[go: up one dir, main page]

WO2025221247A1 - Traitement de l'œsophagite à éosinophiles avec un anticorps anti-tslp - Google Patents

Traitement de l'œsophagite à éosinophiles avec un anticorps anti-tslp

Info

Publication number
WO2025221247A1
WO2025221247A1 PCT/US2024/024850 US2024024850W WO2025221247A1 WO 2025221247 A1 WO2025221247 A1 WO 2025221247A1 US 2024024850 W US2024024850 W US 2024024850W WO 2025221247 A1 WO2025221247 A1 WO 2025221247A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
antibody
set forth
amino acid
sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/024850
Other languages
English (en)
Inventor
Joseph SHERRILL
Scott CAVENEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
MedImmune LLC
Original Assignee
Amgen Inc
MedImmune LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc, MedImmune LLC filed Critical Amgen Inc
Priority to PCT/US2024/024850 priority Critical patent/WO2025221247A1/fr
Priority to PCT/US2025/025157 priority patent/WO2025221995A1/fr
Publication of WO2025221247A1 publication Critical patent/WO2025221247A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates, in general, to methods of treating eosinophilic esophagitis (EOE) using an antibody specific for thymic stromal lymphopoietin (TSLP).
  • EAE eosinophilic esophagitis
  • TSLP thymic stromal lymphopoietin
  • Eosinophilic esophagitis is a rare, chronic inflammatory disorder for which there are few approved treatments.
  • Thymic stromal lymphopoietin is a pro- inflammatory epithelial cytokine.
  • TSLP Thymic stromal lymphopoietin
  • TSLP genetic variants are associated with EOE risk and esophageal TSLP mRNA and protein levels are increased in patients with active disease.
  • Tezepelumab a human monoclonal antibody approved for the treatment of severe asthma, specifically binds to and blocks the activity of TSLP.
  • TSLP along with the other epithelial “alarmins”, IL-25 and IL-33, activates Type 2 innate lymphoid cells (ILC2) and other inflammatory cell (including mast cells, basophils, and macrophages), thus promoting T2 inflammation by up-regulating Type 2 cytokines in response to an epithelial insult (e.g., pollutants, microbes, cigarette smoke, bacterial and viral infections, mechanical injury, trauma and pro-inflammatory cytokines etc.) (Camelo et al 2017).
  • an epithelial insult e.g., pollutants, microbes, cigarette smoke, bacterial and viral infections, mechanical injury, trauma and pro-inflammatory cytokines etc.
  • Tezepelumab also known as AMG 157 (Gilliet, et al., J Exp Med 2003; 197:1059- 63) is a fully human monoclonal antibody (immunoglobulin G2A) that targets TSLP, which promotes inflammatory responses to environmental stimuli through its activities on multiple pathways, including (but not limited to) activities on dendritic cells (Gilliet, et al., 2003;
  • the anti-TSLP antibody described herein addresses an unmet need in patients with EOE in which other medications may not control symptoms.
  • the disclosure provides a method for treating eosinophilic esophagitis (EOE) in a subject comprising, administering an anti-TSLP antibody to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or 4 weeks, wherein the antibody comprises: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i.
  • EAE eosinophilic esophagitis
  • a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method for treating eosinophilic esophagitis (EOE) in a subject comprising, administering an anti-TSLP antibody to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or 4 weeks, wherein the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • the light chain variable domain comprises the amino acid sequence set forth in SEQ ID NO:12 and the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NQ:10.
  • the antibody is administered every 2 weeks. In various embodiments, the antibody is administered every 4 weeks. In various embodiments, the antibody is administered at a dose of 210 mg. In various embodiments, the antibody is administered at a dose of 420 mg. In various embodiments, the antibody is an lgG2 antibody. In various embodiments, the antibody is a human igG2 antibody.
  • the disclosure also provides a method for treating eosinophilic esophagitis (EOE) in a subject comprising administering anti-TSLP antibody or antibody variant in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b.
  • EOE eosinophilic esophagitis
  • a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2;
  • the disclosure provides a method for treating eosinophilic esophagitis (EOE) in a subject comprising administering an anti-TSLP antibody or antibody variant in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain comprising a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • EEE eosinophilic esophagitis
  • the disclosure further provides a method for eosinophilic esophagitis (EOE) in a subject comprising selecting a subject in need of treatment for EOE and administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a.
  • a light chain variable domain comprising: i.
  • a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • Also contemplated is a method for treating eosinophilic esophagitis (EOE) in a subject comprising selecting a subject in need of treatment for EOE, administering an anti- TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • EOE eosinophilic esophagitis
  • the sequence of amino acids is at least about 80%, 85%, 90% 95%, 96%, 97%, 98%, 99% or more identical to the heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 10 or at least about 80%, 85%, 90% 95%, 96%, 97%, 98%, 99% or more identical to the light chain variable region domain comprising the amino acid sequence set forth in SEQ ID NO: 12.
  • heavy chain variable region sequences less than 100% identical to SEQ ID NO: 10 retain the CDR amino acid sequences set forth in SEQ ID NOs: 6-8
  • light chain variable region sequences less than 100% identical to SEQ ID NO: 12 retain the CDR amino acid sequences set forth in SEQ ID NOs: 3-5.
  • the light chain variable domain comprises the amino acid sequence set forth in SEQ ID NO:12 and the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NO:10.
  • the antibody or antibody variant is administered every 4 weeks.
  • the antibody or antibody variant is administered at a dose of 420 mg every 2 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 420 mg every 4 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 2 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 4 weeks.
  • the antibody is administered at a dose of 420 mg every 2 weeks. In various embodiments, the antibody is administered at a dose of 420 mg every 4 weeks. In various embodiments, the antibody is administered at a dose of 210 mg every 2 weeks. In various embodiments, the antibody is administered at a dose of 210 mg every 4 weeks. In various embodiments, the antibody is an lgG2 antibody. In various embodiments, the antibody is a human igG2 antibody.
  • the disclosure provides a method of treating eosinophilic esophagitis (EOE) in a subject comprising, administering an anti-TSLP antibody to the subject in a dose of 210 mg at an interval of every 4 weeks, wherein the antibody has a full- length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • EAE eosinophilic esophagitis
  • Also contemplated is a method for treating eosinophilic esophagitis (EOE) in a subject comprising, administering an anti-TSLP antibody to the subject in a dose of 420 mg at an interval of every 4 weeks, wherein the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • EAE eosinophilic esophagitis
  • the subject is also receiving treatment with proton pump inhibitors, corticosteroids, glucocorticoids, or combinations thereof.
  • the corticosteroids are oral corticosteroids (OCS) or inhaled corticosteroids (ICS) which are swallowed topical corticosteroids (STC).
  • the corticosteroids are one or more of prednisone, prednisolone, deflazacort, fluticasone, budesonide, ciclesonide, or combinations thereof.
  • the method comprises administering an anti-TSLP antibody or antibody variant in conjunction with proton pump inhibitors (PPIs), glucocorticoids, corticosteroids, or combinations thereof.
  • PPIs proton pump inhibitors
  • glucocorticoids glucocorticoids
  • corticosteroids or combinations thereof.
  • the subject is unresponsive to STC.
  • the anti-TSLP antibody variant has substantially similar pK characteristics as tezepelumab-ekko in humans.
  • the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or more.
  • the anti-TSLP antibody or antibody variant thereof is bivalent and selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG 1 antibody, an lgG2 antibody, an lgG3 antibody, and an lgG4 antibody.
  • the anti-TSLP antibody variant is selected from the group consisting of a Fab fragment, a single domain antibody, an scFv, wherein the dose is adjusted such that the binding sites are equimolar to those dosed by bivalent antibodies.
  • the anti-TSLP antibody is an anti-TSLP antibody derivative.
  • the antibody is an lgG2 antibody.
  • the antibody or antibody variant is a human antibody.
  • the antibody is tezepelumab.
  • tezepelumab is an lgG2 antibody.
  • tezepelumab has the full length heavy and light chain amino acid sequences set out in SEQ ID NOs: 13 and 14, respectively.
  • the tezepelumab is tezepelumab-ekko.
  • the antibody or antibody variant further is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
  • the subject is suffering from asthma, atopic dermatitis, allergic rhinitis/sinusitis, environmental allergies, and/or food allergies.
  • the subject is an adult or an adolescent.
  • administering decreases levels of Th2 cytokines in the subject.
  • the method improves one or more measures of EOE in a subject selected from the group consisting of histologic response of peak esophageal eosinophils per HPF count of ⁇ 6 across all available esophageal levels, EOE Endoscopic Reference Score (EREFS) (including esophageal edema, rings, exudates, furrows, and stricture), EOE-Histological Scoring System (EOE-HSS) grade score and EOE-HSS stage score (including eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina limba fibrosis) and Dysphagia Symptom Questionnaire (DSQ) score.
  • EOE Endoscopic Reference Score EREFS
  • EOE-HSS EOE-Histological Scoring System
  • EOE-HSS EOE-
  • the administration improves one or more symptoms of EOE as measured by patient diary.
  • a patient diary include, but are not limited to, Dysphagia Symptom Questionnaire (DSQ) score.
  • DSQ Dysphagia Symptom Questionnaire
  • treatment with anti-TSLP antibody or antibody variant modulates the levels of one or more biomarkers of EOE, including, serum biomarkers, urine biomarkers (e.g., markers of mast cell activation tetranor PGDM, 11 b-PGF2a, and t-MlAA), cytokines, IgE, CCL17, CCL18, CCL22, and RNA transcriptional changes in esophageal epithelium.
  • treatment with anti-TSLP reduces the level of Th2 cytokines.
  • the treatment modulates (reduces or moderates) levels of or activity of one or more of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31 , IL-33, or combinations thereof.
  • Also provided herein is a method for reducing the number of eosinophils per high- power microscopy field (HPF) in a subject having EOE, comprising administering an anti- TSLP antibody or antibody variant in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method of reducing the number of eosinophils per high-power field (HPF) (e.g., HPF microscopy) in a subject having EOE comprising administering an anti-TSLP antibody or antibody variant in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • HPF high-power field
  • Also contemplated is a method of reducing the number of eosinophils per high- power field (HPF) (e.g., HPF microscopy) in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 420 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • HPF high- power field
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method of reducing the number of eosinophils per high-power field (HPF) (e.g., HPF microscopy) in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 420 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • HPF high-power field
  • Also contemplated is a method of reducing the number of eosinophils per high- power field (HPF) (e.g., HPF microscopy) in a subject comprising, administering an anti- TSLP antibody or antibody variant to the subject in a dose of 210 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • HPF high- power field
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method of reducing the number of eosinophils per high-power field (HPF) (e.g., HPF microscopy) in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • HPF high-power field
  • the eosinophils per HPF (eos/HPF) count is reduced to ⁇ 6 across all available esophageal levels in a subject receiving treatment.
  • a method for reducing dysphagia and/or Dysphagia Symptom Questionnaire (DSQ) score in a subject having EOE comprising administering an anti-TSLP antibody or antibody variant in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method for reducing dysphagia and/or Dysphagia Symptom Questionnaire (DSQ) score in a subject having EOE comprising administering an anti-TSLP antibody or antibody variant in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • Also contemplated is a method for reducing dysphagia and/or Dysphagia Symptom Questionnaire (DSQ) score in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 420 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • DSQ Dysphagia Symptom Questionnaire
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method for reducing dysphagia and/or Dysphagia Symptom Questionnaire (DSQ) score in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 420 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • a method for reducing dysphagia and/or Dysphagia Symptom Questionnaire (DSQ) score in a subject comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b.
