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:2; (iii) the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:3; (iv) the HVR-H
  • the anti-integrin beta7 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 11. In certain embodiments, the anti-integrin beta7 antibody comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 12. In certain embodiments, the anti- integrin beta7 antibody is etrolizumab.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9.
  • the anti- integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 11.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 12.
  • an article of manufacture comprising a subcutaneous administration device.
  • the subcutaneous administration device delivers to a subject a flat dose of an anti-integrin beta7 antibody or an antigen-binding fragment thereof.
  • the flat dose is about 100 mg.
  • the flat dose is 105 mg.
  • the flat dose is about 200 mg.
  • the flat dose is 210 mg.
  • the anti-integrin beta7 antibody is etrolizumab.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof in the subcutaneous administration device is formulated as described above such that it is provided in a stable pharmaceutical formulation.
  • the subcutaneous administration device is a needle safety device.
  • the needle safety device comprises a prefilled syringe.
  • the anti-integrin beta7 antibody is stable at the subcutaneous administration device for at least about 60 months at 5°C, or at least about 3 months at 25°C.
  • the prefilled syringe comprises a glass barrel, a plunger stopper, a needle, and needle shield or a tip cap.
  • the needle shield is a rigid needle shield.
  • the rigid needle shield comprises a rubber formulation having low zinc content.
  • the rigid needle shield comprises an elastomeric component, and a rigid shield.
  • the prefilled syringe is assembled into an autoinjector.
  • the volume of the formulation contained in the prefilled syringe is between about 0.5 mL and about 2.0 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is between about 0.5 mL and about 1.0 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 0.7 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 0.75 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 1.0 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is between about 1.0 mL and about 1.5 mL.
  • the volume of the formulation contained in the prefilled syringe is about 1.4 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 1.5 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 1.45 mL. In certain embodiments, the prefilled syringe has a syringe capacity of 1 mL. In certain embodiments, the prefilled syringe has a syringe capacity of 2.25 mL.
  • the prefilled syringe comprises silicone oil. In certain embodiments, the amount of silicone oil in the prefilled syringe is not greater than about 1 mg. In certain embodiments, the amount of silicone oil in the prefilled syringe is between about 0.1 mg and about 1 mg. In certain embodiments, wherein the amount of silicone oil in the prefilled syringe is between about 0.2 mg and about 0.6 mg. In certain embodiments, the amount of silicone oil in the prefilled syringe is between about 0.5 mg and 0.9 mg.
  • the needle safety device has an injection forces that is not greater than about 50 Newton (N). In certain embodiments, the needle safety device has an injection force that is not greater than about 35 Newton (N). In certain embodiments, the needle safety device has an injection force that is not greater than about 33 Newton (N).
  • the presently disclosed subject matter provides an article of manufacture comprising about 0.7 mL of a formulation and a subcutaneous administration device, wherein
  • the formulation comprises an anti-integrin beta7 antibody, in 20 mM histidine buffer or about 20 mM histidine buffer, pH 5.8 or pH between 5.7 and 5.9 or pH between 5.75 and 5.85, 0.04% polysorbate 20 or about 0.04% polysorbate 20, and 200 mM arginine succinate or about 200 mM arginine succinate, and wherein the anti-integrin beta7 antibody comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein:
  • HVRs light chain hypervariable regions
  • the HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO: 1;
  • the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:2;
  • the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:3;
  • the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:4;
  • the HVR-H2 comprises the amino acid sequence SEQ ID NO:5;
  • the HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO: 7, and
  • the subcutaneous administration device is a needle safety device that comprises 1 mL of a prefilled syringe with a syringe capacity of 1 mL.
  • the anti-integrin beta7 antibody is present in the formation at a concentration of 150 mg/mL or about 150 mg/ml.
  • the presently disclosed subject matter provides an article of manufacture comprising about 1.4 mL of a formulation and a subcutaneous administration device, wherein
  • the formulation comprises an anti-integrin beta7 antibody, in 20 mM histidine buffer or about 20 mM histidine buffer, pH 5.8 or pH between 5.7 and 5.9 or pH between 5.75 and 5.85, 0.04% polysorbate 20 or about 0.04% polysorbate 20, and 200 mM arginine succinate or about 200 mM arginine succinate, and wherein the anti-integrin beta7 antibody comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein:
  • HVRs light chain hypervariable regions
  • the HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-H2 comprises the amino acid sequence SEQ ID NO:5;
  • the HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:6 or SEQ ID NO:7, and
  • the subcutaneous administration device is a needle safety device that comprises 1 mL of a prefilled syringe with a syringe capacity of 2.25 mL.
  • the anti-integrin beta7 antibody is present in the formation at a concentration of 150 mg/mL or about 150 mg/ml.
  • the presently disclosed subject matter further provides autoinjectors comprising the article of manufacture disclosed herein.
  • the presently disclosed subject matter provides an autoinjector comprising an article of manufacture comprising about 0.7 mL of a formulation and a subcutaneous administration device, wherein
  • the formulation comprises an anti-integrin beta7 antibody, in 20 mM histidine buffer or about 20 mM histidine buffer, pH 5.8 or pH between 5.7 and 5.9 or pH between 5.75 and 5.85, 0.04% polysorbate 20 or about 0.04% polysorbate 20, and 200 mM arginine succinate or about 200 mM arginine succinate, and wherein the anti-integrin beta7 antibody comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein:
  • HVRs light chain hypervariable regions
  • the HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-H2 comprises the amino acid sequence SEQ ID NO:5;
  • the HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:6 or SEQ ID NO:7, and
  • the subcutaneous administration device is a needle safety device that comprises 1 mL of a prefilled syringe with a syringe capacity of 1 mL.
  • the anti-integrin beta7 antibody is present in the formation at a concentration of 150 mg/mL or about 150 mg/ml.
  • the presently disclosed subject matter provides an autoinjector comprising article of manufacture comprising about 1.4 mL of a formulation and a subcutaneous administration device, wherein
  • the formulation comprises an anti-integrin beta7 antibody, in 20 mM histidine buffer or about 20 mM histidine buffer, pH 5.8 or pH between 5.7 and 5.9 or pH between 5.75 and 5.85, 0.04% polysorbate 20 or about 0.04% polysorbate 20, and 200 mM arginine succinate or about 200 mM arginine succinate, and wherein the anti-integrin beta7 antibody comprises three light chain hypervariable regions (HVRs), HVR-Ll, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein:
  • HVRs light chain hypervariable regions
  • the HVR-Ll comprises the amino acid sequence set forth in SEQ ID NO:1;
  • the HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:
  • the HVR-H2 comprises the amino acid sequence SEQ ID NO:5;
  • the HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:6 or SEQ ID NO:7, and
  • the subcutaneous administration device is a needle safety device that comprises 1 mL of a prefilled syringe with a syringe capacity of 2.25 mL.
  • the anti-integrin beta7 antibody is present in the formation at a concentration of 150 mg/mL or about 150 mg/ml.
  • a method of treating a gastrointestinal inflammatory disorder in a subject comprises administering to the subject an effective amount of any of the above formulations.
  • methods of administering subcutaneously a formulation comprising an anti-integrin beta7 antibody or an antigen-binding fragment thereof comprise administering subcutaneously any of the formulations described above.
  • the methods comprise a subcutaneous administration device according to any of the devices described above.
  • the method comprises the autoinjector disclosed herein.
  • the administering results in mild pain or no pain.
  • the administering results in a transient and mild injection site reaction.
  • the full dose is administered or at least 90% of the full dose is administered.
  • the administering provides an equivalent exposure to etrolizumab compared to a prefilled syringe with needle safety device.
  • the presently disclosed subject matter also provides uses of the formulation, the article of manufacture, or the autoinjector disclosed herein in a therapy.
  • the presently disclosed subject matter provides uses of the formulation, the article of manufacture, or the autoinjector disclosed herein in treating a gastrointestinal inflammatory disorder in a subject.
  • the gastrointestinal inflammatory disorder is an inflammatory bowel disease.
  • the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • Figure 1 depicts solubility curves for lauric acid, myristic acid, and palmitic acid as a function of pH and polysorbate 20 (PS20) concentration as described in Example 1.
  • Figure 2 depicts impact of arginine on solution viscosity as described in Example
  • Figure 3 depicts impact of protein concentration on viscosity of formulations comprising 200mM arginine succinate as described in Example 1.
  • Figure 4 depicts the change in the percentage of high molecular weight species (HMWS) of etrolizumab in pre-filled syringes with varying quantities of silicone oil as described in Example 1.
  • HMWS high molecular weight species
  • HMWF high molecular weight forms
  • Figure 5 depicts the percentage of HMWS of etrolizumab in varying concentrations of tungsten over time as described in Example 1.
  • Figure 6 depicts the impact of zinc on the viscosity of etrolizumab at varying protein concentrations in formulations comprising 20 mM histidine, 200 mM arginine succinate, pH 5.8 at 25°C as described in Example 1.
  • Figure 7 shows protein aggregate formation by 50 mM zinc and 150 mg/mL etrolizumab at room temperature as described in Example 1.
  • Figure 8 depicts the HMWS formation by 10 mM zinc and 10 mg/mL or 50 mg/mL etrolizumab at 40°C as described in Example 1.
  • Figure 9 depicts the impact of histidine on HMWS formation in formulations comprising 10 mM zinc and 10 mg/mL etrolizumab at 40°C as described in Example 1.
  • Figure 10 depicts the impact of succinate on HMWS formation in formulations comprisinglO mM zinc and 10 mg/mL etrolizumab at 40°C as described in Example 1.
  • Figure 11 shows varying concentrations of histidine and succinate and the combined impact on HMWS formation in formulations comprising 10 mM zinc and 50 mg/mL etrolizumab at 40°C as described in Example 1.
  • Figure 12 shows exemplary prefilled syringes (top two) and autoinjector (last) as described in Example 2.
  • Figure 13 shows prefilled autoinjector of etrolizumab as described in Example 2.
  • Figure 14 shows autoinjector (AI) tolerability and human factors study design as described in Example 2.
  • Figure 15 shows graph indicating pain over time by intensity (7-point Visual Descriptive Scale) as described in Example 2.
  • Figure 16 depicts graphs indicating pain over time by injection site (7-point Visual Descriptive Scale) as described in Example 2.
  • Figure 17 shows the two-part pharmacokinetic bridging study design as described in Example 2.
  • GMR geometric mean ratio
  • PFS-NSD needle safety device
  • Figure 18 shows participant disposition as described in Example 3.
  • AI autoinjector AUC area under the curve, PFS-NSD prefilled syringe with needle safety device, PK pharmacokinetic, SC subcutaneous. ⁇ Excluded because of eligibility criteria (weight restriction). Participants were excluded from specific PK analyses because of insufficient PK data for calculations.
  • Figure 19 shows the impact of body weight on etrolizumab Cmax (top) or AUCo-inf (Bottom) as described in Example 3.
  • AI autoinjector AUC area under the curve
  • AUCo-i n f AUC extrapolated to infinity
  • C max maximum concentration PFS-NSD prefilled syringe with needle safety device, SC subcutaneous.
  • Figure 20 shows etrolizumab serum concentrations over time with AI and PFS- NSD on a linear scale (A) and semi -logarithmic scale (B) in the pivotal study as described in Example 3.
