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WO2025029859A2 - Traitement de la dermatite atopique - Google Patents

Traitement de la dermatite atopique Download PDF

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Publication number
WO2025029859A2
WO2025029859A2 PCT/US2024/040285 US2024040285W WO2025029859A2 WO 2025029859 A2 WO2025029859 A2 WO 2025029859A2 US 2024040285 W US2024040285 W US 2024040285W WO 2025029859 A2 WO2025029859 A2 WO 2025029859A2
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WIPO (PCT)
Prior art keywords
antibody
weeks
per dose
seq
dose
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WO2025029859A3 (fr
Inventor
Jason CAMPAGNA
Christina MAYER
Joel SCHERER
Shelia Marie VIOLETTE
Hong Wu
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Q32 Bio Inc
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Q32 Bio Inc
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Publication of WO2025029859A2 publication Critical patent/WO2025029859A2/fr
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Pending legal-status Critical Current
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Interleukin-7 is a member of the common y chain (yc) family of cytokines that also includes IL-2, IL-4, IL-9, IL- 15, and IL-21. Like other members, IL-7 signals via a ternary complex formed with its unique a-receptor, IL-7Ra (CD 127), and the common y receptor (yc, CD132). IL-7 regulates T-cell homeostasis by enhancing survival and proliferation of naive and memory T cells; however, it appears to be dispensable for B cell development in humans. IL-7Ra is expressed on T cells including most mature T cells, on dendritic cells (DCs) and activated monocytes.
  • DCs dendritic cells
  • IL-7 / IL-7R interaction stimulates the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins with subsequent activation of the phosphoinositol 3-kinase (PI3K)/Akt, or Src pathways to facilitate target gene transcription.
  • IL-7 Ra is also used by thymic stromal-derived lymphopoietin (TSLP) as part of a complex that contains a second receptor chain, TSLPR.
  • TSLP thymic stromal-derived lymphopoietin
  • the TSLPR complex contains CD 127 and TSLPR (CRLF2), and is expressed on several types of immune cells, including B cells, T cells, monocytes and DCs.
  • TSLP has been shown to be a potent activator of antigen presenting cells such as DCs to induce TH2- mediated immune responses.
  • Lor example, TSLP-stimulated DCs increase OX40L expression and production of TH2 chemokines, such as CCL17 and CCL21, leading to the priming of TH2 cell development.
  • IL-7 plays a critical role in the development of a normal immune system, as it is essential for the thymic development, peripheral maintenance, and survival of lymphocytes. Thymic T cell precursors require IL-7 for proliferation, differentiation, and survival. In the periphery, IL-7 regulates T cell hemostasis by enhancing the survival and proliferation of naive and memory T cells.
  • IL-7 is a tissue-derived cytokine and is primarily produced from stromal and epithelial cells in various tissues. Lor instance, in the small and large intestines, IL-7 is produced by the intestinal goblet epithelial cells and has been described as being essential for the persistence of chronic colitis in animal models. IL-7 has also been shown to interfere with the immunosuppressive capabilities of regulatory T cells (T reg s). Thus, agents that can modulate the activity of IL-7 in vivo and thereby decrease the survival/function of pathogenic T cells and/or increase the induction of regulatory T cells are highly desirable for the treatment of inflammatory diseases, such as inflammatory bowel disease.
  • Atopic dermatitis (synonymous with Atopic eczema) is the most common chronic inflammatory skin disease. Approximately 80% of cases start in infancy or childhood, with the remaining developing during adulthood (Silverberg et al 2021, Nutten 2015, Barbarot et al 2018). Historically, the main therapeutic approaches have included avoidance of triggers, paired with the use of agents that are intended to exert local control of skin lesions and/or itch, and broad-spectrum immunosuppressive agents for more severe or high surface area disease. Many of these commonly used treatments have limited efficacy and/or harbor substantial long-term toxicity concerns. Lastly, most of these treatments are not designed to target specific pathways underlying disease biology.
  • a method of treating atopic dermatitis (AD) in a subject in need thereof comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT), and wherein
  • compositions for use in treating atopic dermatitis (AD) in a subject in need thereof comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7- 22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT), and wherein the composition comprising the antibody is administered
  • a method of treating atopic dermatitis (AD) in a subject comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNS
  • HCVR heavy chain variable region
  • compositions for use in treating atopic dermatitis (AD) in a subject comprising an antibody for IL- 7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT), wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH C
  • a pharmaceutical composition comprising an antibody having two heavy chains and two light chains, wherein each said heavy chain has the amino acid sequence of SEQ ID NO: 23, and each said light chain has the amino acid sequence of SEQ ID NO: 24; and wherein the antibody is formulated in a pharmaceutically acceptable solution comprising about 50-200 mg/mL (e.g., about 100 mg/mL) of the antibody in about 15-25 mM (e.g., about 20 mM) histidine, 200-300 mM (e.g., about 260 mM) sucrose, and about 0.03-0.07% (w/v) (e.g., about 0.05% (w/v)) polysorbate 80 at pH 6.0.