  • a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method for reducing dysphagia and/or Dysphagia Symptom Questionnaire (DSQ) score in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg at an interval of every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • a method a method of reducing the frequency of EOE exacerbation in a subject having EOE comprising selecting a subject in need of treatment for EOE, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method of reducing the frequency of EOE relapse in a subject having EOE comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • the disclosure provides a method of treating eosinophilic esophagitis (EOE) in a subject in need thereof comprising administering to an anti-TSLP antibody to the subject in a dose of 210 mg or 420 mg as described herein administered every 2 weeks to every 4 weeks.
  • EEE eosinophilic esophagitis
  • the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • the antibody is tezepelumab.
  • the disclosure provides a method of treating eosinophilic esophagitis (EOE) in a subject in need thereof comprising administering to the subject between 210 mg and 420 mg of anti-TSLP antibody as described herein administered over a period of two to four weeks.
  • EOE eosinophilic esophagitis
  • the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • the antibody is tezepelumab.
  • the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14. In various embodiments, the antibody is tezepelumab.
  • the disclosure provides a method for reducing the number of eosinophils in the esophagus of a subject comprising administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • Also provided is a method for reducing the number of eosinophils in the esophagus of a subject comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • the disclosure provides a method of reducing inflammation in the esophagus of a subject in need thereof comprising administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b.
  • a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method for reducing inflammation in the esophagus of a subject in need thereof comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • the disclosure provides a method reducing fibrosis associated with inflammation of the esophagus in a subject in need thereof comprising administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • a method of reducing fibrosis associated with inflammation of the esophagus in a subject in need thereof comprising, administering an anti-TSLP antibody or antibody variant to the subject in a dose of 210 mg to 420 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, and the antibody comprises a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • the subject has EOE.
  • the disclosure provides a composition comprising an anti-TSLP antibody or antibody variant for treating eosinophilic esophagitis (EOE) in a subject, wherein the composition is administered in a dose of 210 mg to 420 mg at an interval of every 2 weeks or 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, the antibody comprising a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • EOE eosinophilic esophagitis
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and, b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29- 159 of SEQ ID NO:2.
  • compositions comprising an anti-TSLP antibody or antibody variant for treating eosinophilic esophagitis (EOE) in a subject, wherein the composition is administered in a dose of 210 mg to 420 mg at an interval of every 2 weeks or 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP , the antibody comprising: a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • compositions comprising an anti-TSLP antibody or antibody variant in the manufacture of a medicament for treating eosinophilic esophagitis (EOE) in a subject, wherein the composition is in a dose of 210 mg to 420 mg for administration at an interval of every 2 weeks or 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, the antibody comprising a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill.
  • a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID N0:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • compositions comprising an anti-TSLP antibody or antibody variant in the preparation of a medicament for treating eosinophilic esophagitis (EOE), wherein the composition is in a dose of 210 mg to 420 mg for administration at an interval of every 2 weeks or 4 weeks, wherein both binding sites of the antibody are identical binding sites that bind TSLP, the antibody comprising a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill.
  • the light chain variable domain comprises the amino acid sequence set forth in in SEQ ID NO:12 and the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NQ:10.
  • the composition for treating eosinophilic esophagitis (EOE) in a subject comprises an anti-TSLP antibody, wherein the antibody is administered in a dose of 210 mg at an interval of every 4 weeks, wherein the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • a composition for treating eosinophilic esophagitis (EOE) in a subject comprises an anti-TSLP antibody, wherein the antibody is administered in a dose of 420 mg at an interval of every 4 weeks, wherein the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • the disclosure further provides for use of a composition comprising an anti-TSLP antibody in the preparation of a medicament for treating eosinophilic esophagitis (EOE), wherein the composition is in a dose of 210 mg for administration at an interval of every 4 weeks, wherein the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • EEE eosinophilic esophagitis
  • a composition comprising an anti-TSLP antibody in the preparation of a medicament for treating eosinophilic esophagitis (EOE), wherein the composition is in a dose of 420 mg for administration at an interval of every 4 weeks, wherein the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • the composition is a pharmaceutical composition comprising an anti-TSLP antibody or variant thereof and one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises an anti-TSLP antibody and a surfactant, proline, and a buffer.
  • the surfactant is polysorbate 80.
  • the buffer is selected from the group consisting of: succinate, glutamate, histidine, and acetate.
  • the formulation is at pH between 4.5 and 6.8.
  • the composition comprises anti-TSLP antibody and one or more basic amino acids (e.g., arginine, histidine or lysine) or salt thereof, or a calcium or magnesium salt, and a surfactant (e.g., polysorbate 20 or polysorbate 80).
  • the formulation is at pH between 4.5 and 6.8.
  • the antibody or antibody variant is administered every 4 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 420 mg.
  • the antibody is an lgG2 antibody.
  • the antibody has a full-length heavy chain amino acid sequence set forth in SEQ ID NO: 13 and a full-length light chain amino acid sequence set forth in SEQ ID NO: 14.
  • the antibody is tezepelumab.
  • the antibody or antibody variant is administered every 4 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 420 mg every 2 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 420 mg every 4 weeks. In various embodiments, the antibody or antibody variant is administered at a dose of 210 mg every 4 weeks.
  • the dosing and antibody and antibody variant types referenced above apply to each method, composition or use contemplated herein.
  • the antibody or antibody variant is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.
  • the administration delays the time to a EOE exacerbation or relapse compared to a subject not receiving the anti-TSLP antibody. In various embodiments, the administration reduces the severity of a EOE exacerbation or relapse compared to a subject not receiving the anti-TSLP antibody.
  • the administration is subcutaneous. In various embodiments, the administration is intravenous.
  • Syringes e.g., single use or pre-filled syringes, sterile sealed containers, e.g. vials, bottle, vessel, and/or kits or packages comprising any of the foregoing antibodies or compositions, optionally with suitable instructions for use, are also contemplated for use in the methods.
  • the administration is via pre-filled syringe or autoinjector.
  • the auto-injector is an Ypsomed YpsoMate® device.
  • each feature or embodiment, or combination, described herein is a non-limiting, illustrative example of any of the aspects of the invention and, as such, is meant to be combinable with any other feature or embodiment, or combination, described herein.
  • each of these types of embodiments is a non-limiting example of a feature that is intended to be combined with any other feature, or combination of features, described herein without having to list every possible combination.
  • Such features or combinations of features apply to any of the aspects of the invention.
  • any of values falling within ranges are disclosed, any of these examples are contemplated as possible endpoints of a range, any and all numeric values between such endpoints are contemplated, and any and all combinations of upper and lower endpoints are envisioned.
  • FIG. 1 Enrichment of TSLP gene lists in patients with EoE. *p ⁇ 0.05; **p ⁇ 0.01 ; ***p ⁇ 0.001 ; ****p ⁇ 0.000.
  • EOE eosinophilic esophagitis
  • GSVA gene set variation analyses
  • mDC myeloid dendritic cell
  • ns not significant (p > 0.05)
  • STCs swallowed topical corticosteroid
  • TSLP thymic stromal lymphopoietin.
  • Figure 2 Amino acid and nucleotide sequences of TSLP and anti-TSLP antibody.
  • This present disclosure investigates TSLP-mediated gene expression changes in patients with EOE and the effects of anti-TSLP antibody, e.g., tezepelumab, as a treatment for EOE. It is hypothesized that inhibition of upstream TSLP by tezepelumab will be effective in reducing esophageal inflammation in patients with EOE and reducing histological symptoms of EOE.
  • anti-TSLP antibody e.g., tezepelumab
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1 , 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term “about” or “approximately” precedes the first numerical value in a series of two or more numerical values, it is understood that the term “about” or “approximately” applies to each one of the numerical values in that series.
  • EOE eosinophilic esophagitis
  • EOE exacerbation refers to an acute increase in EOE symptoms, and/or relapse of symptoms and may warrant a change in regular medication.
  • cytokine refers to one or more small (5-20 kD) proteins released by cells that have a specific effect on interactions and communications between cells or on the behavior of cells, such as immune cell proliferation and differentiation. Functions of cytokines in the immune system include, promoting influx of circulating leukocytes and lymphocytes into the site of immunological encounter; stimulating the development and proliferation of B cells, T cells, peripheral blood mononuclear cells (PBMCs) and other immune cells; and providing antimicrobial activity.
  • PBMCs peripheral blood mononuclear cells
  • Exemplary immune cytokines include but are not limited to, IL-1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL- 12, IL-13, IL-15, IL17A, IL-17F, IL-18, IL-21 , IL-22, IL-23, IL-31 , IL-33, interferon (including IFN alpha, beta, and gamma), tumor necrosis factor (including TNF alpha, beta), transforming growth factor (including TGF alpha, beta), granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GMCSF) and thymic stromal lymphopoietin (TSLP).
  • interferon including IFN alpha, beta, and gamma
  • tumor necrosis factor including TNF alpha, beta
  • transforming growth factor including TGF alpha, beta
  • GCSF granulocyte colony stimulating factor
  • a “T helper (Th) 1 cytokine” or “Th 1 -specific cytokine” refers to cytokines that are expressed (intracellularly and/or secreted) by Th1 T cells, and include IFN-g, TNF-a, and IL- 12.
  • a “Th2 cytokine” or “Th2-specific cytokine” refers to cytokines that are expressed (intracellularly and/or secreted) by Th2 T cells, including IL-4, IL-5, IL-13, and IL-10.
  • Th17 cytokine or “Th17-specific cytokine” refers to cytokines that are expressed (intracellularly and/or secreted) by Th17 T cells, including IL-17A, IL-17F, IL-22 and IL-21 . Certain populations of Th17 cells express IFN-g and/or IL-2 in addition to the Th17 cytokines listed herein.
  • a polyfunctional CTL cytokine includes IFN-g, TNF-a, IL-2 and IL-17.
  • the term “specifically binds” is "antigen specific”, is “specific for”, “selective binding agent”, “specific binding agent”, “antigen target” or is “immunoreactive” with an antigen refers to an antibody or polypeptide that binds a target antigen with greater affinity than other antigens of similar sequence. It is contemplated herein that the agent specifically binds target proteins useful in identifying immune cell types, for example, a surface antigen (e.g., T cell receptor, CD3), a cytokine (e.g., TSLP, IL-4, IL-5, IL-13, IL-17, IFN-g, TNF-a) and the like. In various embodiments, the antibody specifically binds the target antigen, but can cross-react with an ortholog of a closely related species, e.g., an antibody may bind human protein and also bind a closely related primate protein.
  • a surface antigen e.g., T cell receptor, CD3
  • antibody refers to a tetrameric glycoprotein that consists of two heavy chains and two light chains, each comprising a variable region and a constant region.
  • Heavy Chains and “Light Chains” refer to substantially full-length canonical immunoglobulin light and heavy chains (see e.g., Immunobiology, 5th Edition (Janeway and Travers et al., Eds., 2001).
  • Antigen-binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies.
  • antibody includes monoclonal antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, and humanized antibodies.