  • AI anti drug antibody
  • AI autoinjector PFS-NSD prefilled syringe with needle safety device.
  • Figure 22 shows the different force definitions during injection as described in Example 4.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.
  • a “sterile” formulation is aseptic or free or essentially free from all living microorganisms and their spores.
  • a “frozen” formulation is one at a temperature below 0°C. Generally, the frozen formulation is not freeze-dried, nor is it subjected to prior, or subsequent, lyophilization. In certain embodiments, the frozen formulation comprises frozen drug substance for storage (in stainless steel tank) or frozen drug product (in final vial configuration).
  • a “stable” formulation is one in which the protein therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage. In certain embodiments, the formulation essentially retains its physical and chemical stability, as well as its biological activity upon storage. The storage period is generally selected based on the intended shelf-life of the formulation.
  • a formulation having “extended stability” means one in which the protein therein essentially retains its physical stability, chemical stability, and biological activity upon storage at 5°C for one year or more.
  • the storage is at 5 °C for one year or more.
  • the storage is at 5 °C for up to five years or six years.
  • the anti-integrin beta7 antibody is stable for at least about 1 day at room temperature.
  • the anti-integrin beta7 antibody is stable for up to about one month at room temperature.
  • the room temperature is between about 20 and about 22 °C. In certain embodiments, the room temperature is about 20 °C.
  • a protein “retains its physical stability” in a pharmaceutical formulation if it shows no signs or very little of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography.
  • a protein “retains its chemical stability” in a pharmaceutical formulation if the chemical stability at a given time is such that the protein is considered to still retain its biological activity as defined below.
  • Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein.
  • Chemical alteration may involve size modification (e.g. clipping) which can be evaluated using size exclusion chromatography, SDS-PAGE and/or matrix-assisted laser desorption ionization/time-of- flight mass spectrometry (MALDI/TOF MS), for example.
  • Other types of chemical alteration include charge alteration (e.g. occurring as a result of deamidation) which can be evaluated by ion-exchange chromatography or imaged capillary isoelectric focusing (icIEF), for example.
  • An antibody “retains its biological activity” in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within about 20% (within the errors of the assay) of the biological activity exhibited at the time the pharmaceutical formulation was prepared as determined in an antigen binding assay or a potency assay, for example.
  • biological activity of a monoclonal antibody refers to the ability of the antibody to bind to antigen. It can further include antibody binding to antigen and resulting in a measurable biological response which can be measured in vitro or in vivo. Such activity may be antagonistic or agonistic.
  • the antibody which is formulated is essentially pure and desirably essentially homogeneous (e.g., free from contaminating proteins etc.).
  • Essentially pure antibody means a composition comprising at least about 90% by weight of the antibody, based on total weight of the composition, or at least about 95% by weight.
  • Essentially homogeneous antibody means a composition comprising at least about 99% by weight of antibody, based on total weight of the composition.
  • isotonic is meant that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to 350 mOsm. Isotonicity can be measured using a vapor pressure or ice-freezing type osmometer, for example.
  • buffer refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components.
  • a “surfactant” refers to a surface-active agent, typically a nonionic surfactant.
  • surfactants herein include polysorbate (for example, polysorbate 20 and, polysorbate 80); poloxamer (e.g.
  • poloxamer 188 Triton; sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g.
  • lauroamidopropyl myristamidopropyl-, palmidopropyl-, or isostearamidopropyl- dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUATTM series (Mona Industries, Inc., Paterson, N.J.); poly ethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g. Pluronics,
  • the surfactant is polysorbate 20.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed before or during the course of clinical pathology. Desirable effects of treatment include preventing the occurrence or recurrence of a disease or a condition or symptom thereof, alleviating a condition or symptom of the disease, diminishing any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, ameliorating or palliating the disease state, and achieving remission or improved prognosis.
  • an “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • a “therapeutically effective amount” of a therapeutic agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agent are outweighed by the therapeutically beneficial effects.
  • an “individual,” “subject” or “patient” is a vertebrate.
  • the vertebrate is a mammal.
  • Mammals include, but are not limited to, primates (including human and non-human primates) and rodents (e.g., mice and rats).
  • rodents e.g., mice and rats.
  • a mammal is a human.
  • a “medicament” is an active drug to treat a disease, disorder, and/or condition.
  • Antibodies (Abs) and “immunoglobulins” (Igs) refer to glycoproteins having similar structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules which generally lack antigen specificity. Polypeptides of the latter kind are, for example, produced at low levels by the lymph system and at increased levels by myelomas.
  • antibody and “immunoglobulin” are used interchangeably in the broadest sense and include monoclonal antibodies (e.g., full length or intact monoclonal antibodies), polyclonal antibodies, monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g, bispecific antibodies so long as they exhibit the desired biological activity) and may also include certain antibody fragments (as described in greater detail herein).
  • An antibody can be chimeric, human, humanized and/or affinity matured.
  • full length antibody “intact antibody” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below. The terms particularly refer to an antibody with heavy chains that contain the Fc region.
  • Antibody fragments comprise a portion of an intact antibody, preferably comprising the antigen binding region thereof.
  • Examples of antibody fragments include Fab, Fab’, F(ab’) 2 , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab’) 2 fragment that has two antigen-combining sites and is still capable of cross- linking antigen.
  • Fv is a minimum antibody fragment which contains a complete antigen-binding site.
  • a two-chain Fv species consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association.
  • the six CDRs of an Fv confer antigen-binding specificity to the antibody.
  • a single variable domain or half of an Fv comprising only three CDRs specific for an antigen has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • the Fab fragment contains the heavy- and light-chain variable domains and also contains the constant domain of the light chain and the first constant domain (CHI) of the heavy chain.
  • Fab’ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.
  • Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • F(ab’) 2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • a monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts. Thus, the modifier “monoclonal” indicates the character of the antibody as not being a mixture of discrete antibodies.
  • such a monoclonal antibody typically includes an antibody comprising a polypeptide sequence that binds a target, wherein the target binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, or recombinant DNA clones.
  • a selected target binding sequence can be further altered, for example, to improve affinity for the target, to humanize the target binding sequence, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered target binding sequence is also a monoclonal antibody of this invention.
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler et al., Nature, 256: 495 (1975); Harlow et al., Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2 nd ed.
  • Methods 284(1-2): 119- 132(2004), and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences see, e.g., W098/24893; WO96/34096; W096/33735; WO91/10741; Jakobovits et al, Proc. Natl. Acad. Sci. USA 90: 2551 (1993); Jakobovits et al, Nature 362: 255-258 (1993); Bruggemann et al, Year in Immunol. 7:33 (1993); U.S. Patent Nos.
  • the monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al, Proc. Natl. Acad. Sci. USA 81:6855-9855 (1984)).
  • “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures.
  • native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain.
  • VH variable region
  • VL variable region
  • the light chain of an antibody may be assigned to one of two types, called kappa and lambda, based on the amino acid sequence of its constant domain.
  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (V H and V L , respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs).
  • FRs conserved framework regions
  • HVRs hypervariable regions
  • antibodies that bind a particular antigen may be isolated using a V H or V L domain from an antibody that binds the antigen to screen a library of complementary V L or V H domains, respectively.
  • V H or V L domain from an antibody that binds the antigen to screen a library of complementary V L or V H domains, respectively.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
  • a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
  • a “humanized form” of an antibody, e.g., a non-human antibody refers to an antibody that has undergone humanization.
  • hypervariable region when used herein refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops.
  • antibodies comprise six hypervariable regions; three in the VH (HI, H2, H3), and three in the VL (LI, L2, L3).
  • a number of hypervariable region delineations are in use and are encompassed herein.
  • the Rabat Complementarity Determining Regions are based on sequence variability and are the most commonly used (Rabat etal, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).
  • Chothia refers instead to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)).
  • the AbM hypervariable regions represent a compromise between the Rabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.
  • the “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below.
  • H3 H95-H102 H95-H102 H96-H101 H93-H101 Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 49-56 or 50-56 or 52-56 (L2) and 89-97 (L3) in the VL and 26-35 (HI), 50-65 or 49-65 (H2) and 93-102, 94-102 or 95-102 (H3) in the VH.
  • the variable domain residues are numbered according to Kabat el al, supra for each of these definitions.
  • antibodies can be assigned to different classes.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g ., IgGi, IgG2, IgG 3 , IgG 4 , IgAi, and IgA2.
  • the heavy-chain constant domains that correspond to the different classes of immunoglobulins are called a, d, e, g, and m, respectively.
  • An antibody may be part of a larger fusion molecule, formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.
  • the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA,
  • IgD, IgE, IgG, and IgM may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl , and IgA2.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 6, 8, y, and m, respectively.
  • an “isolated” biological molecule such as a nucleic acid, polypeptide, or antibody, is one which has been identified and separated and/or recovered from at least one component of its natural environment.
  • a “subcutaneous administration device” refers to a device which is adapted or designed to administer a drug, for example a therapeutic antibody, or pharmaceutical formulation by the subcutaneous route.
  • exemplary subcutaneous administration devices include, but are not limited to, a needle safety device (e.g., one comprising a pre-filled syringe), an injection device, including an autoinjector (e.g., one comprising a pre-filled syringe), infusion pump, injector pen, needleless device, and patch delivery system.
  • a subcutaneous administration device administers a certain volume of the pharmaceutical formulation, for example about 0.5 mL, about 0.7 mL, about 1.0 mL, about 1.25 mL, about 1.4 mL, about 1.5 mL, about 1.75 mL, about 2.0 mL or about 5.0 mL.
  • a “package insert” or “label” is used to refer to instructions customarily included in commercial packages of therapeutic products or medicaments, that contain information about the indications, usage, dosage, administration, contraindications, other therapeutic products to be combined with the packaged product, and/or warnings concerning the use of such therapeutic products or medicaments and the like.
  • gastrointestinal inflammatory disorders refer to a group of chronic disorders that cause inflammation and/or ulceration in the mucous membrane. These disorders include, for example, inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, indeterminate colitis and infectious colitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis and proctitis), necrotizing enterocolitis, and esophagitis.
  • inflammatory bowel disease e.g., Crohn’s disease, ulcerative colitis, indeterminate colitis and infectious colitis
  • mucositis e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis and proctitis
  • necrotizing enterocolitis esophagitis.
  • IBD Inflammatory Bowel Disease
  • IBD ulcerative colitis
  • Crohn’s disease CD
  • Ulcerative colitis are chronic inflammatory bowel diseases of unknown etiology. Crohn’s disease, unlike ulcerative colitis, can affect any part of the bowel. The most prominent feature Crohn’s disease is the granular, reddish-purple edmatous thickening of the bowel wall. With the development of inflammation, these granulomas often lose their circumscribed borders and integrate with the surrounding tissue. Diarrhea and obstruction of the bowel are the predominant clinical features. As with ulcerative colitis, the course of Crohn’s disease may be continuous or relapsing, mild or severe, but unlike ulcerative colitis, Crohn’s disease is not curable by resection of the involved segment of bowel. Most patients with Crohn’s disease require surgery at some point, but subsequent relapse is common and continuous medical treatment is usual.
  • Crohn’s disease may involve any part of the alimentary tract from the mouth to the anus, although typically it appears in the ileocolic, small-intestinal or colonic- anorectal regions. Histopathologically, the disease manifests by discontinuous granulomatomas, crypt abscesses, fissures and aphthous ulcers.