  • antibody and “anti-TSLP antibody” refer to a tetrameric glycoprotein that consists of two heavy chains and two light chains, each comprising a variable region and a constant region and having an IgG 1 , lgG2, lgG3 or lgG4 Fc region.
  • Antibody variants include antibody fragments and antibody like proteins with changes to structure of canonical tetrameric antibodies.
  • antibody variants include V regions with a change to the constant regions, or, alternatively, adding V regions to constant regions, optionally in a non-canonical way.
  • Examples include antibody fragments that can bind an antigen (e.g., Fab', F'(ab)2, Fv,), biparatopic and recombinant peptides comprising the forgoing as long as they exhibit the desired biological activity.
  • Variants may comprise an Fc region from an IgG antibody, e.g., an IgG 1 , lgG2, lgG3 or lgG4 Fc region.
  • An antibody variant contemplated herein also includes antibody derivatives having the CDRs set out in SEQ ID NO: 3-8, but may have an amino acid change or chemical modification (e.g., oxidation, methylation) in a variable region amino acid of SEQ ID NO: 10 or 12, or a Fc region amino acid set out in SEQ ID NO: 13 or 14, as a result of manufacturing or purification procedures, or due to improvement in manufacturing or purification procedures.
  • Antibody variants/derivatives of tezepelumab are described in PCT/US22/25994 (International Publication WO 2022/226339) and PCT/US22/25999 (International Publication WO 2022/226342), incorporated herein by reference in their entireties.
  • Antibody fragments include antigen-binding portions of the antibody including, inter alia, Fab, Fab', F(ab')2, Fv, domain antibody (dAb), complementarity determining region (CDR) fragments, CDR-grafted antibodies, or a variant or a derivative thereof, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide, such as one, two, three, four, five or six CDR sequences, as long as the antibody retains the desired biological activity.
  • Fab fragment antigen-binding portions of the antibody including, inter alia, Fab, Fab', F(ab')2, Fv, domain antibody (dAb), complementarity determining region (CDR) fragments, CDR-grafted antibodies, or a variant or a derivative thereof, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide, such as one, two, three, four, five
  • Validation refers to the number of antigen binding sites on each antibody or antibody fragment that targets an epitope.
  • a typical full length IgG molecule, or F(ab)2 is “bivalent” in that it has two identical target binding sites.
  • a “monovalent’ antibody fragment such as a F(ab)’ or scFv with a single antigen binding site.
  • Trivalent or tetravalent antigen binding proteins can also be engineered to be multivalent.
  • “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 naturally occurring mutations that may be present in minor amounts.
  • the term “inhibits TSLP activity” includes inhibiting any one or more of the following: binding of TSLP to its receptor; proliferation, activation, or differentiation of cells expressing TSLPR in the presence of TSLP; inhibition of Th2 cytokine production in a polarization assay in the presence of TSLP; dendritic cell activation or maturation in the presence of TSLP; and mast cell cytokine release in the presence of TSLP. See, e.g., US Patent 7982016 B2, column 6 and example 8 and US 2012/0020988 A1 , examples 7-10.
  • sample refers to a specimen obtained from a subject for use in the present methods, and includes urine, whole blood, plasma, serum, saliva, sputum, skin or tissue biopsies, cerebrospinal fluid, peripheral blood mononuclear cells with in vitro stimulation, peripheral blood mononuclear cells without in vitro stimulation, gut lymphoid tissues with in vitro stimulation, gut lymphoid tissues without in vitro stimulation, gut lavage, bronchioalveolar lavage, nasal lavage, and induced sputum.
  • treat refers to eliminating, reducing, suppressing or ameliorating, either temporarily or permanently, either partially or completely, a clinical symptom, manifestation or progression of an event, disease or condition associated with an inflammatory disorder described herein.
  • drugs employed as therapeutic agents may reduce the severity of a given disease state, but need not abolish every manifestation of the disease to be regarded as useful therapeutic agents.
  • a prophylactically administered treatment need not be completely effective in preventing the onset of a condition in order to constitute a viable prophylactic agent.
  • One embodiment of the invention is directed to a method for determining the efficacy of treatment comprising administering to a patient therapeutic agent in an amount and for a time sufficient to induce a sustained improvement over baseline of an indicator that reflects the severity of the particular disorder.
  • terapéuticaally effective amount refers to an amount of therapeutic agent that is effective to ameliorate or lessen symptoms or signs of disease associated with a disease or disorder.
  • EOE is defined histologically by esophageal inflammation of > 15 EOS/HPF as obtained from biopsies from one location: either the proximal, mid, and/or distal esophagus and exclusion of secondary causes of esophageal eosinophilia.
  • additional histologic features may include eosinophil microabscesses, basal zone hyperplasia, dilated intercellular spaces, eosinophil surface layering, papillary elongation, and lamina intestinal fibrosis (Lucendo et al 2017). These diagnostic criteria are the same for both adults and adolescent patients.
  • Eosinophilic esophagitis is thought to be generally progressive, with persistent symptoms and inflammation leading to impairment of quality of life (QoL).
  • Esophageal eosinophilic, mastocytic, and lymphocytic infiltrate causes symptoms of esophageal dysfunction (Lucendo et al 2017), and chronic eosinophilic inflammation is associated with tissue remodeling with fibrosis, which may result in strictures in the esophagus.
  • Eosinophilic esophagitis prevalence is also reported to vary by ancestry.
  • a retrospective study of the demographics of EOE from over 30 million individuals’ electronic healthcare records in US-based healthcare systems found 7840 diagnoses of EOE with 89.3% in Caucasians, 6.1% in African Americans, and 5.6% in Asian backgrounds (Mansoor and Cooper 2016). These data supported earlier results of a retrospective analysis of 208 EOE cases in North Carolina where 82% were Caucasian and 12% African American (Sperry et al 2012). African American patients were younger at presentation and less likely to have esophageal rings present.
  • EOE prevalence also differs with EOE identified in 2.4% to 6% of individuals undergoing an EGD (for any cause) in the US, while only diagnosed in ⁇ 0.4% of individuals undergoing EGD in China (Dellon and Hirano 2018). Yet in all cohorts, the prevalence of EOE is recognized to be increasing.
  • JORVEZA® orodispersible budesonide tablet
  • DUPIXENT® diupilumab
  • Esophageal dilation may be used as an effective therapy in symptomatic patients with strictures that persist despite medical or dietary therapy. Although considered minimally invasive, esophageal dilation may cause bruising, soreness, and difficulty swallowing after the procedure and has an inherent risk of perforation and even mediastinitis. Moreover, dilation does not address esophageal inflammation associated with EOE (Hirano et al 2020a). Because of ongoing fibrotic processes that persist in the tissue of the esophagus, patients may require repeated dilations over time. As EOE is chronic and symptoms recur when treatments are discontinued, maintenance therapy should be considered in all patients (Dellon et al 2013).
  • Dupilumab a dual inhibitor of IL-4 and IL-13 signaling, is the only biologic approved (in the US) for the treatment of EOE.
  • Studies in patients with EOE have shown evidence of the efficacy of IL-4 receptor inhibition and esophageal tissue eosinophil depletion following treatment with dupilumab (Hirano et al 2020b).
  • dupilumab showed significant improvements in clinical, endoscopic, histologic, symptomatic, and molecular measures of EOE (Dellon et al 2020b, Chehade et al 2021 , Rothenberg et al 2022).
  • Eosinophilic and mastocytic inflammation is central to the pathophysiology of EOE; hence, therapies that target one or more of these cell types, such as tezepelumab, which selectively blocks TSLP from interacting with its heterodimeric receptor, may provide a safe and effective treatment option for patients with EOE.
  • the key goals of treatment for EOE are to decrease the signs and symptoms of the disease. These goals can be achieved by reducing esophageal eosinophilic inflammation. It is presumably through persistent esophageal eosinophilic inflammation that patients with EOE have an increased risk of progression to fibrostenosis and an increased potential for complications from food impactions (Warners et al 2018). Reducing the progression of esophageal eosinophilic inflammation to esophageal fibrosis may lead to avoidance of stricture formation and subsequent lower need for esophageal dilation, failure to thrive in children, and improvement in patient QoL.
  • Thymic stromal lymphopoietin is an epithelial cell-derived cytokine that is produced in response to pro-inflammatory stimuli and drives allergic inflammatory responses primarily through its activity on dendritic cells (Gilliet, J Exp Med. 197:1059-1067, 2003;
  • TSLP signals through a heterodimeric receptor consisting of the interleukin (IL)-7 receptor alpha (IL-7Ra) chain and a common y chain-like receptor (TSLPR) (Pandey, Nat Immunol. 1 :59- 64, 2000; Park, J Exp Med. 192:659-669, 2000).
  • IL-7Ra interleukin-7 receptor alpha
  • TSLPR common y chain-like receptor
  • Tezepelumab selectively blocks TSLP from interacting with its heterodimeric receptor.
  • tezepelumab has demonstrated important benefits in both a Phase lib study (PATHWAY; Corren et al 2017) and a Phase III study (NAVIGATOR; Menzies-Gow et al 2021 ) in reducing exacerbations and improving lung function, asthma control, and asthma-related QoL.
  • Tezepelumab has been shown to decrease eosinophilic infiltration of the bronchial submucosa in asthma patients through bronchoscopy biopsy (CASCADE; Diver et al 2021).
  • TSLP-driven eosinophilic inflammation is a central finding in EOE.
  • tezepelumab By blocking the interaction of TSLP with its heterodimeric receptor and interfering with multiple downstream inflammatory pathways, tezepelumab has the potential to reduce the initiation and persistence of esophageal eosinophilia and inflammation which are important factors in the histologic pathogenesis of EOE.
  • Specific binding agents such as antibodies and antibody variants or fragments that bind to their target antigen, e.g., TSLP, are useful in the methods of the disclosure.
  • the specific binding agent is an antibody.
  • the antibodies may be monoclonal (MAbs); recombinant; chimeric; humanized, such as complementarity-determining region (C DR) -grafted; human; antibody variants, including single chain; and/or bispecific; as well as fragments; variants; or derivatives thereof.
  • Antibody fragments include those portions of the antibody that bind to an epitope on the polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments generated by enzymatic cleavage of full-length antibodies.
  • Other binding fragments include those generated by recombinant DNA techniques, such as the expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions.
  • Monoclonal antibodies may be modified for use as therapeutics or diagnostics.
  • One embodiment is a "chimeric" antibody in which a portion of the heavy (H) and/or light (L) chain is identical with or homologous to a corresponding sequence in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is/are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass.
  • fragments of such antibodies so long as they exhibit the desired biological activity. See U.S. Pat. No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81 :6851- 55.
  • a monoclonal antibody is a "humanized" antibody.
  • Methods for humanizing non-human antibodies are well known in the art. See U.S. Pat. Nos. 5,585,089 and 5,693,762.
  • a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human.
  • Humanization can be performed, for example, using methods described in the art (Jones et al., 1986, Nature 321 :522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36), by substituting at least a portion of a rodent complementarity-determining region (CDR) or framework region for the corresponding regions of a human antibody.
  • CDR rodent complementarity-determining region
  • framework region for example, with CDR-grafting, non-human CDR sequences are inserted into human framework regions (Lu et al. Journal of Biomedical Science (2020) 27:1).
  • Human antibody refers to an antibody generated from human immunoglobulin sequences and comprising human variable and constant regions.
  • transgenic animals e.g., mice
  • a polypeptide antigen i.e., having at least 6 contiguous amino acids
  • a carrier e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci.
  • Human antibodies can also be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells, using phage display libraries, or by single B cell cloning (Lu et al. Journal of Biomedical Science (2020) 27:1 ).
  • Chimeric, CDR grafted, and humanized antibodies and/or antibody variants are typically produced by recombinant methods. Nucleic acids encoding the antibodies are introduced into host cells and expressed using materials and procedures described herein. In a preferred embodiment, the antibodies are produced in mammalian host cells, such as CHO cells. Monoclonal (e.g., human) antibodies may be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein. [0124] Antibodies and antibody variants (including antibody fragments) useful in the present methods comprise an anti-TSLP antibody comprising: a. a light chain variable domain comprising: i.