  • the inflammatory infiltrate is mixed, consisting of lymphocytes (both T and B cells), plasma cells, macrophages, and neutrophils. There is a disproportionate increase in IgM- and IgG- secreting plasma cells, macrophages and neutrophils.
  • Anti-inflammatory drugs sulfasalazine and 5-aminosalisylic acid (5-ASA) are useful for treating mildly active colonic Crohn’s disease and is commonly prescribed to maintain remission of the disease.
  • Metroidazole and ciprofloxacin are similar in efficacy to sulfasalazine and appear to be particularly useful for treating perianal disease.
  • corticosteroids are effective in treating active exacerbations and can even maintain remission.
  • Azathioprine and 6-mercaptopurine have also shown success in patients who require chronic administration of cortico steroids. It is also possible that these drugs may play a role in the long-term prophylaxis. Unfortunately, there can be a very long delay (up to six months) before onset of action in some patients.
  • Antidiarrheal drugs can also provide symptomatic relief in some patients.
  • Nutritional therapy or elemental diet can improve the nutritional status of patients and induce symtomatic improvement of acute disease, but it does not induce sustained clinical remissions.
  • Antibiotics are used in treating secondary small bowel bacterial overgrowth and in treatment of pyogenic complications.
  • “Ulcerative colitis (UC)” afflicts the large intestine.
  • the course of the disease may be continuous or relapsing, mild or severe.
  • the earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkiihn. Coalescence of these distended and raptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration.
  • Symptoms of the disease include cramping, lower abdominal pain, rectal bleeding, and frequent, loose discharges consisting mainly of blood, pus and mucus with scanty fecal particles.
  • a total colectomy may be required for acute, severe or chronic, unremitting ulcerative colitis.
  • UC ulcerative colitis
  • serum sample refers to any serum sample obtained from an individual. Methods for obtaining sera from mammals are well known in the art.
  • whole blood refers to any whole blood sample obtained from an individual. Typically, whole blood contains all of the blood components, e.g., cellular components and plasma. Methods for obtaining whole blood from mammals are well known in the art. THERAPEUTIC AGENTS
  • IBD Inflammatory bowel disease
  • IBD Inflammatory bowel disease
  • IBD is a chronic gastrointestinal disease that severely affects patient quality of life and often results in the need for surgical intervention (Casellas et al., DigDis. 1999;17(4):208-18; Carter et al., Gut. 2004;53(Suppl 5):V1-16; Borren et al., Nat Rev Gastroenterol Hepatol. 2019;16(4):247-59).
  • IBD ulcerative colitis
  • Crohn’s disease 2 distinct conditions that share some common symptoms and exhibit a partially overlapping etiology
  • Current pharmacologic therapies for IBD are not curative.
  • many pharmacologic therapies for IBD lose efficacy over the duration of the disease and can result in systemic side effects (Abraham and Cho, N Engl JMed. 2009;361(21):2066-78; Rogler, Best Pract Res Clin Gastroenterol . 2010;24(2): 157-65).
  • Etrolizumab is an anti-P7 integrin monoclonal antibody in development for patients with UC and Crohn’s disease.
  • Etrolizumab selectively inhibits a4b7 and cEb7 to reduce trafficking of immune cells into the gut and subsequent inflammatory effects on the gut lining (Zundler et al., Gut. 2019;68(9): 1688-700).
  • the efficacy and safety of etrolizumab in patients with UC was demonstrated in the phase 2 EUCALYPTUS study (Vermeire et al., Lancet. 2014;384(9940):309-18).
  • the therapeutic agent is an anti-integrin beta7 antibody or an antigen-binding fragment thereof.
  • the anti-integrin beta7 antibody is a humanized monoclonal anti-integrin beta7 antibody.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises three light chain hypervariable regions (HVRs), HVR-L1, HVR-L2, and HVR-L3, and three heavy chain HVRs, HVR-H1, HVR-H2, and HVR-H3, wherein: (i) the HVR-L1 comprises the amino acid sequence set forth SEQ ID NO: 1; (ii) the HVR- L2 comprises the amino acid sequence set forth in SEQ ID NO: 2; (iii) the HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 3; (iv) the HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 4; (v) the HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof further comprises a light chain variable region domain comprising the amino acid sequence set forth in SEQ ID NO:8 and a heavy chain variable region domain comprising the amino acid sequence set forth in SEQ ID NO:9.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain variable region domain comprising the amino acid sequence set forth in SEQ ID NO: 8 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain variable region domain comprising the amino acid sequence set forth in SEQ ID NO: 9.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof further comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 11 or a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 12.
  • the anti-integrin beta7 antibody is etrolizumab. SEQ ID NOS: 1-12 are provided below. Anti-integrin beta7 antibodies or antigen-binding fragments thereof are further described in Intn’l Pub. No. W02006/026759, which is incorporated herein by reference.
  • biomarkers are quantitated in a biological sample obtained from a subject as a means of selecting subjects for treatment with a given therapeutic agent.
  • International Pat. Nos. WO2014160753, WO2015148809, and W02009140684 describe methods of predicting the responsiveness of subjects having a gastrointestinal inflammatory disorder to anti-integrin beta7 antibody formulations described herein, and methods of selecting subjects having a gastrointestinal inflammatory disorder for treatment with anti-integrin beta7 antibody formulations described herein.
  • Formulations comprising anti-integrin beta7 antibodies or antigen-binding fragments thereof may be prepared and analyzed using certain excipients and techniques known in the art and as further described herein.
  • the antibody to be formulated has not been subjected to prior lyophilization and the formulation of interest herein is an aqueous formulation.
  • the antibody is a full- length antibody.
  • the antibody in the formulation is an antibody fragment, such as an F(ab’)2, in which case problems that may not occur for the full- length antibody (such as clipping of the antibody to Fab) may need to be addressed.
  • the therapeutically effective amount of antibody present in the formulation is determined by taking into account the desired dose volumes and mode(s) of administration.
  • from about 0.1 mg/mL to about 250 mg/mL, or from about 10 mg/mL to about 220 mg/mL, or from about 50 mg/mL to about 220 mg/mL, or from about 100 mg/mL to about 220 mg/mL, or from about 100 mg/mL to about 150 mg/mL, or from about 150 mg/mL to about 200 mg/mL is an exemplary antibody concentration in the formulation.
  • the anti-integrin beta7 antibody is formulated at a concentration of 150 mg/mL.
  • An aqueous formulation is prepared comprising the anti-integrin beta7 antibody or an antigen-binding fragment thereof in a pH-buffered solution.
  • the buffer can have a pH in the range from about 4.5 to about 6.5. In certain embodiments, the pH is greater than 5.0 and up to 7.0. In certain embodiments, the pH is greater than 5.5. In certain embodiments, the pH is between 5.5 and 6.1. In certain embodiments, the pH is between 5.6 and 6.1. In certain embodiments, the pH is 5.8 or about 5.8. In certain embodiments, the pH is 5.8. In certain embodiments, the pH is between 5.7 and 5.9. In certain embodiments, the pH is between 5.75 and 5.85.
  • the pH of the presently disclosed formulation is higher than standard for an antibody formulation with similar excipient composition.
  • Typical antibody formulations have a pH of 5.5, whereas the presented disclosed formulation has a pH of greater than 5.5, e.g., a pH of 5.8, between 5.7 and 5.9 or between 5.75 and 5.85.
  • the higher formulation pH lowers the risk of particle formation as a result of polysorbate degradation during long term storage in a pre-filled syringe at high protein concentration. The risk of particle formation is lowered due to the increased solubility of free fatty acids at the higher pH which can result from polysorbate degradation.
  • the buffer concentration can be from about 1 mM to about 600 mM, depending, for example, on the buffer and the desired isotonicity of the formulation.
  • the buffer comprises histidine.
  • the presence of histidine in the formulation can greatly reduce the rate of high molecular weight species (HMWS) formation in the presence of zinc.
  • HMWS high molecular weight species
  • the concentration of the histidine in the formulation can be between about 5 mM and about 40 mM, between about 5 mM and about 30 mM, between about 10 mM and about 40 mM, between about 10 mM and about 30 mM, between about 15 mM and about 25 mM, between about 10 mM and about 20 mM, or between about 15 mM and about 20 mM. In certain embodiments, the concentration of the histidine in the formulation is about 20 mM.
  • the buffer is 20 mM histidine, pH 5.8.
  • the formulation comprises arginine succinate.
  • the concentration of the arginine succinate in the formulation is from about 20 mM to 300 mM. In certain embodiments, the concentration of the arginine succinate in the formulation is from about 100 mM to 300 mM, from about 100 mM to about 200 mM, from about 150 mM to about 300 mM, from about 200 mM to about 300 mM, from about 100 mM to about250 mM, from about 150 mM to about 250 mM, or from about 150 mM to about 200 mM. In certain embodiments, the concentration of the arginine succinate in the formulation is about 200 mM.
  • the high arginine concentration, and high conductivity formulation shields charge on the antibody and prevents shifts in pH.
  • arginine can impact the viscosity of the formulation, e.g., formulation viscosity is decreased by the addition of arginine to the formulation.
  • the formulation has a viscosity of less than about 20 centipoise (cP) at 25°C.
  • the viscosity of the formulation is between about 1 cP and about 20 cP at 25°C, between about 5 cP and about 20 cP at 25°C, between about 5 cP and about 15 cP at 25°C, between about 1 cP and about 10 cP at 25°C, or between about 5 cP and about 10 cP at 25°C.
  • the viscosity of the formulation is about 7 cP at 25°C.
  • the antibody formulation comprises a surfactant.
  • surfactants include nonionic surfactants. Suitable non-ionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), poloxamers (184, 188, etc.), Pluronic polyols, Triton®, polyoxyethylene sorbitan monoethers (Tween®-20, Tween®-80, etc.), lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, sucrose fatty acid ester, methyl celluose and carboxymethyl cellulose.
  • Anionic detergents that can be used include sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents include benzalkonium chloride or benzethonium chloride.
  • the surfactant is polysorbate 20.
  • Non-ionic surfactants can help solubilize the therapeutic agent as well as to protect the therapeutic protein against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stress without causing denaturation of the active therapeutic protein or antibody.
  • the amount of surfactant added is such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces adsorption.
  • the surfactant may be present in the formulation in an amount of greater than 0.005% weight/volume (w/v).
  • the concentration of the surfactant in the formulation is greater than 0.005% w/v and up to about 1% w/v.
  • the concentration of the surfactant in the formulation can be between about 0.005% and about 0.5% w/v, between about 0.02% w/v and about 0.5% w/v, between about 0.03% w/v and about 0.5% w/v, between 0.03% w/v and 0.1% w/v.
  • concentration of the surfactant in the formulation is 0.04% w/v.
  • the surfactant is polysorbate 20 present in the formulation in an amount of 0.04% w/v.
  • the typical concentration of polysorbate 20 for an antibody formulation is 0.02% (w/v).
  • the presently disclosed formulation comprises 0.04% w/v Polysorbate 20.
  • the higher concentration of polysorbate 20 helps solubilize free fatty acids, which can be generated as a result of polysorbate degradation, thereby lowering the risk of forming particles.
  • the formulation contains the above-identified agents (e.g., antibody, buffer, and surfactant) and is essentially free of one or more preservatives, such as benzyl alcohol, phenol, m-cresol, chlorobutanol and benzethonium Cl.
  • the formulation does not comprise a preservative.
  • a preservative may be included in the formulation, particularly where the formulation is a multidose formulation.
  • the concentration of preservative may be in the range from about 0.1% to about 2%, or from about 0.5% to about 1%.
  • One or more other pharmaceutically acceptable carriers, excipients or stabilizers such as those described in Remington’ s Pharmaceutical Sciences 16th edition, Osol, A. Ed.
  • Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include; additional buffering agents; co-solvents; anti-oxidants including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g. Zn-protein complexes); biodegradable polymers such as polyesters; and/or salt-forming counterions.
  • Metal ion chelators are well known by those of skill in the art and include, but are not necessarily limited to aminopolycarboxylates, EDTA (ethylenediaminetetraacetic acid), EGTA (ethylene glycol-bis(beta-aminoethyl ether)-N,N,N’,N’-tetraacetic acid), NTA (nitrilotriacetic acid), EDDS (ethylene diamine disuccinate), PDTA (1,3- propylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), ADA (beta-alaninediacetic acid), MGCA (methylglycinediacetic acid), etc. Additionally, some embodiments herein comprise phosphonates/phosphonic acid chelators.
  • Tonicity agents sometimes known as “stabilizers” are present to adjust or maintain the tonicity of a liquid composition. When used with large, charged biomolecules such as proteins and antibodies, they are often termed “stabilizers” because the can interact with the charged groups of the amino acid side chains, thereby lessening the potential for inter and intra-molecular interactions. Tonicity agents can be present in any amount between 0.1% to 25% by weight, or 1 to 5%, taking into account the relative amounts of the other ingredients. Tonicity agents include polyhydric sugar alcohols, thrihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • Additional stabilizers include a broad range of excipients which range in function from bulking agents to solubility enhancers, to agents preventing denaturation or adherence to the container wall.
  • Stabilizers can be present in the range from 0.1 to 10,000 parts per weight active protein or antibody.
  • Typical stabilizers include: polyhydric sugar alcohols (enumerated above); amino acids such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, methionine, ornithine, leucine, 2- phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols such as sucrose, lactose, lactitol, trehalose, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol,
  • Stability can be measured at a selected temperature for a selected time period.
  • the formulation is stable at about 40°C for at least about 1 week.
  • the formulation is stable at about 5°C for at least about 12 months, and/or or stable at about 5°C for at least about 18 months, and/or or stable at about 5°C for at least about 2 years, and/or or stable at about 5°C for at least about 3 years, and/or or stable at about 5°C for at least about 4 years, and/or or stable at about 5°C for at least about 5 years.
  • the formulation is stable at about -20°C for at least 2 years, and/or stable at about -20°C for at least 4 years, and/or stable at about -20°C for at least about 5 years, and/or stable at about -20°C for at least about 6 years, and/or stable at about -20°C for at least about 7 years.
  • the formulation is stable at about 25°C for at least about 1 week, and/or stable at about 25°C for at least about 2 weeks, or stable at about 25°C for at least about 4 weeks.
  • the formulation is stable following freezing (to, e.g., -70°C) and thawing of the formulation, for example following 1, 2, 3,
  • Stability can be evaluated qualitatively and/or quantitatively in a variety of different ways, including evaluation of aggregate formation (for example using size exclusion chromatography, by measuring turbidity, and/or by visual inspection); by assessing charge heterogeneity using cation exchange chromatography, image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis; amino-terminal or carboxy-terminal sequence analysis; mass spectrometric analysis; SDS-PAGE analysis to compare reduced and intact antibody; peptide map (for example tryptic or LYS-C) analysis; evaluating biological activity or antigen binding function of the antibody; etc.
  • aggregate formation for example using size exclusion chromatography, by measuring turbidity, and/or by visual inspection
  • icIEF image capillary isoelectric focusing
  • capillary zone electrophoresis amino-terminal or carboxy-terminal sequence analysis
  • mass spectrometric analysis SDS-PAGE analysis to compare reduced and intact antibody
  • peptide map for example tryp
  • Instability may involve any one or more of: aggregation, deamidation (e.g. Asn deamidation), oxidation (e.g. Met oxidation), isomerization (e.g. Asp isomerization), clipping/hydrolysis/fragmentation (e.g. hinge region fragmentation), succinimide formation, unpaired cysteine(s), N-terminal extension, C-terminal processing, glycosylation differences, etc.
  • deamidation e.g. Asn deamidation
  • oxidation e.g. Met oxidation
  • isomerization e.g. Asp isomerization
  • clipping/hydrolysis/fragmentation e.g. hinge region fragmentation
  • succinimide formation unpaired cysteine(s)
  • N-terminal extension e.g. Asp isomerization
  • C-terminal processing e.g., glycosylation differences, etc.
  • the formulations to be used for in vivo administration should be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to, or following, preparation of the formulation.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof is administered using, for example, a self-inject device, autoinjector device, or other device designed for self-administration. In certain embodiments, the anti-integrin beta7 antibody or antigen-binding fragment thereof is administered using a subcutaneous administration device.
  • a self-inject device for example, a self-inject device, autoinjector device, or other device designed for self-administration.
  • the anti-integrin beta7 antibody or antigen-binding fragment thereof is administered using a subcutaneous administration device.
  • Various self-inject devices and subcutaneous administration devices, including autoinjector devices are known in the art and are commercially available.
  • Exemplary devices include, but are not limited to, prefilled syringes (such as BD HYPAK SCF®, BD NEOPAKTM, READYFILLTM, and STERIFILL SCFTM from Becton Dickinson; CLEARSHOTTM copolymer prefilled syringes from Baxter; and Daikyo Seiko CRYSTAL ZENITH® prefilled syringes available from West Pharmaceutical Services); disposable pen injection devices such as BD Pen from Becton Dickinson; ultra-sharp and microneedle devices (such as INJECT- EASE Tm and microinfuser devices from Becton Dickinson; and H-PATCHTM available from Valeritas) as well as needle-free injection devices (such as BIOJECTOR® and IJECT® available from Bioject; and SOF-SERTER® and patch devices available from Medtronic).
  • prefilled syringes such as BD HYPAK SCF®, BD NEOPAK
  • subcutaneous administration devices are described further herein. Co-formulations or co-administrations with such self-inject devices or subcutaneous administration devices of an anti-integrin beta7 antibody or an antigen binding fragment thereof with at least a second therapeutic compound are envisioned.
  • Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567.
  • a nucleic acid molecule encoding an anti-integrin beta7 antibody or an antigen-binding fragment thereof described herein is provided.
  • Such nucleic acid molecule may encode an amino acid sequence comprising the VL and/or an amino acid sequence comprising the VH of the antibody (e.g., the light and/or heavy chains of the antibody).
  • one or more vectors e.g., expression vectors
  • a host cell comprising such nucleic acid molecule is provided.
  • a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid molecule that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid molecule that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid molecule that encodes an amino acid sequence comprising the VH of the antibody.
  • the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., YO, NSO, Sp20 cell).
  • a method of making an anti-integrin beta7 antibody comprises culturing a host cell comprising a nucleic acid molecule encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).
  • nucleic acid molecules encoding an antibody e.g., as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell.
  • nucleic acid molecules may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
  • Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein.
  • prokaryotic or eukaryotic cells described herein.
  • antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed.
  • Fc effector function are not needed.
  • eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern.
  • Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.
  • Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIESTM technology for producing antibodies in transgenic plants).
  • Vertebrate cells may also be used as hosts.
  • mammalian cell lines that are adapted to grow in suspension may be useful.
  • useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et ah, J.
  • TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3 A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et ah, Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells.
  • CHO Chinese hamster ovary
  • DHFR-CHO cells Urlaub et ah, Proc. Natl. Acad. Sci. USA 77:4216 (1980)
  • myeloma cell lines such as YO, NSO and Sp2/0.
  • Yazaki and Wu Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).
  • Anti-integrin beta7 antibodies provided herein may be identified, screened for, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art.
  • the etrolizumab potency assay measures the ability of etrolizumab to inhibit RPMI8866 B cell binding to MAdCAM.
  • MAdCAM was coated onto a 96-well microtiter plate. Following overnight incubation, etrolizumab standards, controls, and samples were added to the plate, along with a fixed amount of cells. The plate was incubated at 37°C in a humidified incubator to allow binding of the cells to the MAdCAM. A wash step was performed to remove non-adherent cells, and the remaining live cells were quantified by adding the redox dye alamar Blue, which is blue and non-fluorescent in its oxidized state but is reduced by the intracellular environment into a pink form that is highly fluorescent.
  • alamar Blue which is blue and non-fluorescent in its oxidized state but is reduced by the intracellular environment into a pink form that is highly fluorescent.
  • An article of manufacture which comprises the formulation and provides instructions for its use.
  • the article of manufacture comprises a container.
  • an article of manufacture comprising a subcutaneous administration device which delivers to a subject a flat dose of an anti- integrin beta7 antibody or an antigen-binding fragment thereof, wherein the flat dose is for example, but not limited to, 105 mg, or 210 mg.
  • the anti- integrin beta7 antibody is etrolizumab.
  • the anti-integrin beta7 antibody or antigen binding fragment thereof in the subcutaneous administration device is formulated in a buffer, for example, histidine pH 5.8, and other excipients, for example, polysorbate and arginine succinate, such that it is provided in a stable pharmaceutical formulation.
  • the subcutaneous administration device is a prefilled syringe comprising a glass barrel with needle and optionally, a needle shield and also optionally, a needle shield device.
  • the volume of the formulation contained in the syringe is between about 0.1 mL and about 2 mL, between about 0.1 mL and about 2 mL, between about 0.5 mL and about 2 mL, or between about 1 mL and about 2 mL. In certain embodiments, the volume of the formulation contained in the syringe is between about 0.5 mL and about 2 mL.
  • the volume of the formulation contained in the syringe is about 0.5 mL, about 0.7 mL, about 1 mL, about 1.4 mL, about 1.5 mL, or about 2.0 mL. In certain embodiments, the volume of the formulation contained in the syringe is about 0.7 mL. In certain embodiments, the volume of the formulation contained in the syringe is about 0.75 mL.
  • the volume of the formulation contained in the syringe is about 1 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is between about 0.5 mL and about 1.0 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is between about 1.0 mL and about 1.5 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 1.4 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 1.5 mL. In certain embodiments, the volume of the formulation contained in the prefilled syringe is about 1.45 mL.
  • the needle is a staked-in needle comprising a 3-bevel tip or a 5-bevel tip. In certain embodiments, the needle is between 25 gauge (G) and 30G.
  • the needle is between 1/2 inch long and 5/8 inch long.
  • the subcutaneous administration device comprises a prefilled 1.0 mL low tungsten borosilicate glass (type I) syringe and a stainless steel 5-bevel 27G 1/2 inch long thin-wall staked-in needle.
  • the subcutaneous administration device comprises a rigid needle shield.
  • the rigid needle shield comprises a rubber formulation having low zinc content and comprises a rigid polypropylene shield.
  • the rubber plunger stopper comprises Daikyo 777-7 rubber and FluroTec® ethylene-tetrafluoroethylene (ETFE) coating (West Pharmaceutical Services, Inc.).