  • a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and, b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody or antibody variant specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
  • an antibody or antibody variant comprising a. a light chain variable domain selected from the group consisting of: i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11 ; ill. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11 ; and, b. a heavy chain variable domain selected from the group consisting of: i.
  • Tezepelumab is an exemplary anti-TSLP antibody having: a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; ill. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and ill. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8.
  • Tezepelumab also comprises a light chain variable domain having the amino acid sequence set out in SEQ ID NO:12; encoded by a polynucleotide sequence set out in SEQ ID N0:11 ; and a heavy chain variable domain having the amino acid sequence set out in SEQ ID NO:10, encoded by a polynucleotide sequence set out in SEQ ID NO:9.
  • Tezepelumab is an lgG2 antibody.
  • Exemplary sequences of tezepelumab are also set out in US Patent 7,982,016 SEQ ID NOs: 13, 60, 105, 145, 173, 212; SEQ ID NOs: 361 and 363; and a light chain comprising a light chain variable domain comprising the amino acid sequence as set forth in SEQ ID NO:363 and a lambda light chain constant domain comprising the amino acid sequence as set forth in SEQ ID NO:369; and a heavy chain comprising a heavy chain variable domain comprising the amino acid sequence as set forth in SEQ ID NO:361 and an lgG2 heavy constant domain comprising the amino acid sequence as set forth in SEQ ID NO:365, herein incorporated by reference.
  • anti-TSLP antibody derivatives are described in International Patent Publications WO 2022/226342 and WO 2022/226339, incorporated herein by reference in their entireties.
  • Exemplary derivatives include tezepelumab antibodies that may have modifications after purification of antibody or after long term storage, including but not limited to, an isomerization derivative, a deamidation derivative, an oxidation derivative, a glycosylation derivative, disulfide isoform derivatives, and/or high molecular weight (HMW) species or antibody fragments.
  • HMW high molecular weight
  • Exemplary derivatives may also be variants that have the amino acid sequences set out in SEQ ID NOs: 13-36 of WO2022/226342 as well as variants therein of SEQ ID NO: 3-8, e.g., including residues identified as possible sources of reduced stability in anti-TSLP antibody tezepelumab CDRs (SEQ ID NOs: 3-8) or in the variable region (SEQ ID NOs: 10 and 12), which include CDRH1 M34, CDRH2 W52, CDRH2 D54, CDRH2 N57, CDRH2 D62, CDRH3 W102, FRH1 N25, FRH1 N26, CDRL2 D49, CDRL2 D50, FRL2 N65, CDRL3 W90, CDRL3 D91 , CDRL3 S92,S93,S94, and/or CDRL3 D95.
  • SEQ ID NOs: 3-8 residues identified as possible sources of reduced stability in anti-TSLP antibody tezepelumab CDRs
  • the anti-TSLP antibody or antibody variant thereof is bivalent and selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG 1 antibody, an lgG2 antibody, an lgG3 antibody, and an lgG4 antibody.
  • the anti-TSLP antibody is bivalent and selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an IgG 1 antibody, an lgG2 antibody, an lgG3 antibody, and an lgG4 antibody.
  • the antibody or antibody variant is an lgG2 antibody.
  • Exemplary sequences for a human lgG2 constant region are available from the Uniprot database as Uniprot number P01859, incorporated herein by reference. Information, including sequence information for other antibody heavy and light chain constant regions is also publicly available through the Uniprot database as well as other databases well-known to those in the field of antibody engineering and production.
  • the anti-TSLP antibody variant or anti-TSLP derivative has substantially similar pK characteristics as tezepelumab-ekko in humans.
  • derivatives of antibodies include tetrameric glycosylated antibodies wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a parent polypeptide.
  • variants comprise a greater or a lesser number of N-linked glycosylation sites than the native protein.
  • substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain.
  • rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created.
  • Additional preferred antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the parent amino acid sequence.
  • Cysteine variants may be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines.
  • amino acid substitutions can be used to identify important residues of antibodies to human TSLP, or to increase or decrease the affinity of the antibodies to human TSLP described herein.
  • preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and/or (4) confer or modify other physiochemical or functional properties on such polypeptides.
  • single or multiple amino acid substitutions may be made in the naturally-occurring sequence (in certain embodiments, in the portion of the polypeptide outside the domain(s) forming intermolecular contacts).
  • a conservative amino acid substitution typically may not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence).
  • a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence.
  • Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991 ), which are each incorporated herein by reference.
  • anti-TSLP antibodies useful to treat EOE as described herein also include those described in the publications set out in Table 1 and described in WO2023098491A1 , WO2021155634A1 , WO2022166072A1 , WO2021043221 A1 , WO2022184074A1 , WO2021104053A1 , WO2023116925A1 , WO2021155861 A1 , WO2022116858A1 , WO2022117079A1 , WO2020244544A1 , WO2021152488A1 , WO2022253147A1 , W02023070948A1 , WO2023142309A1 , WO2022095689A1 , WO2021115240A1 , WO2022166739A1 and W02019100111 A1 , the
  • methods of the present disclosure include a step of administering a therapeutic anti-TSLP antibody or antibody variant described herein, optionally in a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is a sterile composition.
  • Contemplated herein are methods for treating EOE in a subject.
  • the method comprises selecting a subject in need of treatment for EOE, and administering an anti-TSLP antibody as described herein.
  • the antibody is tezepelumab or tezepelumab variant or tezepelumab derivative.
  • the subject to be treated is human.
  • the subject may be an adult or an adolescent.
  • Therapeutic antibody (or antibody variant) compositions may be delivered to the patient at multiple sites.
  • the multiple administrations may be rendered simultaneously or may be administered over a period of time. In certain cases it is beneficial to provide a continuous flow of the therapeutic composition. Additional therapy may be administered on a period basis, for example, hourly, daily, weekly, every 2 weeks, every 3 weeks, monthly, bimonthly, or at a longer interval.
  • the amounts of therapeutic agent, such as a bivalent antibody having two TSLP binding sites, in a given dosage may vary according to the size of the individual to whom the therapy is being administered as well as the characteristics of the disorder being treated.
  • the anti-TSLP antibody or antibody variant is administered in a dose range of about 210 mg to about 420 mg per dose.
  • the anti-TSLP antibody or antibody variant may be administered at a dose of about 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410 or 420 mg per dose.
  • concentrations may be administered as a single dosage form or as multiple doses. The above doses are given every two weeks or every four weeks.
  • the anti-TSLP antibody or antibody variant is administered at a single dose of 420 mg every two weeks or every four weeks.
  • the anti-TSLP antibody or antibody variant is administered at a single dose of 420 mg every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered at a single dose of 210 mg every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered at a single dose of 210 mg every four weeks. In various embodiments, the disclosure provides methods of treating eosinophilic esophagitis (EOE) in a subject in need thereof comprising administering to the subject between 210 mg and 420 mg of anti-TSLP antibody as described herein administered over a period of two to four weeks.
  • EOE eosinophilic esophagitis
  • the amount of antibody variant should be such that the number of TSLP binding sites that are in the dose have an equimolar number of TSLP binding sites to canonical bivalent antibody described above.
  • the anti-TSLP antibody or antibody variant is administered every 2 weeks or every 4 weeks for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or more.
  • the administration is subcutaneous or intravenous. In various embodiments, the administration is subcutaneous.
  • T reatment with the anti-TSLP antibody or antibody variant is contemplated to improve one or more measures of EOE including decrease in peak esophageal eosinophils per HPF (eos/hpf) count of ⁇ 6 across all available esophageal levels, EOE Endoscopic Reference Score (EREFS) (including esophageal edema, rings, exudates, furrows, and stricture), EOE- Histological Scoring System (EOE-HSS) grade score and EOE-HSS stage score (including eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina limba fibrosis), esophageal fibrosis, dysphagia and Dysphagia Symptom Questionnaire (DSQ) score.
  • EOE Endoscopic Reference Score e
  • the administration improves one or more symptoms of EOE including, but not limited to, DSQ score, histological measures, such as number or severity of strictures, Histological Scoring System (EOE-HSS) grade score and EOE-HSS stage score.
  • EOE-HSS Histological Scoring System
  • the peak eos/HPF in treated patients decreases to at least ⁇ 15 eos/HPF.
  • treatment with anti-TSLP modulates the levels of one or more biomarkers of EOE, including, serum biomarkers, urine biomarkers (e.g., markers of mast cell activation tetranor PGDM, 11 b-PGF2a, and t-MlAA), cytokines, IgE, CCL17, CCL18, CCL22, and RNA transcriptional changes in esophageal epithelium.
  • treatment with anti-TSLP reduces the level of Th2 cytokines.
  • the treatment modulates levels of or activity of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31 , and/or IL-33, or combinations thereof.
  • treatment with the anti-TSLP antibody delays the time to a EOE exacerbation or relapse compared to a subject not receiving the anti-TSLP antibody.
  • treatment results in remission of EOE.
  • the treatment reduces esophageal inflammation.
  • agents such as an antibody composition in conjunction with a second agent as described herein, including but not limited to an anti-inflammatory agent, antibiotic or EOE therapy, such as leukotriene inhibitor, glucocorticoids, proton pump inhibitor (PPI), potassiumcompetitive acid blockers, or swallowed topical corticosteroids (STC).
  • antibiotic or EOE therapy such as leukotriene inhibitor, glucocorticoids, proton pump inhibitor (PPI), potassiumcompetitive acid blockers, or swallowed topical corticosteroids (STC).
  • PPI proton pump inhibitor
  • STC swallowed topical corticosteroids
  • Exemplary leukotriene inhibitors include montelukast, zafirlukast and zileuton.
  • the subject is also receiving treatment with corticosteroids.
  • the swallowed topical corticosteroids are selected from the group consisting of budesonide, fluticasone mometasone, deflazacort, prednisone, prednisolone, ciclesonide, and beclomethasone or combinations thereof.
  • the method comprises administering anti-TSLP antibody or antibody variant in conjunction with a co-administered therapy, e.g., PPI, or STC.
  • a co-administered therapy e.g., PPI, or STC.
  • the subject is unresponsive to treatment with STCs.
  • the disclosure contemplates use of pharmaceutical compositions comprising a therapeutically effective amount of an anti-TSLP antibody or antibody variant together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and/or adjuvant.
  • the disclosure provides methods of treating a subject by administering such pharmaceutical composition.
  • acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.
  • the pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCI, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)) ; complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, sucrose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; e
  • amino acids
  • a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, and may further include sorbitol or a suitable substitute therefor.
  • the formulation components are present preferably in concentrations that are acceptable to the site of administration.
  • buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 4.5 to about 8. Including about 4.5, about 4.6, about 4.7, about 4.8, about 4.9., about 5.0, about 5.1 , about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about
  • the anti-TSLP antibody or antibody variant is in a formulation containing one or more basic amino acids (e.g., arginine, histidine or lysine) or salt thereof, or a calcium or magnesium salt, and a surfactant.
  • the formulation comprises 0.005% (w/v) to about 0.015% (w/v) polysorbate 20 or polysorbate 80.
  • the formulation is at pH between 4.5 and 6.8.
  • the antibody or antibody fragment in the formulation is at a concentration of greater than 110 mg/ml, e.g., from about 110 mg/ml to about 250 mg/ml, e.g., from about 140 mg/ml to about 250 mg/ml, from about 160 mg/mL to about 250 mg/mL, or from about 140 mg/mL to about 210 mg/mL, or about 180 mg/ml or about 210 mg/ml.
  • the formulation may be stored at 2°to 8° C or -20°to -70° C. Exemplary formulations are described in coowned application PCT/US2021/17880, incorporated herein by reference.