  • the subcutaneous administration device comprises a needle safety device. Exemplary needle safety devices include, but are not limited to, Ultrasafe Passive® Needle Guard X100L (Becton Dickinson and Company) and Rexam Safe n SoundTM (Rexam).
  • the injection device is a prefilled syringe.
  • prefilled syringes include BD HYPAK SCF®, READYFILLTM, and STERIFILL SCFTM from Becton Dickinson; CLEARSHOTTM copolymer prefilled syringes from Baxter; and Daikyo Seiko CRYSTAL ZENITH® prefilled syringes available from West Pharmaceutical Services.
  • the prefilled syringe comprises silicone oil. The etrolizumab prefilled syringe was developed with optimal levels of silicone oil in order to ensure low injection forces while maintaining a low risk of particle formation.
  • the amount of silicone oil in the prefilled syringe is not greater than about 1 mg. In certain embodiments, the amount of silicone oil in the prefilled syringe is between about 0.1 mg and about 1 mg. In certain embodiments, the amount of silicone oil in the prefilled syringe is between about 0.2 mg and about 0.6 mg. In certain embodiments, the amount of silicone oil in the prefilled syringe is between about 0.5 mg and 0.9 mg.
  • the prefilled syringe may have any suitable syringe capacity.
  • the prefilled syringe has a syringe capacity of between about 0.5 mL and about 10 mL, between about 0.5 mL and about 5 mL, between about 0.5 mL and about 2.5 mL, between about 1 mL and about 5 mL, or between about 1 mL and about 2.5 mL.
  • the prefilled syringe has a syringe capacity of 1 mL.
  • the prefilled syringe has a syringe capacity of 2.25 mL.
  • the injection device is an autoinjector, e.g., autoinjectors disclosed in U.S. Pat. Nos. 2014/0148763 and 2014/0114247, which are incorporated by reference herein.
  • the autoinjector is a single-use autoinjector.
  • the autoinjector is based on Rotaject ® technology (e.g., accessible at https://www.shl.group/products-and-services/rotaject-technology-auto- injector/).
  • Additional devices suitable for subcutaneous delivery include for example, but not limited to, an injection device such as INJECT-EASETM and GENJECTTM devices; an infusion pump such as ACCU-CHECKTM; an injector pen such as BD VystraTM from Becton Dickinson, a needleless device such as MEDDCTORTMand BIOJECTORTM and DECTTM, and a subcutaneous patch delivery system such as BD Libertas TM, H- PATCHTM available from Valeritas, and SOF-SERTERTM.
  • an injection device such as INJECT-EASETM and GENJECTTM devices
  • an infusion pump such as ACCU-CHECKTM
  • an injector pen such as BD VystraTM from Becton Dickinson
  • a needleless device such as MEDDCTORTMand BIOJECTORTM and DECTTM
  • a subcutaneous patch delivery system such as BD Libertas TM, H- PATCHTM available from Valeritas, and SOF-SERTERTM.
  • Kits will typically comprise the container described above and one or more other containers comprising materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a label may be present on the container to indicate that the composition is used for a specific therapy.
  • Important aspects of the optimization of the etrolizumab drug product formulation and configuration are minimizing viscosity to minimize injection force, maximizing the accuracy of the injection volume and optimizing compatibility with device components. Balancing the optimal formulation excipients to sufficiently protect the antibody from physical and chemical degradation, while maintaining biological activity (potency) and achieving high concentration of antibody while maintaining low viscosity is important. These aspects of the formulation must be balanced in concert with the prefilled syringe configuration and specifications such as silicone oil concentration, syringe materials of construction, barrel width, and needle wall thickness, which allow for lower injection force, shorter injection time and less pain as the result of injection.
  • an etrolizumab formulation comprising 150 mg/ml etrolizumab, 20 mM histidine, 200 mM arginine succinate, and 0.04% w/v of polysorbate 20 (PS20) at pH 5.8 was prepared. It was shown that this etrolizumab formulation was unexpectedly well suited for long-term storage at high concentration in a pre-filled syringe. Furthermore, when paired with prefilled syringes, this formulation minimized the risk of subvisible and visible particle formation upon long-term storage, which allow for extended shelf-life and patient-convenience.
  • a formulation of this pH minimizes the rate of aspartic acid (Asp) isomerization and succinimide intermediate formation, which allows for patient convenience in combination with the device by allowing storage at ambient temperatures without substantially impacting the chemical stability of the antibody and thereby the product quality. Furthermore, the risk of particle formation is lowered due to the increased solubility of free fatty acids at the higher pH which can result from polysorbate degradation.
  • Low viscosity is desired, as low viscosity can reduce injection force and ensure accuracy of injection volume.
  • Use of arginine hydrochloride or arginine succinate in antibody formulations has been described previously. See, e.g., U.S. Patent No. 8,142,776, and International Patent Application Publication Nos. W02006065746 and W02010102241.
  • the impact of the arginine succinate on the viscosity of the formulation was investigated. First, the viscosity of an etrolizumab formulation with arginine succinate was compared to the viscosity of etrolizumab formulation absent arginine succinate, and the results are shown in Figure 2. As shown in Figure 2, solution viscosity was decreased significantly by the addition of arginine succinate to the formulation.
  • arginine in this case, 200 mM arginine succinate, can impact the viscosity of an etrolizumab formulation of different antibody concentration.
  • the viscosities of an etrolizumab formulation comprising 100 mg/mL,
  • prefilled syringe drug products typically contain silicone oil and because it is known that silicone oil may cause protein aggregation and/or particle formation over time, the inventors investigated the effect of silicone oil on etrolizumab formulations.
  • HMWS high molecular weight species
  • SEC size exclusion chromatography
  • the specific combination of the formulation excipients at the target pH and in the presence of silicone oil are uniquely well suited to long term storage of a high concentration antibody formulation stored in a prefilled syringe. This finding is supported by about 6 years (e.g., 74 months) of long-term stability of etrolizumab in prefilled syringes without the observation of visible particles.
  • the presently disclosed formulations have the advantage to protect the antibody from additional stresses which can results from the storage in a prefilled syringe. Leachables from the prefilled syringe can lead to chemical and physical degradation of the antibody. For example, zinc and tungsten can contribute to metal-catalyzed degradation. During the syringe manufacturing process, a hot tungsten pin is inserted into the glass barrel to make the hole for needle insertion. This process can leave residual tungsten particles in the syringe barrel, which can interact with the drug solution causing the formation of aggregates. Tungsten can induce protein aggregation and formation of proteinaceous particles. Protein oxidation can be induced by tungsten as well leading to protein aggregation. Succinic acid protected from zinc-based metal-catalyzed degradation. Further, the presently disclosed formulation was not susceptible to tungsten-spiking mediated aggregation.
  • HMWS hydroxy-3-methylcellulose
  • Both the plunger stopper and the needle shield may be composed of rubber material which may leach zinc into the formulation. It is known that zinc may complex with protein leading to protein aggregates (e.g., HMWS) and increased viscosity of antibody formulations. The effect of zinc on the viscosity of etrolizumab formulations at varying protein concentrations was investigated.
  • HMWS HMWS
  • histidine can reduce the formation of HMWS.
  • the presence of histidine in the formulation greatly reduced the rate of HMWS formation in presence of zinc.
  • succinate also suppressed the interaction between etrolizumab and zinc to form HMWS.
  • the impact of varying concentrations of histidine and succinate on the HMWS formation was studied.
  • the combination of histidine and succinate minimized the HMWS formation in the presence of zinc.
  • etrolizumab drug substance formulated at 150 mg/mL in 20mM histidine, pH 5.8, 200mM arginine succinate, 0.04% polysorbate 20 was evaluated in at 30°C, 5°C, and -20°C.
  • the stability was also evaluated up to five freeze/thaw cycles to support at-scale storage and handling. No changes in the chemical, physical, or bioactivity properties were observed after five freeze/thaw cycles or after storage of the DS at -20°C for seven years (84 months). After storage at 5°C for six months, there was no change observed by all assays except ion exchange chromatography. After storage at 30°C for 14 days, degradation was measured by nonreduced capillary electrophoresis, ion exchange, and size exclusion chromatography.
  • IEC Ion exchange chromatography
  • etrolizumab drug product formulated at 150 mg/mL in 20mM histidine, pH 5.8, 200mM arginine succinate, 0.04% polysorbate 20 in a 105mg (0.7 ml) prefilled syringe configuration was investigated.
  • Etrolizumab showed no change in product quality after 60 months at 5°C, as assessed by clarity, opalescence, and coloration (COC), pH, protein concentration, size exclusion chromatography (SEC), and potency.
  • COC clarity, opalescence, and coloration
  • SEC size exclusion chromatography
  • IEC ion exchange chromatography
  • Typical antibody formulations comprise polysorbate 20 at 0.02% w/v and typical antibody formulations are at pH 5.5.
  • the higher than typical polysorbate 20 concentration (e.g., 0.04% w/v) and higher than typical pH (e.g., pH 5.8) can solubilize free fatty acids, thereby lowering the risk of particle formation as a result of polysorbate degradation, e.g., during long term storage in a pre filled syringe.
  • the excipient combination of the etrolizumab formulation is especially effective at controlling pH during Tangential Flow Filtration (TFF) at large scale manufacturing.
  • TDF Tangential Flow Filtration
  • the high arginine concentration and high conductivity formulation shields charge on the antibody and prevents shifts in pH.
  • the histidine concentration effectively buffers the formulation at the target pH. This is important to ensure robust control of the pH during manufacturing and allow for a narrow pH range of the formulation to enable this optimal configuration.
  • the formulation also maintained chemical and physical stability and maintained potency over various time periods and at various temperatures as described above.
  • Etrolizumab is a novel, dual -action, anti-P7 integrin antibody in development for patients with moderate to severe ulcerative colitis or Crohn’s disease.
  • Phase 3 studies utilize a prefilled syringe (PFS) for etrolizumab administration.
  • PFS prefilled syringe
  • AI autoinjector
  • HVs healthy volunteers
  • AEs Adverse events
  • PK Pharmacokinetic
  • ISRs Mild injection-site reactions
  • results from this first-in-human study demonstrate that single injections of etrolizumab 105 mg using an AI are well tolerated in HVs, with transient, mild pain and minimal usage errors. Results from this study also informed the design of a subsequent PK comparability study comparing the PFS and AI. Overall, the availability of an AI may provide an attractive option for patients desiring a convenient, easy to use delivery mechanism for etrolizumab.
  • Etrolizumab is being evaluated in an extensive clinical program of phase 3 studies in patients with moderate to severe UC and Crohn’s disease (Etro Studies. The Etro Studies: Explore Innovation: Contribute to Science. Genentech; 2019. Accessed July 26, 2019), where etrolizumab is administered once per month via subcutaneous (SC) injection using a prefilled syringe (PFS) with a needle safety device (NSD).
  • SC subcutaneous
  • PFS prefilled syringe
  • NSD needle safety device
  • AIs Single-use, prefilled autoinjectors
  • PFS-NSDs Single-use, prefilled autoinjectors
  • Exemplary PFS and AI are shown in Figure 12.
  • AIs also offer increased convenience, ease of use, reduced risk of dosage error, and improved patient comfort. Studies have consistently shown that many patients who self-administer prefer an AI over a syringe-based device (Kivitz et ak, Clin Ther. 2006;28(10): 1619-29; Kivitz and Segurado, Expert Rev Med Devices . 2007;4(2): 109-16; Borras-Blasco et ak, Expert OpinBiol Ther.