  • the anti-TSLP antibody or antibody variant is in a formulation comprising greater than about 100 mg/mL of an anti-TSLP antibody, a surfactant, proline, and a buffer.
  • the surfactant e.g., polysorbate 80
  • the composition comprises equal to or less than about 3.0% (w/v) proline, e.g., about 2.4% (w/v) to about 2.8% (w/v) proline or about 2.5% (w/v) to about 2.8% (w/v) proline.
  • the proline is L-proline. In certain aspects, proline is the only amino acid present in the composition.
  • the buffer is selected from the group consisting of: succinate, glutamate, histidine, and acetate. In some embodiments, the buffer is acetate.
  • the composition comprises about 1 mM to about 50 mM buffer, e.g., about 10 mM to about 30 mM buffer, optionally, about 15 mM to about 30 mM buffer, about 20 mM to about 30 mM buffer, or about 10 mM to about 25 mM buffer. Exemplary formulations are described in coowned application PCT/US2021/018561 , incorporated herein by reference.
  • the anti-TSLP antibody or antibody variant is administered in a dose of 110 mg/mL in 10 mM acetate, 3.0% (w/v) L-proline, 0.01 % (w/v) polysorbate 80, at pH 5.2.
  • tezepelumab is administered in a dose of 110 mg/mL in 10 mM acetate, 3.0% (w/v) L-proline, 0.01 % (w/v) polysorbate 80, at pH 5.2.
  • the therapeutic compositions for use may be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired anti-TSLP antibody in a pharmaceutically acceptable vehicle.
  • a particularly suitable vehicle for parenteral injection is sterile distilled water in which the antibody is formulated as a sterile, isotonic solution, properly preserved.
  • the preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that may provide controlled or sustained release of the product which can be delivered via depot injection.
  • hyaluronic acid may also be used, having the effect of promoting sustained duration in the circulation.
  • implantable drug delivery devices may be used to introduce the antibody.
  • the administration may be via prefilled syringe or autoinjector.
  • the auto-injector is an Ypsomed YpsoMate®.
  • the auto-injector is disclosed in WO 2018/226565, WO 2019/094138, WO 2019/178151 , WO 20120/072577, W02020/081479, WO 2020/081480, PCT/US20/70590, PCT/US20/70591 , PCT/US20/53180, PCT/US20/53179, PCT/US20/53178, or PCT/US20/53176.
  • kits which comprise one or more compounds or compositions packaged in a manner which facilitates their use to practice methods of the disclosure.
  • a kit includes a compound or composition described herein, packaged in a container such as a sealed bottle or vessel, with a label affixed to the container or included in the package that describes use of the compound or composition in practicing the method.
  • the compound or composition is packaged in a unit dosage form for administration as described herein.
  • the kit may further include a device suitable for administering the composition according to a specific route of administration or for practicing a screening assay.
  • the kit contains a label that describes use of the antibody composition.
  • This analysis aimed to determine whether TSLP-mediated gene expression changes are enriched in patients with EOE to understand whether tezepelumab could be a potential treatment for EOE.
  • TSLP gene lists were generated from two independent transcriptomic data sets obtained from: 1) bronchial brushings at week 28 from patients with moderate-to-severe, uncontrolled asthma treated with tezepelumab in the phase 2 CASCADE study (NCT03688074); and 2) human myeloid dendritic cells treated ex vivo with recombinant TSLP for 24 hours.
  • the TSLP gene lists were composed of 18 upregulated genes and 32 downregulated genes in bronchial brushings from CASCADE, and 183 upregulated and 161 downregulated genes in myeloid dendritic cells (Figure 1).
  • the TSLP gene lists identified were enriched in patients with active EOE, including those unresponsive to STCs, compared with healthy individuals. Compared with patients with inactive treated EOE, TSLP gene lists were enriched in patients with active EOE that was unresponsive to STCs.
  • the first evidence suggesting a role for TSLP in EOE pathogenesis involved the identification of genetic risk variants in the TSLP locus and demonstration of increased TSLP gene expression in the esophagus of patients with EOE that is influenced by the TSLP SNP genotype (Rothenberg et al 2010), a linkage replicated in studies using genome-wide and candidate gene approaches (Sherrill et al 2010, Kottyan et al 2014). Esophageal levels of both TSLP messenger RNA and protein are elevated in EOE, and it has been shown that TSLP gene expression in the esophagus returns to baseline levels during disease remission (Noti et al 2013).
  • Recombinant TSLP has shown to be sufficient to drive esophageal eosinophilia and structural changes in the esophageal tissue (e.g., thickening and fibrosis) in an aeroallergen-induced mouse model of EOE (Collins et al 2017, Collison et al 2015).
  • tezepelumab has reduced blood eosinophils in both adolescents and adults (Menzies-Gow et al 2021), and reduction in blood eosinophils may correlate with EOE disease activity and esophageal tissue eosinophils (Colson et al 2014, Konikoff et al 2006, Rodnguez-Sanchez et al 2001). Tezepelumab has also been demonstrated to significantly reduce submucosal eosinophils in the airways of severe asthma participants compared to placebo (Diver et al 2021).
  • the aim of this global Phase III study is to investigate the use of tezepelumab as a treatment for patients with EOE.
  • This study will evaluate the efficacy and safety of tezepelumab 210 mg every 4 weeks (Q4W) and tezepelumab 420 mg Q4W administered subcutaneously (SC) using an accessorized pre-filled syringe (APFS) versus placebo in adult and adolescent participants with EOE.
  • Q4W tezepelumab 210 mg every 4 weeks
  • APFS accessorized pre-filled syringe
  • the study consists of a screening/run-in period of 2 to 8 weeks and a 52-week randomized double-blind placebo-controlled treatment period. After completion of the treatment period, participants will be eligible to participate in an optional 24-week active treatment extension period, followed by a 12-week off-treatment safety follow-up period. Participants who choose not to participate in the optional active treatment extension period will participate in a 12- week off treatment safety follow-up period following completion of the 52-week treatment period.
  • Participant must be 12 to 80 years of age inclusive, at the time of signing the informed consent/assent.
  • stable diet is defined as no initiation of single or multiple elimination diets or reintroduction of previously eliminated food groups.
  • participant must have the diagnosis of active EOE confirmed during the screening period of this study by a centrally read esophageal biopsy (confirmed diagnosis defined as an eosinophil count of > 15 EOS/HPF at 2 or more esophageal levels).
  • esophageal biopsy confirmed diagnosis defined as an eosinophil count of > 15 EOS/HPF at 2 or more esophageal levels.
  • Two to four biopsies should be obtained from both the proximal and distal esophagus. Two to four biopsies can be taken from the mid-esophagus for additional evaluation.
  • participant must have been adherent to daily diary assessments: (a) Must have completed 70% of daily diary entries between Visit 1 and Visit 2 AND (b) Must have at least 8 non-missing DSQ daily scores in the 14 days prior to randomization.
  • participant At randomization, participant must have symptomatic EOE as defined by > 4 episodes of dysphagia (DSQ > 2) over the 2 weeks prior to randomization, documented in an eDiary, of which > 2 episodes require liquids, coughing, or gagging, vomiting or medical attention to obtain relief (DSQ > 3).
  • Exclusion criteria include:
  • [0192] 1 Other gastrointestinal disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, EGE, EG, eosinophilic enteritis, colitis, diverticulitis, irritable bowel syndrome, or other clinically significant gastrointestinal conditions as per investigator discretion.
  • Other gastrointestinal disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, EGE, EG, eosinophilic enteritis, colitis, diverticulitis, irritable bowel syndrome, or other clinically significant gastrointestinal conditions as per investigator discretion.
  • Solid food is defined as food that requires chewing before swallowing.
  • Hypereosinophilic syndrome defined by multiple organ involvement and persistent blood eosinophil count > 1500 eosinophils/pL.
  • Tezepelumab is administered as a 110 mg/mL solution for injection in 10 mM acetate, 3.0% (w/v) L-proline, 0.01% (w/v) polysorbate 80, pH 5.2 given 210 mg once every 4 weeks (Q4W) or 420 mg Q4W by SC injection.
  • Placebo is administered 0.7% (w/v) sodium carboxy methyl cellulose in 10 mM acetate, 250 mM L-proline, 0.01% (w/v) polysorbate 80, pH 5.0, solution for injection, Q4W by SC injection.
  • EOE-HSS EOE-Histological Scoring System
  • EOE-HSS is a histology scoring system for esophageal biopsies that evaluates 8 features: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina intestinal fibrosis. Severity (grade) and extent (stage) of abnormalities are scored using a 4-point scale (0 normal; 3 maximum change) (Collins et al 2017).
  • EOE Endoscopic Reference Score (EOE EREFS)
  • the EOE EREFS is a scoring system for assessing the presence and severity of the major endoscopic signs of EOE, including esophageal edema, rings, exudates, furrows, and stricture.
  • the EOE EREFS will be evaluated at the time of each biopsy collection.
  • DSQ Dysphagia Symptom Questionnaire
  • the DSQ is a PRO measure validated for participants aged 12 and older with dysphagia related to EOE (Dellon et al 2013). The presence and severity of dysphagia symptoms in the past day are captured in a 4-item questionnaire. Questions 1 and 2 utilize yes/no response capture if the participant consumed solid food that day (yes/no; unscored) and instances of food going down slowly or becoming stuck in the throat or chest (scored 0 for no and 2 for yes). If the participant reports not eating solid food, then the DSQ is considered missing for that day.
  • Question 3 asks about the severity of dysphagia, based on actions the participant took to relieve the dysphagia at its worst point during the day.
  • Diasphagia cleared up on its own It ranges from 0 (dysphagia cleared up on its own) to 4 (participant sought medical attention for dysphagia).
  • Question 4 asks the participant to report the worst pain experienced while swallowing food over the past 24 hours (no pain [0] to very severe pain [4]).
  • the total DSQ score ranges from 0 to 84, with a lower score indicating less severe dysphagia.
  • Questions 2 and 3 are the only questions that contribute to the total DSQ score.
  • the score is calculated by multiplying the daily scores of questions 2 and 3 by 14 days and dividing by the number of days in the past 14 days with no missing data.
  • Question 4 is a standalone item intended to be evaluated separately.
  • the MCID and CID in DSQ score (mean absolute change) were estimated to be -6.5 points and -13.5 points, respectively (Hudgens et al 2017).
  • dysphagia-free days over each 28-day period following randomization will also be summarized.
  • PEESS Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2, Children and Teens Report (PEESS)
  • the PEESS is a 20-item assessment of EoE symptom severity and frequency validated for use in participants aged 8 to 18 years. The recall period is 1 month. The first 18 questions alternate between a question about a given symptom’s frequency (never, almost never, sometimes, often, almost always) and a question about the symptom’s severity (face rating scale with drawings representing not bad at all, a little bad, kind of bad, bad, very bad). The remaining 2 questions ask about frequency of eating less food than others and frequency of needing more time to eat than others. The overall score ranges from 0 to 100, with higher scores representing more severe and frequent EoE symptoms.
  • Histologic Response Rate The proportion of participants achieving histologic response of peak esophageal eosinophil per HPF count of ⁇ 6 across all available esophageal levels at Week 24 will be compared between each tezepelumab dose and placebo using CMH test controlling for region (Asia vs Rest of World), age category (adults vs adolescents), baseline STC use (yes vs no), and baseline strictures (yes vs no). Participants with strictures severe enough to prevent easy passage of a standard EGD or any critical esophageal stricture that requires dilation are excluded from the study but participants with milder strictures may be enrolled. The baseline stricture status is considered prognostic and adjusted in addition to the stratification factors.
  • Strata may be pooled in case of sparse data and the pooling strategy will be described in the SAP.
  • the results of the analysis will be presented using an odds ratio, together with its associated 95% Cis and 2-sided p-value. Participants receiving rescue therapy or discontinued IP due to reasons related to the treatment prior to Week 24 will be considered as non- responders. Missing biopsy data due to other reasons at Week 24 will be imputed assuming MAR.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente divulgation concerne, en général, des méthodes de traitement de l'œsophagite à éosinophiles (EOE) à l'aide d'un anticorps spécifique pour la lymphopoïétine stromale thymique (TSLP).
PCT/US2024/024850 2024-04-17 2024-04-17 Traitement de l'œsophagite à éosinophiles avec un anticorps anti-tslp Pending WO2025221247A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2024/024850 WO2025221247A1 (fr) 2024-04-17 2024-04-17 Traitement de l'œsophagite à éosinophiles avec un anticorps anti-tslp
PCT/US2025/025157 WO2025221995A1 (fr) 2024-04-17 2025-04-17 Traitement de l'œsophagite à éosinophiles à l'aide d'un anticorps anti-tslp

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2024/024850 WO2025221247A1 (fr) 2024-04-17 2024-04-17 Traitement de l'œsophagite à éosinophiles avec un anticorps anti-tslp

Publications (1)

Publication Number Publication Date
WO2025221247A1 true WO2025221247A1 (fr) 2025-10-23

Family

ID=91128175

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2024/024850 Pending WO2025221247A1 (fr) 2024-04-17 2024-04-17 Traitement de l'œsophagite à éosinophiles avec un anticorps anti-tslp
PCT/US2025/025157 Pending WO2025221995A1 (fr) 2024-04-17 2025-04-17 Traitement de l'œsophagite à éosinophiles à l'aide d'un anticorps anti-tslp

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2025/025157 Pending WO2025221995A1 (fr) 2024-04-17 2025-04-17 Traitement de l'œsophagite à éosinophiles à l'aide d'un anticorps anti-tslp

Country Status (1)

Country Link
WO (2) WO2025221247A1 (fr)

Citations (37)

* 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
EP0546073A1 (fr) 1990-08-29 1993-06-16 Genpharm Int Animaux non humains transgeniques capables de produire des anticorps heterologues.
US5545807A (en) 1988-10-12 1996-08-13 The Babraham Institute Production of antibodies from transgenic animals
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US7982016B2 (en) 2007-09-10 2011-07-19 Amgen Inc. Antigen binding proteins capable of binding thymic stromal lymphopoietin
US20120020988A1 (en) 2010-07-15 2012-01-26 Hoffmann-La Roche Inc. Antibodies specifically binding to human TSLPR and methods of use
WO2012072577A1 (fr) 2010-11-30 2012-06-07 Erwin Steiner Dispositif de montage pour éléments de façade
US9100245B1 (en) 2012-02-08 2015-08-04 Amazon Technologies, Inc. Identifying protected media files
US9306926B2 (en) 2013-03-15 2016-04-05 Brian A. Truong User authentication using unique hidden identifiers
US9605928B2 (en) 2007-09-17 2017-03-28 J. Craig Oxford Apparatus and method for broad spectrum radiation attenuation
WO2018226565A1 (fr) 2017-06-08 2018-12-13 Amgen Inc. Dispositif d'administration de médicament entraîné par couple
WO2019094138A1 (fr) 2017-11-10 2019-05-16 Amgen Inc. Pistons pour dispositifs d'administration de médicament
WO2019100111A1 (fr) 2017-11-21 2019-05-31 Monash University Méthodes de traitement et de diagnostic d'états
WO2019178151A1 (fr) 2018-03-13 2019-09-19 Amgen Inc. Procédés de préparation de polypeptides résistant à la trypsine pour analyse par spectrométrie de masse
WO2020081479A1 (fr) 2018-10-15 2020-04-23 Amgen Inc. Dispositif d'administration de médicament comprenant un mécanisme d'amortissement
WO2020081480A1 (fr) 2018-10-15 2020-04-23 Amgen Inc. Procédé d'assemblage de plate-forme pour dispositif d'administration de médicament
WO2020244544A1 (fr) 2019-06-04 2020-12-10 江苏恒瑞医药股份有限公司 Anticorps capable de se lier à la lymphopoïétine stromale thymique et son utilisation
WO2021043221A1 (fr) 2019-09-04 2021-03-11 Biosion Inc. Anticorps se liant à tslp et leurs utilisations
WO2021104053A1 (fr) 2019-11-29 2021-06-03 康诺亚生物医药科技（成都）有限公司 Développement et utilisation d'agents thérapeutiques pour des maladies associées à tslp
WO2021115240A1 (fr) 2019-12-13 2021-06-17 四川科伦博泰生物医药股份有限公司 Anticorps anti-tslp et utilisations de celui-ci
WO2021152488A1 (fr) 2020-01-29 2021-08-05 Novartis Ag Méthodes de traitement d'une maladie inflammatoire ou obstructive des voies respiratoires à l'aide d'un anticorps anti-tslp
WO2021155861A1 (fr) 2020-02-07 2021-08-12 北京汇智和源生物技术有限公司 Anticorps monoclonal humain de lymphopoïétine stromale thymique et son utilisation
WO2021155634A1 (fr) 2020-02-05 2021-08-12 北京智仁美博生物科技有限公司 Anticorps anti-tslp humaine et son utilisation
WO2022095689A1 (fr) 2020-11-06 2022-05-12 上海麦济生物技术有限公司 Anticorps dirigé contre la lymphopoïétine stromale thymique humaine, son procédé de préparation et son utilisation
WO2022117079A1 (fr) 2020-12-03 2022-06-09 江苏恒瑞医药股份有限公司 Anticorps pouvant se lier à la lymphopoïétine stromale thymique et son utilisation
WO2022116858A1 (fr) 2020-12-03 2022-06-09 江苏恒瑞医药股份有限公司 Composition pharmaceutique d'anticorps anti-tslp et son utilisation
WO2022166739A1 (fr) 2021-02-04 2022-08-11 Staidson (Beijing) Biopharmaceuticals Co., Ltd. Anticorps reconnaissant spécifiquement la lymphopoïétine stromale thymique et leurs utilisations
WO2022166072A1 (fr) 2021-02-03 2022-08-11 北京智仁美博生物科技有限公司 Anticorps contre la tslp humaine et leur utilisation
WO2022184074A1 (fr) 2021-03-03 2022-09-09 正大天晴药业集团股份有限公司 Composition pharmaceutique contenant un anticorps anti-tslp
WO2022226339A1 (fr) 2021-04-23 2022-10-27 Amgen Inc. Compositions d'anticorps anti-tslp et leurs utilisations
WO2022226342A2 (fr) 2021-04-23 2022-10-27 Amgen Inc. Anticorps anti-tslp modifiés
WO2022253147A1 (fr) 2021-06-02 2022-12-08 启愈生物技术(上海)有限公司 Anticorps anti-lymphopoïétine stromale thymique (tslp) et son utilisation
WO2023070948A1 (fr) 2021-11-01 2023-05-04 江苏荃信生物医药股份有限公司 Procédé de préparation d'une solution concentrée contenant un anticorps monoclonal anti-lymphopoïétine stromale thymique humaine (tslp), et préparation liquide
WO2023098491A1 (fr) 2021-12-02 2023-06-08 北京东方百泰生物科技股份有限公司 Anticorps monoclonal anti-tslp, fragment de liaison à l'antigène de celui-ci et son utilisation
WO2023116925A1 (fr) 2021-12-24 2023-06-29 Inmagene Biopharmaceuticals (Hangzhou) Co., Ltd. Nouveaux anticorps anti-tslp
WO2023142309A1 (fr) 2021-02-05 2023-08-03 上海洛启生物医药技术有限公司 Nanocorps anti-tslp et son utilisation
WO2023166418A2 (fr) * 2022-03-03 2023-09-07 Pfizer Inc. Anticorps multispécifiques et leurs utilisations