  • the AI currently under development consists of an automated delivery system encasing the same PFS used in the phase 3 studies (see Figure 13).
  • the drug product contained in both the AI and the PFS-NSD consists of a liquid formulation of 105 mg of etrolizumab solution (0.7 mL, nominal volume of 150 mg/mL) for single-dose administration. The entire dose is typically administered in about 2 seconds.
  • the AI includes many features aimed to improve the patient experience and increase patient comfort with self-administration.
  • the automated drug delivery system is activated by lightly pressing the device onto skin perpendicularly. Once activated, the AI automatically inserts the needle and dispenses the syringe contents upon activation. Once injection is complete, a needle cover extends and locks over the needle, keeping the needle out of view at all times during injection and protecting the user and others from accidental contact with the used needle.
  • the AI also incorporates both visual and auditory mechanisms designed to assist users with self-injection; a visible spinning top and an audible clicking sound both indicate whether drug administration is ongoing or completed. In addition, a visible plunger rod moves across the viewing window while the injection is in progress.
  • NCT02629744 The primary objectives of this study (NCT02629744) were to evaluate the safety and tolerability of etrolizumab administered by the AI and primarily injection site pain following self-injection with the AI and to document critical use errors.
  • This first-in-human AI tolerability study was an open-label, single-arm study in healthy volunteers evaluating pain, safety, and usability of an AI when self-administered subcutaneously. Participants were assigned (1:1) into 2 groups. In order to simulate prior experience of self-injection, 1 group (“needle- experienced”) received training before self-injection with the AI; the other group (“needle-naive”) did not. Training involved simulated needle experience by self-injection with placebo. Before etrolizumab administration, all participants (irrespective of needle experience group) received an instructions for use (IFU) leaflet regarding the AI for review before self-injection. Subjects were randomly assigned to administer study drug to their abdomen or anterior thigh.
  • IFU instructions for use
  • Participants Eligible participants were to be between the ages of 18 and 65 years, have a body mass index (BMI) of between 18.0 and 32.0 kg/m 2 (inclusive), and be in good health with no significant medical history or laboratory test abnormalities. Both men and women were enrolled, with the target of 55% to 60% male participants to mimic the sex distribution of patients with IBD. Participants with any prior use of anti- integrin therapies (including etrolizumab) or immunosuppressive drugs were excluded, as were participants with a recent history of corticosteroid use. Participants with a history of tuberculosis were also excluded. Procedures. Participants assigned to the needle-experienced group received training (simulated self-injection experience) 5 and 7 days before etrolizumab injection.
  • BMI body mass index
  • VAS 100-point continuous visual analog scale
  • the primary end point was the proportion of participants with greater than mild pain (VDS-7 > 3) immediately following injection. To meet the primary end point, the upper bound of the 2-sided 95% confidence interval (Cl) around the proportion of participants experiencing greater than mild pain immediately following injection must not exceed 30%. Secondary end points included the proportion of participants experiencing greater than mild pain at 5, 10, 20, 60, and 240 minutes (4 hours) following injection, and the proportion of participants in each VDS-7 category over time. Tolerability was assessed intensively in this study via active monitoring for injection site reactions (ISRs) on study day 1 at 5, 60, and 240 minutes after injection, and on study days 2, 8, 43, and 85.
  • ISRs injection site reactions
  • LISSA local injection site symptom assessment
  • All ISRs were categorized and reported as an adverse event (AE) or serious AE as appropriate.
  • AE adverse event
  • participants knowledge of the IFU and their overall opinions of the AI experience were collected.
  • Safety was assessed via AE monitoring, laboratory assessment, vital signs, physical examinations, electrocardiograms (ECGs), and immunogenicity. For this study, no formal statistical testing was planned. Determination of PK variability on a single time point of study day 8 following self-injection was assessed as an exploratory end point.
  • ISRs are mild (grade 1) and transient; all resolved by study completion. The most frequent ISR was redness, which ranged from ⁇ 18 to 31 mm in diameter. Most ISRs resolved within 60 minutes following injection.
  • One volunteer reported formation of hives (18 mm in diameter) at the abdominal injection site 60 minutes postdose; the hives resolved within 3 hours without treatment. Injection site did not appear to affect either the frequency or severity of ISRs.
  • TEAE treatment-emergent adverse event
  • PK assessment was incorporated into the study protocol with a single blood sample taken on study day 8, around the time of maximum serum concentration following a single SC dose.
  • the intent of this exploratory PK assessment was to understand the intersubject exposure variability following etrolizumab SC delivery by AI.
  • these preliminary PK data helped to evaluate potential differences in exposure following AI injection compared with the predicted exposure using a model generated based on PK data from administration with a vial and syringe in patients with UC.
  • day 8 etrolizumab exposure observed in this analysis was approximately 75% higher than the predicted value (predicted day 8 median etrolizumab serum concentration ⁇ 7.9 pg/mL [90% Cl 4.15-16.3], data not shown).
  • the PK variability and unexpected higher day 8 exposure from this analysis informed the decision to conduct a 2-part study comparing the pharmacokinetics of etrolizumab delivered by the AI and PFS-NSD in healthy volunteers (see Figure 17 and Example 3). Results from this study effectively eliminated the requirement for additional AI ease of use and/or clinical studies.
  • results from this study demonstrate that single SC injections of etrolizumab with an AI are well-tolerated in healthy volunteers, with tolerable levels of pain following injection. Most participants found the AI easy to use and experienced only minimal usage errors.
  • the AI may be an appropriate delivery mechanism for certain patients with IBD who desire the safety and convenience of self-injection with an invisible needle.
  • the positive results from this first-in-human tolerability study, in combination with data gathered during the subsequent 2-part PK comparability study, comprise a complete development plan to support the use of AI in patients treated with etrolizumab.
  • Example 3 Comparable Pharmacokinetics, Safety, and Tolerability of Etrolizumab Administered via Prefilled Syringe or Autoinjector in a Randomized
  • Etrolizumab is a novel, dual -action anti-b? integrin antibody being studied in several phase 3 trials in patients with inflammatory bowel disease.
  • An autoinjector (AI) device is being developed in parallel to complement the prefilled syringe (PFS) with needle safety device (NSD) used for subcutaneous administration in these trials.
  • PFS prefilled syringe
  • NSD needle safety device
  • Primary PK results from part 1 supported modification of the part 2 study design.
  • Results from part 2 demonstrated that etrolizumab exposure was equivalent between devices, with geometric mean ratios (GMRs) between AI and PFS-NSD of 102% for Cmax, 98.0% for AUCiast, and 97.6% for AUCo-inf.
  • Median T max and mean terminal ti/2 were also similar between devices.
  • the GMRs and 90% confidence intervals of all primary PK parameters were fully contained within the predefined equivalence limits (80% to 125%).
  • the PK comparability study (NCT02996019) presented in this Example aimed to demonstrate the comparability of etrolizumab exposure following SC administration using the AI and PFS-NSD, and to evaluate the safety and tolerability of etrolizumab following SC injection using the 2 devices.
  • Part 1 of the study was an exploratory pilot cohort used to evaluate the geometric mean ratio (GMR) and variability of PK parameters for etrolizumab administration with the AI versus PFS-NSD. Those results informed the study design including sample size and study duration for part 2 (the pivotal cohort).
  • the study aimed to demonstrate exposure comparability between a single dose of etrolizumab administered via AI or PFS-NSD.
  • the PK comparability study presented in this Example leveraged the exploratory PK results from the tolerability study presented in Example 2 to refine the study design and final protocol.
  • This study was a randomized, multi center, open- label, parallel-group study conducted in healthy participants at three clinical sites within the United States (see Figure 18).
  • This 2-part study consisted of a pilot cohort (part 1) and a pivotal cohort (part 2) with a sample size sufficient for 80% power to detect the exposure difference (if any) between the 2 device groups.
  • healthy participants were randomly assigned 1:1 to receive a single dose of etrolizumab 105 mg SC via either AI (test device) or PFS-NSD (reference device).
  • Etrolizumab was administered by a health care professional (HCP) into the participant’s abdomen. Randomization in both cohorts was stratified by body weight ( ⁇ 79.9 vs > 80 kg).
  • Eligible healthy participants included men and women between 18 and 55 years of age with a body mass index (BMI) between 18.0 and 30.0 kg/m 2 . Based on results from the pilot cohort, it was also required that participants in the pivotal cohort have a body weight within the range of 60 to 100 kg (inclusive) at the time of study entry. Participants must have been in good health (no clinically significant findings from medical history, physical examination, 12-lead electrocardiogram, or vital signs). Participants with any prior exposure to immunosuppressants or anti-integrin therapies (including etrolizumab) were excluded.
  • Cmax, AUCiast, and AUCo-inf were measured as primary endpoints.
  • Secondary PK parameters included the time to maximum concentration of etrolizumab (tmax), the terminal elimination half-life (ti / 2), and AUCR.
  • Blood samples for determination of antidrug antibodies (AD As) in parts 1 and 2 were collected before dosing on day 1, and on days 29, 57, and 71. Data from all ADApositive participants were included in the final PK statistical analysis unless the participant met the PK analysis predefined exclusion criteria.
  • Safety and tolerability assessments included the incidence, nature, and severity of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. The incidence of injection-site reactions, changes in vital signs, physical examination findings, clinical laboratory results, and the incidence of AD As were also assessed.
  • Etrolizumab concentrations were measured using a validated immunoassay (ICON).
  • This Gyrolab fluorescence immunoassay utilized a minimum required dilution (MRD) of 1/100, with a minimum quantifiable concentration of 80 ng/mL etrolizumab in UC, CD, and healthy volunteer sera.
  • Anti-etrolizumab antibodies in serum were detected using a validated assay.
  • This colorimetric ELISA used a 1/20 MRD and a monoclonal anti-etrolizumab control antibody. Relative sensitivity of the method was determined to be 12.0 ng/mL in healthy volunteer serum. Drug tolerance of the assay was established: 28 ng/mL of the positive control ADA could be detected in the presence of 50 pg/mL etrolizumab.
  • Sample Size Determination Enrollment of up to 30 healthy participants in part 1 was planned to ensure at least 12 participants in each arm (24 total) had evaluable PK profiles to enable estimation of the GMR and coefficient of variation (CV%) for PK parameters (Cmax, AUCiast, and AUCo-inf).
  • Part 2 planned for enrollment of 146 participants. Assuming a dropout rate or non-evaluable PK profiles from approximately 10% of participants through day 71, a total of approximately 131 healthy participants with evaluable full PK profiles were expected to provide at least 80% power to demonstrate exposure comparability for Cmax, AUCiast, and AUCo-inf based on the GMR and PK variability outcomes from the part 1 pilot cohort.
  • Pharmacokinetic analyses PK parameters were determined from the serum etrolizumab concentrations using noncompartmental methods (NCA) and were performed using Phoenix WinNolin (Centara USA, Inc., Version 6.4). .
  • the analysis population consisted of all participants who received an SC injection of etrolizumab and who had an evaluable PK profile, which was defined as having sufficient samples available to accurately determine key PK parameters. In particular, participants with early termination on or before day 15 were considered not having an evaluable PK profile. Participants with no sample available to determine the concentration of day 71 were excluded from statistical analysis of AUCi as t; participants with ⁇ 3 available samples among days 28, 43, 51, and 71 were excluded from statistical analysis of AUCo-inf. Participants with predose concentration > 5% of C max may be excluded from statistical analysis of all PK parameters at the discretion of the study and sponsor clinical pharmacokinetist/biostatistician.
  • PK parameters Descriptive, exploratory analysis of PK parameters was carried out with data from part 1 (pilot), with a focus on evaluating GMRs, CV%, and distribution of AUCR to inform the part 2 (pivotal) sample size and final study design. Only data from the pivotal cohort (part 2) were included in comparability statistical analysis. In part 2, an analysis of variance, including treatment as the fixed effect, was performed to assess comparability of Cmax, AUCiast, and AUCo-inf between the AI and PFS-NSD groups.
  • Data for Cmax, AUCiast, and AUCo-inf were natural log (ln)-transformed before analysis, and the 90% confidence intervals (CIs) of the GMRs for the AI group relative to those from the PFS-NSD group were calculated by taking the antilog of the corresponding 90% CIs for the differences between the means (log scale). Exposure between the AI and PFS-NSD groups met PK comparability criteria if the 90% CIs of the GMRs for Cmax, AUCiast, and AUCo-inf were all within 80% to 125%.
  • AI autoinjector BMI body mass index. JCV John Cunningham virus. PFS-NSD prefilled syringe with needle safety device.
  • PK evaluable population meeting the body weight restriction of 60 to 100 kg in part 1 included 14 participants in the AI arm and 11 participants in the PFS- NSD arm.
  • AI versus PFS-NSD group primary PK parameter GMR values were 0.95, 1.02, and 1.02 for C max , AUCi ast , and AUCo-mf, respectively (Table 4).
  • AI autoinjector ANOVA analysis of variance. A UCo- n/AUC extrapolated to infinity. A area under the concentration-time curve from the time of drug administration to the last measurable concentration (hast is Day 71 for all available data). Cmax maximum concentration. GMR geometric mean ratio. PFS-NSD prefilled syringe with needle safety device. a Number of observations in each treatment eligible for analysis. b Geometric means are based on the least-squares means for Cmax and AUC parameters from ANOVA, calculated by transforming the natural log means back to the linear scale.
  • the sample size for pivotal cohort was calculated based on these GMR and CV% values, and a body weight restriction was added for the part 2 study as an inclusion criterion. Furthermore, all participants had AUCR values > 80% (data not shown), which meets the requirement for bioequivalence study stated in the US Food and Drug Administration (FDA) guideline (US Department of Health and Human Services. Guidance for industry: statistical approaches to establishing bioequivalence. Accessed March 4, 2020), and hence resulted in a modification of the last day of the pivotal study from originally planned day 85 to day 71.
  • FDA US Food and Drug Administration
  • Etrolizumab serum concentrations over time for the AI and PFS-NSD groups are shown in Figure 20; PK parameters are summarized in Table 5.
  • GMRs (90% CIs) between the AI and PFS-NSD groups were 102% (94.2-111%) for Cmax, 98.0% (89.3- 107%) for AUC last , and 97.6% (88.6-107%) for AUCo-i nf (Table 6).
  • AI autoinjector A UCo-mf AUC extrapolated to infinity. A UCiast area under the concentration-time curve from the time of drug administration to the last measurable concentration. AUCR ratio of AUCiast to AUCo-inf. Cmax maximum concentration. PFS-NSD prefilled syringe with needle safety device. PK pharmacokinetic ti/2 terminal elimination half-life tmax time to maximum concentration. Geometric mean (geometric CV%) data are presented unless otherwise indicated. includes only participants who met body weight restrictions (60 to 100 kg) in the pilot cohort. b Median (min, max) presented for tmax. Arithmetic mean (SD) presented for ti / 2. d n (%) presented.
  • AI autoinjector ANOVA analysis of variance.
  • Geometric means are based on the least-squares means for Cmax and AUC parameters from ANOVA, calculated by transforming the natural log means back to the linear scale.
  • Natural log-transformed ratios transformed back to the linear scale d 90% confidence interval for ratio of parameter means of natural log-transformed parameter (expressed as a percent). Natural log-transformed confidence limits transformed back to the linear scale.
  • the 90% CIs of the GMRs for each of these primary PK parameters were within the predefined equivalence limits of 80% to 125%, which meets the predefined comparability criteria and supports equivalent exposure of etrolizumab between 2 device groups.
  • the results also demonstrated similar median time to maximum observed concentration (tmax, 5.04 vs 6.97 days) and mean terminal elimination half-life (ti/2, 11.8 vs 12.2 days) between AI and PFS-NSD groups.
  • Treatment-Emergent Adverse Events (TEAE) AE adverse event; AI autoinjector, ISR injection site reaction, NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events, PFS-NSD prefilled syringe with needle safety device, SAE serious adverse event, TEAE treatment-emergent adverse event, Data are reported as n (%) unless otherwise specified.
  • the pivotal cohort in this study confirmed comparable etrolizumab exposure between AI and PFS-NSD groups following a single dose of SC etrolizumab in healthy participants.
  • the GMRs observed with each of the primary PK parameters were between 98% and 102%, with 90% CIs within the prespecified equivalence limits. These GMRs for all primary exposure parameters are impressive, given the GMRs obtained when comparing other AIs and PFS-NSDs in healthy participants.
  • a small pilot cohort was added to the original study protocol with the intent of gaining certainty around GMR values of the primary PK parameters and PK variability following administration of etrolizumab by AI or PFS-NSD.
  • the GMR and PK variability values obtained from the pilot cohort provided added confidence in estimating the sample size for the pivotal cohort.
  • body weight was stratified at randomization, the final body weight distribution range was still imbalanced in the pilot cohort, which may have biased the final GMR outcome. To minimize such bias, only data from participants with a body weight within the range of 60 to 100 kg (a common body weight range for both arms within the pilot cohort) were used for the estimation of GMR and PK variabilities.
  • This body weight restriction of 60 to 100 kg was also implemented in the pivotal cohort as an inclusion criterion.
  • the pilot cohort also evaluated a study duration of 10 weeks (70 days), 2 weeks shorter than the original study planned study duration as suggested by the FDA. As expected, all evaluable participants in the pilot cohort had AUCR values > 80%, the value required by the FDA for PK comparability studies. This result suggested that the 10-week study duration is long enough to capture more than 80% of AUCi nf and hence the duration of the pivotal study could be shortened from 12 weeks to 10 weeks without the risk of missing the requirement of ⁇ 20% extrapolated AUC for the calculated AUCi nf . Immunogenicity was relatively high in this study compared with other studies using etrolizumab.
  • ADA rate in the current study may have been the result of differences in study design: the current study had a single SC dose regimen and a study population of healthy participants not taking immunosuppressive drugs. In comparison, patients in prior trials of etrolizumab had insufficiently controlled, moderate-to-severe UC and were commonly being treated with immunosuppressive agents. Although the incidence of ADAs after a single SC injection of etrolizumab was relatively high (>20%) in this study, the impact of ADA positivity on PK appears to be minimal, given that the PK profiles of ADA-positive participants largely overlapped with those observed in ADA-negative participants (Figure 21).
  • This Example provides details relating to PFS-NSD injection forces.
  • injection time is relevant attribute.
  • the injection time is between about 0.4 seconds and about 9 seconds. In certain embodiment, the injection time is about 5 seconds.
  • the autoinjector used for the presently disclosed formulation provides advantageous injection times and extended stability.

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Abstract

L'invention concerne des formulations comprenant un anticorps anti-intégrine bêta7 ou un fragment de liaison à l'antigène associé, notamment des formulations pharmaceutiques. L'invention concerne également un article manufacturé comprenant de telles formulations, et des méthodes d'utilisation de telles formulations.
PCT/US2021/043690 2020-07-31 2021-07-29 Formulations d'anticorps anti-intégrine bêta7 et dispositifs WO2022026699A1 (fr)

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MX2023001157A MX2023001157A (es) 2020-07-31 2021-07-29 Formulaciones de anticuerpo anti-integrina beta7 y dispositivos.