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20250154267A2 (en) * 2020-05-22 2025-05-15 Regeneron Pharmaceuticals, Inc. Methods for treating eosinophilic esophagitis by administering an il-4r inhibitor

Patent Citations (39)

* 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
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US5693762A (en) 1988-12-28 1997-12-02 Protein Design Labs, Inc. Humanized immunoglobulins
EP0546073A1 (fr) 1990-08-29 1993-06-16 Genpharm Int Animaux non humains transgeniques capables de produire des anticorps heterologues.
EP0546073B1 (fr) 1990-08-29 1997-09-10 GenPharm International, Inc. production et utilisation des animaux non humains transgeniques capable de produire des anticorps heterologues
US7982016B2 (en) 2007-09-10 2011-07-19 Amgen Inc. Antigen binding proteins capable of binding thymic stromal lymphopoietin
US9605928B2 (en) 2007-09-17 2017-03-28 J. Craig Oxford Apparatus and method for broad spectrum radiation attenuation
US20120020988A1 (en) 2010-07-15 2012-01-26 Hoffmann-La Roche Inc. Antibodies specifically binding to human TSLPR and methods of use
WO2012072577A1 (fr) 2010-11-30 2012-06-07 Erwin Steiner Dispositif de montage pour éléments de façade
US9100245B1 (en) 2012-02-08 2015-08-04 Amazon Technologies, Inc. Identifying protected media files
US9306926B2 (en) 2013-03-15 2016-04-05 Brian A. Truong User authentication using unique hidden identifiers
WO2018226565A1 (fr) 2017-06-08 2018-12-13 Amgen Inc. Dispositif d'administration de médicament entraîné par couple
WO2019094138A1 (fr) 2017-11-10 2019-05-16 Amgen Inc. Pistons pour dispositifs d'administration de médicament
WO2019100111A1 (fr) 2017-11-21 2019-05-31 Monash University Méthodes de traitement et de diagnostic d'états
WO2019178151A1 (fr) 2018-03-13 2019-09-19 Amgen Inc. Procédés de préparation de polypeptides résistant à la trypsine pour analyse par spectrométrie de masse
WO2020081479A1 (fr) 2018-10-15 2020-04-23 Amgen Inc. Dispositif d'administration de médicament comprenant un mécanisme d'amortissement
WO2020081480A1 (fr) 2018-10-15 2020-04-23 Amgen Inc. Procédé d'assemblage de plate-forme pour dispositif d'administration de médicament
WO2020244544A1 (fr) 2019-06-04 2020-12-10 江苏恒瑞医药股份有限公司 Anticorps capable de se lier à la lymphopoïétine stromale thymique et son utilisation
WO2021043221A1 (fr) 2019-09-04 2021-03-11 Biosion Inc. Anticorps se liant à tslp et leurs utilisations
WO2021104053A1 (fr) 2019-11-29 2021-06-03 康诺亚生物医药科技（成都）有限公司 Développement et utilisation d'agents thérapeutiques pour des maladies associées à tslp
WO2021115240A1 (fr) 2019-12-13 2021-06-17 四川科伦博泰生物医药股份有限公司 Anticorps anti-tslp et utilisations de celui-ci
WO2021152488A1 (fr) 2020-01-29 2021-08-05 Novartis Ag Méthodes de traitement d'une maladie inflammatoire ou obstructive des voies respiratoires à l'aide d'un anticorps anti-tslp
WO2021155634A1 (fr) 2020-02-05 2021-08-12 北京智仁美博生物科技有限公司 Anticorps anti-tslp humaine et son utilisation
WO2021155861A1 (fr) 2020-02-07 2021-08-12 北京汇智和源生物技术有限公司 Anticorps monoclonal humain de lymphopoïétine stromale thymique et son utilisation
WO2022095689A1 (fr) 2020-11-06 2022-05-12 上海麦济生物技术有限公司 Anticorps dirigé contre la lymphopoïétine stromale thymique humaine, son procédé de préparation et son utilisation
WO2022117079A1 (fr) 2020-12-03 2022-06-09 江苏恒瑞医药股份有限公司 Anticorps pouvant se lier à la lymphopoïétine stromale thymique et son utilisation
WO2022116858A1 (fr) 2020-12-03 2022-06-09 江苏恒瑞医药股份有限公司 Composition pharmaceutique d'anticorps anti-tslp et son utilisation
WO2022166072A1 (fr) 2021-02-03 2022-08-11 北京智仁美博生物科技有限公司 Anticorps contre la tslp humaine et leur utilisation
WO2022166739A1 (fr) 2021-02-04 2022-08-11 Staidson (Beijing) Biopharmaceuticals Co., Ltd. Anticorps reconnaissant spécifiquement la lymphopoïétine stromale thymique et leurs utilisations
WO2023142309A1 (fr) 2021-02-05 2023-08-03 上海洛启生物医药技术有限公司 Nanocorps anti-tslp et son utilisation
WO2022184074A1 (fr) 2021-03-03 2022-09-09 正大天晴药业集团股份有限公司 Composition pharmaceutique contenant un anticorps anti-tslp
WO2022226339A1 (fr) 2021-04-23 2022-10-27 Amgen Inc. Compositions d'anticorps anti-tslp et leurs utilisations
WO2022226342A2 (fr) 2021-04-23 2022-10-27 Amgen Inc. Anticorps anti-tslp modifiés
WO2022253147A1 (fr) 2021-06-02 2022-12-08 启愈生物技术(上海)有限公司 Anticorps anti-lymphopoïétine stromale thymique (tslp) et son utilisation
WO2023070948A1 (fr) 2021-11-01 2023-05-04 江苏荃信生物医药股份有限公司 Procédé de préparation d'une solution concentrée contenant un anticorps monoclonal anti-lymphopoïétine stromale thymique humaine (tslp), et préparation liquide
WO2023098491A1 (fr) 2021-12-02 2023-06-08 北京东方百泰生物科技股份有限公司 Anticorps monoclonal anti-tslp, fragment de liaison à l'antigène de celui-ci et son utilisation
WO2023116925A1 (fr) 2021-12-24 2023-06-29 Inmagene Biopharmaceuticals (Hangzhou) Co., Ltd. Nouveaux anticorps anti-tslp
WO2023166418A2 (fr) * 2022-03-03 2023-09-07 Pfizer Inc. Anticorps multispécifiques et leurs utilisations

Non-Patent Citations (86)