EP21766732.8A EP4188958A1 (fr) 2020-07-31 2021-07-29 Formulations d'anticorps anti-intégrine bêta7 et dispositifs
AU2021316017A AU2021316017A1 (en) 2020-07-31 2021-07-29 Anti-integrin beta7 antibody formulations and devices
BR112023001734A BR112023001734A2 (pt) 2020-07-31 2021-07-29 Formulações, artigos de fabricação, autoinjetores e métodos para tratar um distúrbio inflamatório gastrointestinal em um indivíduo e para administrar por via subcutânea uma formulação
CA3190109A CA3190109A1 (fr) 2020-07-31 2021-07-29 Formulations d'anticorps anti-integrine beta7 et dispositifs
IL300133A IL300133A (en) 2020-07-31 2021-07-29 Anti-integrin antibody compositions in cell 7 and devices
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Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO1991010741A1 (fr) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation d'anticorps xenogeniques
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5648237A (en) 1991-09-19 1997-07-15 Genentech, Inc. Expression of functional antibody fragments
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1998024893A2 (fr) 1996-12-03 1998-06-11 Abgenix, Inc. MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
US5789199A (en) 1994-11-03 1998-08-04 Genentech, Inc. Process for bacterial production of polypeptides
US5840523A (en) 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
US5959177A (en) 1989-10-27 1999-09-28 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
US6040498A (en) 1998-08-11 2000-03-21 North Caroline State University Genetically engineered duckweed
US6420548B1 (en) 1999-10-04 2002-07-16 Medicago Inc. Method for regulating transcription of foreign genes
WO2006026759A2 (fr) 2004-09-03 2006-03-09 Genentech, Inc. Antagonistes anti-beta7 humanises et utilisations de ceux-ci
WO2006065746A2 (fr) 2004-12-16 2006-06-22 Genentech, Inc. Procedes de traitement de troubles induits par ige comprenant l'administration de formulations d'anticorps anti-ige a concentration elevee
US7125978B1 (en) 1999-10-04 2006-10-24 Medicago Inc. Promoter for regulating expression of foreign genes
WO2009140684A2 (fr) 2008-05-16 2009-11-19 Genentech, Inc. Utilisation de biomarqueurs pour évaluer le traitement de troubles inflammatoires gastro-intestinaux avec des antagonistes de l'intégrine bêta7
WO2010102241A1 (fr) 2009-03-06 2010-09-10 Genentech, Inc. Formulation d'anticorps
US8142776B2 (en) 2000-10-12 2012-03-27 Genentech, Inc. Reduced-viscosity concentrated protein formulations
US20140114247A1 (en) 2011-06-17 2014-04-24 Shl Group Ab Injection Device
US20140148763A1 (en) 2011-06-17 2014-05-29 Shl Group Ab Injection Device
WO2014160753A1 (fr) 2013-03-27 2014-10-02 Genentech, Inc. Utilisation de biomarqueurs pour évaluer le traitement de troubles gastro-intestinaux inflammatoires par des antagonistes de l'intégrine bêta7
WO2015148809A1 (fr) 2014-03-27 2015-10-01 Genentech, Inc. Méthodes permettant le diagnostic et le traitement d'une maladie inflammatoire de l'intestin
WO2016138207A1 (fr) * 2015-02-26 2016-09-01 Genentech, Inc. Antagonistes d'intégrine bêta7 et procédés de traitement de la maladie de crohn
US20180346578A1 (en) * 2011-05-02 2018-12-06 Millennium Pharmaceuticals, Inc. Formulation for anti-alpha4beta7 antibody
WO2019246455A1 (fr) * 2018-06-20 2019-12-26 Progenity, Inc. Traitement d'une maladie du tractus gastro-intestinal par un inhibiteur de l'intégrine

Patent Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
US6417429B1 (en) 1989-10-27 2002-07-09 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
US5959177A (en) 1989-10-27 1999-09-28 The Scripps Research Institute Transgenic plants expressing assembled secretory antibodies
WO1991010741A1 (fr) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation d'anticorps xenogeniques
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5648237A (en) 1991-09-19 1997-07-15 Genentech, Inc. Expression of functional antibody fragments
US5789199A (en) 1994-11-03 1998-08-04 Genentech, Inc. Process for bacterial production of polypeptides
US5840523A (en) 1995-03-01 1998-11-24 Genetech, Inc. Methods and compositions for secretion of heterologous polypeptides
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1998024893A2 (fr) 1996-12-03 1998-06-11 Abgenix, Inc. MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
US6040498A (en) 1998-08-11 2000-03-21 North Caroline State University Genetically engineered duckweed
US7125978B1 (en) 1999-10-04 2006-10-24 Medicago Inc. Promoter for regulating expression of foreign genes
US6420548B1 (en) 1999-10-04 2002-07-16 Medicago Inc. Method for regulating transcription of foreign genes
US8142776B2 (en) 2000-10-12 2012-03-27 Genentech, Inc. Reduced-viscosity concentrated protein formulations
WO2006026759A2 (fr) 2004-09-03 2006-03-09 Genentech, Inc. Antagonistes anti-beta7 humanises et utilisations de ceux-ci
WO2006065746A2 (fr) 2004-12-16 2006-06-22 Genentech, Inc. Procedes de traitement de troubles induits par ige comprenant l'administration de formulations d'anticorps anti-ige a concentration elevee
WO2009140684A2 (fr) 2008-05-16 2009-11-19 Genentech, Inc. Utilisation de biomarqueurs pour évaluer le traitement de troubles inflammatoires gastro-intestinaux avec des antagonistes de l'intégrine bêta7
WO2010102241A1 (fr) 2009-03-06 2010-09-10 Genentech, Inc. Formulation d'anticorps
US20180346578A1 (en) * 2011-05-02 2018-12-06 Millennium Pharmaceuticals, Inc. Formulation for anti-alpha4beta7 antibody
US20140114247A1 (en) 2011-06-17 2014-04-24 Shl Group Ab Injection Device
US20140148763A1 (en) 2011-06-17 2014-05-29 Shl Group Ab Injection Device
WO2014160753A1 (fr) 2013-03-27 2014-10-02 Genentech, Inc. Utilisation de biomarqueurs pour évaluer le traitement de troubles gastro-intestinaux inflammatoires par des antagonistes de l'intégrine bêta7
WO2015148809A1 (fr) 2014-03-27 2015-10-01 Genentech, Inc. Méthodes permettant le diagnostic et le traitement d'une maladie inflammatoire de l'intestin
WO2016138207A1 (fr) * 2015-02-26 2016-09-01 Genentech, Inc. Antagonistes d'intégrine bêta7 et procédés de traitement de la maladie de crohn
WO2019246455A1 (fr) * 2018-06-20 2019-12-26 Progenity, Inc. Traitement d'une maladie du tractus gastro-intestinal par un inhibiteur de l'intégrine

Non-Patent Citations (65)

* Cited by examiner, † Cited by third party
Title
ABBAS ET AL.: "Cellular andMol. Immunology", 2000, W. B. SAUNDERS, CO.
ABRAHAMCHO, NENGL J MED., vol. 361, no. 21, 2009, pages 2066 - 78
ANUMOLU ET AL., CLIN PHARMACOL DRUG DEV., vol. 7, no. 8, 2018, pages 829 - 36
BARBADILLO ET AL., SPRINGER SEMIN. IMMUNOPATHOL., vol. 16, 1995, pages 391404 - 379
BORRAS-BLASCO ET AL., EXPERT OPIN BIOL THER., vol. 10, no. 3, 2010, pages 301 - 7
BORREN ET AL., NAT REV GASTROENTEROL HEPATOL., vol. 16, no. 4, 2019, pages 247 - 59
BRUGGEMANN ET AL., YEAR IN IMMUNOL., vol. 7, 1993, pages 33
BUTCHER ET AL., SCIENCE, vol. 272, 1996, pages 60 - 66
CARTER ET AL., GUT, vol. 53, 2004, pages V1 - 16
CASELLAS ET AL., DIG DIS., vol. 17, no. 4, 1999, pages 208 - 18
CHOTHIALESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
CLARKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
CLELAND ET AL., CRITICAL REVIEWS IN THERAPEUTIC DRUG CARRIER SYSTEMS, vol. 10, no. 4, 1993, pages 307 - 377
ELICES ET AL., CELL, vol. 60, 1990, pages 577 - 584
FALCONER ROBERT J.: "Advances in liquid formulations of parenteral therapeutic proteins", BIOTECHNOLOGY ADVANCES., vol. 37, no. 7, 1 November 2019 (2019-11-01), GB, pages 107412, XP055799326, ISSN: 0734-9750, DOI: 10.1016/j.biotechadv.2019.06.011 *
FELLOUSE, PROC. NATL. ACAD. SCI. USA, vol. 101, no. 34, 2004, pages 12467 - 12472
FISHWILD ET AL., NATURE BIOTECHNOL., vol. 14, 1996, pages 826 - 851
GERNGROSS, NAT. BIOTECH., vol. 22, 2004, pages 1409 - 1414
GRAHAM ET AL., J. GEN VIROL., vol. 36, 1977, pages 59
HAMMERLING ET AL.: "Monoclonal Antibodies and T-Cell Hybridomas", 1981, ELSEVIER, pages: 563 - 681
HARLOW ET AL.: "Antibodies: A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY PRESS
HEMLER, ANNU. REV. IMMUNOL., vol. 8, 1990, pages 365 - 368
HYNES, CELL, vol. 69, 1992, pages 11 - 25
JAKOBOVITS ET AL., NATURE, vol. 362, 1993, pages 255 - 258
JAKOBOVITS ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 2551
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH
KIVITZ ET AL., CLIN THER., vol. 28, no. 10, 2006, pages 1619 - 29
KIVITZSEGURADO, EXPERT REV MED DEVICES., vol. 4, no. 2, 2007, pages 109 - 16
KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
LABERGE ET AL., AM. J. RESPIR. CRIT. CARE MED., vol. 151, 1995, pages 822 - 829
LEE ET AL., J. IMMUNOL. METHODS, vol. 284, no. 1-2, 2004, pages 119 - 132
LI ET AL., NAT. BIOTECH., vol. 24, 2006, pages 210 - 215
LIM ET AL., CLIN THER., vol. 34, no. 9, 2012, pages 1948 - 53
LONBERG ET AL., NATURE, vol. 368, 1994, pages 812 - 813
LONBERGHUSZAR, INTERN. REV. IMMUNOL., vol. 13, 1995, pages 65 - 93
MAKAREM ET AL., J. BIOL. CHEM., vol. 269, 1994, pages 4005 - 4011
MARKS ET AL., BIO.TECHNOLOGY, vol. 10, 1992, pages 779 - 783
MARKS ET AL., J. MOL. BIOL., vol. 222, 1992, pages 581 - 597
MATHER ET AL., ANNALS N.Y. ACAD. SCI., vol. 383, 1982, pages 44 - 68
MATHER, BIOL. REPROD., vol. 23, 1980, pages 243 - 251
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6855 - 9855
NAKAJIMA ET AL., J. EXP. MED., vol. 179, 1994, pages 1145 - 1154
PODALSKI, N. ENG. J. MED., vol. 325, 1991, pages 928 - 937
PORTOLANO ET AL., J. IMMUNOL., vol. 150, 1993, pages 880 - 887
POWRIE ET AL., THER. IMMUNOL., vol. 2, 1995, pages 115 - 123
RAMAEL ET AL., RHEUMATOL THER., vol. 5, no. 2, 2018, pages 403 - 21
REMINGTON'S PHARMACEUTICAL SCIENCES, 1980
ROGLER, BEST PRACTRES CLIN GASTROENTEROL., vol. 24, no. 2, 2010, pages 157 - 65
RUTGEERTS PJ ET AL., GUT, vol. 62, no. 8, 2013, pages 1122 - 1130
SANDBOM ET AL.: "Etrolizumab as Induction Therapy in Moderate to Severe Crohn's Disease: Results from Bergamot Cohort 1", UNITED EUROPEAN GASTROENTEROLOGY WEEK CONGRESS, 28 October 2017 (2017-10-28)
SHIN ET AL., DRUGDES DEVEL THER., vol. 12, 2018, pages 3799 - 805
SIDHU ET AL., J. MOL. BIOL., vol. 340, no. 5, 2004, pages 1073 - 1093
TANG ET AL., ALIMENT PHARMACOL THER., vol. 47, no. 11, 2018, pages 1440 - 52
THAKUR ET AL., RHEUMATOL THER., vol. 3, no. 2, 2016, pages 245 - 56
URLAUB ET AL., PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216
VERMEIRE ET AL., LANCET., vol. 384, no. 9940, 2014, pages 309 - 18
VERMEIRE ET AL., PATIENT PREFER ADHERENCE., vol. 12, 2018, pages 1413 - 202
VERMEIRE, S. ET AL., LANCET, vol. 384, no. 9940, 2014, pages 309 - 18
VINEY, J. IMMUNOL., vol. 157, 1996, pages 2488 - 2497
WANG WEI ED - BLANCO-PRIETO MARIA J ET AL: "Instability, stabilization, and formulation of liquid protein pharmaceuticals", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 185, no. 2, 20 August 1999 (1999-08-20), pages 129 - 188, XP002323952, ISSN: 0378-5173, DOI: 10.1016/S0378-5173(99)00152-0 *
WYANT TIM ET AL: "An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab", JOURNAL OF CROHN'S AND COLITIS, vol. 10, no. 12, 1 June 2016 (2016-06-01), NL, pages 1437 - 1444, XP055854349, ISSN: 1873-9946, DOI: 10.1093/ecco-jcc/jjw092 *
YAZAKIWU: "Methods in Molecular Biology", vol. 248, 2003, HUMANA PRESS, pages: 255 - 268
ZHANG WENHUI ET AL: "Comparable Pharmacokinetics, Safety, and Tolerability of Etrolizumab Administered by Prefilled Syringe or Autoinjector in a Randomized Trial in Healthy Volunteers", ADVANCES IN THERAPY, HEALTH COMMUNICATIONS, METUCHEN, NJ, US, vol. 38, no. 5, 29 March 2021 (2021-03-29), pages 2418 - 2434, XP037447970, ISSN: 0741-238X, [retrieved on 20210329], DOI: 10.1007/S12325-021-01661-6 *
ZHANGLI, WORLD J GASTROENTEROL., vol. 20, no. 1, 2014, pages 91 - 9
ZUNDLER ET AL., GUT, vol. 68, no. 9, 2019, pages 1688 - 700

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