* Cited by examiner, † Cited by third party
Title
"Proteins, Structures and Molecular Principles", 1984, W. H. FREEMAN AND COMPANY
"REMINGTON'S PHARMACEUTICAL SCIENCES", 1990, MACK PUBLISHING COMPANY
"Sanofi and Regeneron Pharmaceuticals", 2022, INC. DUPIXENT®
"Uniprot", Database accession no. P01859
ABONIA ET AL., J ALLERGY CLIN IMMUNOL., vol. 126, no. 1, July 2010 (2010-07-01), pages 140 - 9
ACEVES ET AL., J ALLERGY CLIN IMMUNOL., vol. 119, no. 1, 2007, pages 206 - 12
ALLAKHVERDI ET AL., J EXP MED., vol. 204, no. 2, 2007, pages 253 - 258
BAGLIVO ILARIA ET AL: "The last step to achieve barrier damage control", FRONTIERS IN IMMUNOLOGY, vol. 15, 13 February 2024 (2024-02-13), Lausanne, CH, XP093221213, ISSN: 1664-3224, DOI: 10.3389/fimmu.2024.1354556 *
BAGNASCO DIEGO ET AL: "Personalized and Precision Medicine in Asthma and Eosinophilic Esophagitis: The Role of T2 Target Therapy", PHARMACEUTICS, vol. 15, no. 9, 21 September 2023 (2023-09-21), Switzerland, pages 2359, XP093220753, ISSN: 1999-4923, Retrieved from the Internet <URL:https://www.mdpi.com/1999-4923/15/9/2359/pdf> DOI: 10.3390/pharmaceutics15092359 *
BOLTON ET AL., AM J GASTROENTEROL., vol. 115, no. 2, 2020, pages 224 - 33
BRUGGERMANN ET AL., YEAR IN IMMUNO., vol. 7, 1993, pages 33
CHEHADE ET AL., J PEDIATR GASTROENTEROL NUTR., vol. 45, no. 3, 2007, pages 319 - 28
CHEHADE ET AL.: "UEG Week 2021 Poster Presentations", UNITED EUROPEAN GASTROENTEROL J, vol. 9, no. S8, 2021, pages 286
COLLINS ET AL., DIS ESOPHAGUS., vol. 30, no. 3, 2017, pages 1 - 8
COLLISON ET AL., J ALLERGY CLIN IMMUNOL., vol. 136, no. 4, 2015, pages 971 - 82
COLSON ET AL., J ALLERGY CLIN IMMUNOL PRACT., vol. 2, no. 5, 2014, pages 587 - 93
CORREN ET AL., N ENGL J MED., vol. 377, no. 10, 2017, pages 936 - 46
CORREN ET AL., PATHWAY, 2017
CUI ET AL., BIOMETRICS, vol. 55, no. 3, 1999, pages 853 - 7
DE ROOIJ WILLEMIJN E. ET AL: "Pharmacotherapies for the Treatment of Eosinophilic Esophagitis: State of the Art Review", DRUGS, vol. 79, no. 13, 27 July 2019 (2019-07-27), NZ, pages 1419 - 1434, XP093027361, ISSN: 0012-6667, Retrieved from the Internet <URL:https://curedfoundation.org/wp-content/uploads/2020/08/de-Rooij-Drugs-2019-EoE-treatment-review-1.pdf> DOI: 10.1007/s40265-019-01173-2 *
DELLON ET AL., AM J GASTROENTEROL., vol. 108, no. 5, 2013, pages 679 - 92
DELLON ET AL., AMERICAN COLLEGE OF GASTROENTEROLOGY (ACG) VIRTUAL ANNUAL MEETING, 23 October 2020 (2020-10-23)
DELLON ET AL., GASTROENTEROLOGY, vol. 152, no. 4, 2017, pages 776 - 86
DELLON ET AL., GASTROENTEROLOGY, vol. 154, no. 2, 2018, pages 1022 - 32
DELLON ET AL., GASTROINTEST ENDOSC., vol. 79, no. 4, 2014, pages 577 - 85
DELLON ET AL., N ENGL J MED., vol. 383, no. 17, 2020, pages 1624 - 34
DELLON ET AL., PRESENTED AT: DIGESTIVE DISEASE WEEK®, 2 June 2018 (2018-06-02)
DELLONLIACOURAS, GASTROENTEROLOGY, vol. 147, no. 6, 2014, pages 1238 - 54
DIVER ET AL., CASCADE, 2021
DIVER ET AL., LANCET RESPIR MED., vol. 9, no. 11, 2021, pages 1299 - 312
DURRANI ET AL., CLIN REV ALLERGY IMMUNOL., vol. 55, no. 1, 2018, pages 56 - 64
EBINA-SHIBUYALEONARD, NAT REV IMMUNOL., 1 June 2022 (2022-06-01), pages 1 - 14
EIGENMANN ET AL., J PHYSIOL., vol. 595, no. 24, 2017, pages 7311 - 30
EMSON ET AL., J ASTHMA ALLERGY., vol. 14, 2021, pages 91 - 9
GAUVREAU ET AL., N ENGL J MED., vol. 370, no. 22, 2014, pages 2102 - 10
GILLIET ET AL., J EXP MED, vol. 197, 2003, pages 1059 - 63
GILLIET ET AL., J EXP MED., vol. 197, no. 8, 2003, pages 1059 - 1067
GRIFFITHS ET AL., J ALLERGY CLIN IMMUNOL, vol. 149, no. 2, 2022, pages AB14
HIRANO ET AL., GASTROENTEROLOGY, vol. 158, no. 1, 2020, pages 1776 - 22
HUDGENS ET AL., J PATIENT REP OUTCOMES, vol. 1, no. 1, 2017, pages 3
JAKOBOVITS ET AL., NATURE, vol. 362, 1993, pages 255 - 58
JAKOBOVITS ET AL., PROC. NATL. ACAD. SCI., vol. 90, 1993, pages 2551 - 55
JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 25
KHOKHAR DILAWAR ET AL: "Eosinophilic esophagitis: Immune mechanisms and therapeutic targets", CLINICAL & EXPERIMENTAL ALLERGY, vol. 52, no. 10, 1 October 2022 (2022-10-01), UK, pages 1142 - 1156, XP093220760, ISSN: 0954-7894, Retrieved from the Internet <URL:https://pmc.ncbi.nlm.nih.gov/articles/PMC9547832/pdf/CEA-52-1142.pdf> DOI: 10.1111/cea.14196 *
KIRSCH ET AL., PEDIATR GASTROENTEROL NUTR., vol. 44, no. 1, 2007, pages 20 - 6
KONIKOFF ET AL., CLIN GASTROENTEROL HEPATOL, vol. 4, no. 11, 2006, pages 1328 - 36
KOTTYAN ET AL., NAT GENET., vol. 46, no. 8, 2014, pages 895 - 900
KROGER ET AL., MMWR, vol. 60, no. 2, 2011, pages 1 - 64
LAM ANGELA Y ET AL: "Eosinophilic esophagitis: New molecules, better life?", CURRENT OPINION IN PHARMACOLOGY, ELSEVIER SCIENCE PUBLISHERS, NL, vol. 63, 15 February 2022 (2022-02-15), XP087014203, ISSN: 1471-4892, [retrieved on 20220215], DOI: 10.1016/J.COPH.2022.102183 *
LIACOURAS ET AL., J ALLERGY CLIN IMMUNOL., vol. 128, no. 1, 2011, pages 3 - 20
LIEBERMAN ET AL., J ALLERGY CLIN IMMUNOL., vol. 126, no. 1, 2010, pages 160 - 80
LU ET AL., JOURNAL OF BIOMEDICAL SCIENCE, vol. 27, 2020, pages 1
LUCENDO ET AL., GASTROENTEROLOGY, vol. 157, no. 1, 2019, pages 592 - 603
LUCENDO ET AL., UNITED EUROPEAN GASTROENTEROL J., vol. 5, no. 3, 2017, pages 335 - 58
MANSOORCOOPER, DIG DIS SCI, vol. 61, no. 10, 2016, pages 2928 - 34
MARTIN ET AL., J ALLERGY CLIN IMMUNOL., vol. 141, no. 5, 2018, pages 1690 - 8
MENZIES-GOW ANDREW ET AL: "Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 384, no. 19, 13 May 2021 (2021-05-13), US, pages 1800 - 1809, XP093180115, ISSN: 0028-4793, Retrieved from the Internet <URL:https://www.nejm.org/doi/pdf/10.1056/NEJMoa2034975> DOI: 10.1056/NEJMoa2034975 *
MENZIES-GOW ET AL., N ENGL J MED., vol. 384, no. 19, 2021, pages 1800 - 9
MENZIES-GOW ET AL., NAVIGATOR, 2021
MORRISON ET AL., PROC. NATL. ACAD. SCI., vol. 81, 1985, pages 6851 - 55
NAVARRO ET AL., ALIMENT PHARMACOL THER., vol. 49, no. 9, 2019, pages 1116 - 25
NOTI, NAT MED., vol. 19, no. 8, 2013, pages 1005 - 13
PANDEY, NAT IMMUNOL., vol. 1, 2000, pages 59 - 64
PARK, J EXP MED., vol. 192, 2000, pages 659 - 669
PHAM ET AL., AM J RESPIR CRIT CARE MED., vol. 199, 2019, pages A2677
RECHE ET AL., J IMMUNOL, vol. 167, 2001, pages 336 - 43
RECHE ET AL., J IMMUNOL., vol. 167, no. 1, 2001, pages 336 - 343
RIECHMANN ET AL., NATURE, vol. 332, 1998, pages 323 - 27
ROCHMAN YRINA: "TSLP shapes the pathogenic responses of memory CD4+ T cells in eosinophilic esophagitis", 12 September 2023 (2023-09-12), XP093221963, Retrieved from the Internet <URL:https://doi.org/10.1126/scisignal.adg6360> *
RODRIGUEZ-SANCHEZ ET AL., REV ESP ENFERM DIG., vol. 105, no. 8, 2013, pages 462 - 7
ROTHENBERG ET AL., J ALLERGY CLIN IMMUNOL., vol. 149, no. 2, 2022, pages AB312
ROTHENBERG ET AL., NAT GENET., vol. 42, no. 4, 2010, pages 289 - 91
SAMPSON ET AL., J ALLERGY CLIN IMMUNOL., vol. 117, no. 2, 2006, pages 391 - 7
SCHOEPFER ET AL., GASTROENTEROLOGY, vol. 145, no. 6, 2013, pages 1230 - 6
SHAHBETTS, MABS, vol. 5, no. 2, 2013, pages 297 - 305
SINGLETON ET AL.: "DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY", 1994
SOUMELIS ET AL., NAT IMMUNOL., vol. 3, no. 7, 2002, pages 673 - 680
SPERGEL ET AL., J ALLERGY CLIN IMMUNOL., vol. 129, no. 2, 2012, pages 456 - 63
SPERRY ET AL., AM J GASTROENTEROL., vol. 107, no. 2, 2012, pages 215 - 21
STRAUMANN ET AL., GASTROENTEROLOGY, vol. 125, no. 6, 2003, pages 1660 - 9
STRAUMANN ET AL., GUT., vol. 59, no. 1, 2010, pages 21 - 30
STRAUMANN ET AL., J ALLERGY CLIN IMMUNOL., vol. 108, no. 6, 2001, pages 954 - 61
TAFT ET AL., ALIMENT PHARMACOL THER., vol. 34, no. 7, 2011, pages 790 - 8
THORNTON ET AL., NATURE, vol. 354, 1991, pages 105
VERHOEYEN ET AL., SCIENCE, vol. 239, 1988, pages 1534 - 36
WARNERS ET AL., AM J GASTROENTEROL., vol. 113, no. 6, 2018, pages 836 - 44

Also Published As

Publication number Publication date
WO2025221995A1 (fr) 2025-10-23

Similar Documents

Publication Publication Date Title
US20250032608A1 (en) Treatment of asthma with anti-tsl p antibody
US20190040126A1 (en) Methods for treating active eosinophilic esophagitis
US12129294B2 (en) Methods of treatment of diseases in which IL-13 activity is detrimental using anti-IL-13 antibodies
CN115768516A (zh) 通过施用il-4r抑制剂治疗嗜酸细胞性食管炎的方法
RS58091B1 (sr) Metode za tretiranje ili prevenciju astme davanjem antagonista il-4r
TW202304980A (zh) 經修飾的抗ｔｓｌｐ抗體
US20230073888A1 (en) Treatment of atopic dermatitis with anti-tslp antibody
US20240350626A1 (en) Methods for treating eosinophilic gastroenteritis by administering an il-4r antagonist
JP2021147383A (ja) アトピー性皮膚炎及び関連障害を処置するための方法
WO2025221247A1 (fr) Traitement de l&#39;œsophagite à éosinophiles avec un anticorps anti-tslp
TW202544036A (zh) 用抗ｔｓｌｐ抗體治療慢性阻塞性肺病
KR20250140101A (ko) 항-tslp 항체를 이용한 만성 비부비동염의 치료
WO2025147632A1 (fr) Traitement d&#39;une broncho-pneumopathie chronique obstructive à l&#39;aide d&#39;un anticorps anti-tslp
CN118524849A (zh) 用于治疗多血管炎、嗜酸性粒细胞增多综合症、伴有鼻息肉的慢性鼻窦炎嗜酸性粒细胞增多综合症(crswnp)或不伴有鼻息肉慢性鼻窦炎(crssnp)的白细胞介素5结合蛋白给药方案
WO2025120567A1 (fr) Méthode de traitement de l&#39;asthme
AU2024274293A1 (en) Treatment of corticosteroid dependent asthma with anti-tslp antibody
AU2024274293A9 (en) Treatment of corticosteroid dependent asthma with anti-tslp antibody
JP2019178153A (ja) Ｉｌ−４ｒアンタゴニストを投与することにより喘息を処置又は予防するための方法
HK40004820A (en) Methods of treatment of diseases in which il-13 activity is detrimental using anti-il-13 antibodies
HK40004820B (en) Methods of treatment of diseases in which il-13 activity is detrimental using anti-il-13 antibodies

Legal Events

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

Ref document number: 24726399

Country of ref document: EP

Kind code of ref document: A1