  • a pharmaceutically acceptable solution comprising about 50-200 mg/mL (e.g., about 100 mg/mL) of the antibody in about 15-25 mM (e.g., about 20 mM) histidine, 200-300 mM (e.g., about 260 mM) sucrose
  • a container e.g. a polycarbonate bottle
  • a container e.g. a polycarbonate bottle
  • extractable volume of a pharmaceutical composition described herein is provided herein.
  • the term “embodiment”, as used herein, is not to be considered as excluding features recited in other embodiments.
  • FIG. 1 is a schema for the Phase 2 clinical trial described in Example 1.
  • n 6; 4 treated with COMPOUND A and 2 placebo.
  • An additional cohort may be opened (Cohort 3) where COMPOUND A is administered SC Q2W for a total of 7 doses, at an intermediate or lower weight-based dose with respect to Cohorts 1 and 2, or at a fixed dose with predicted exposures ⁇ those at 3 mg/kg.
  • FIGs. 2A-2C show effects of prophylactic treatment with COMPOUND A (Comp. A) and a comparator IL-7Ra antibody (A3312F) in the Hu-NSG mouse model of GvHD on body weight loss (FIG. 2A), plasma cytokine levels (ELISA) (FIG. 2B) and percent human T cells (CD45+ CD3+) in blood as measured by flow cytometry (FIG. 2C). Measurements were determined 21 days post PBMC transfer.
  • COMPOUND A COMPOUND A
  • A3312F comparator IL-7Ra antibody
  • CCL1 antimicrobial protein with bactericidal activity
  • CD cluster differentiation
  • GvHD graft-versus host disease
  • Hu-NSG humanized nod/SCID/IL2rynull
  • IFN interferon
  • IL-7Ra interleukin-7 receptor alpha
  • IP intraperitoneal
  • PBMC peripheral blood mononuclear cells
  • TNF tumor necrosis factor.
  • FIGs. 3A-3B show target engagement and inhibition of pSTAT5 levels on human T cells in blood (FIG. 3A) and spleens (FIG. 3B) of Hu-NSG mice after treatment with (Comp. A) (18B1), a comparator IL-7Ra antibody (A3312F) or vehicle (PBS). Antibodies were administered in vivo at concentrations of 0.2, 1, and 5 mg/kg. IL-7-induced pSTAT5 was evaluated in an ex vivo assay and included a non-targeting IL-7 negative control sample (CTL Unstim).
  • CTL Unstim non-targeting IL-7 negative control sample
  • CTL control
  • Hu-NSG Hu-NSG: humanized nod/SCID/IL2rynull
  • IL-7Ra interleukin-7 receptor alpha
  • MFI mean fluorescence intensity
  • PBS phosphate buffered saline
  • pSTAT5 phosphorylated signal transducer and activator of transcription 5.
  • FIGs. 4A and 4B show data after administration of single ascending dose (SAD; 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg) and multiple doses (MAD; 1 mg/kg) in phase 1 clinical data in human (see Example 8).
  • FIG. 4A shows percentage of IL-7 receptor occupancy (RO) in CD3+ T cells
  • FIG. 4B shows percentage of inhibition of IL- 7 signaling via phosphorylated STAT5 (pSTAT5) in T cells.
  • FIG. 5A shows data (Mean ⁇ SD) on serum concentration profile in patients with topic dermatitis (AD) after subcutaneous administration of COMPOUND A at doses of 2 or 3 mg/kg every 2 weeks. SD: standard deviation. 5 pg/mL represents the concentration with predicted maximum receptor occupancy in skin.
  • FIG. 5B shows preliminary data (mean ⁇ SD) on IL-7Ra receptor occupancy (RO) on circulating CD3+ T cells in patients with atopic dermatitis (AD) after subcutaneous administration of COMPOUND A at doses of 2 or 3 mg/kg every 2 weeks.
  • RO receptor occupancy
  • SD standard deviation.
  • Dashed vertical lines represent the dosing days.
  • a method of treating atopic dermatitis (AD) in a subject comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPL
  • compositions for use in treating atopic dermatitis (AD) in a subject comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT), and wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH C
  • the antibody has a heavy chain sequence of SEQ ID NO: 23 and a light chain sequence of SEQ ID NO: 24.
  • the subject has moderate to severe AD e.g., chronic AD having a disease duration of >3 years, as diagnosed by the Eichenfield revised criteria of Hanifin and Rajka). See Eichenfield et al., Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 70(2):338-351 , Epub Nov. 27, 2013 (incorporated herein by reference).
  • moderate to severe AD e.g., chronic AD having a disease duration of >3 years, as diagnosed by the Eichenfield revised criteria of Hanifin and Rajka). See Eichenfield et al., Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 70(2):338-351 , Epub Nov. 27, 2013 (incorporated herein by reference).
  • the diagnosis of atopic dermatitis is made clinically and is based on historical features, morphology and distribution of skin lesions, and associated clinical signs.
  • One of the earliest and most recognized sets of diagnostic criteria is the 1980 Hanifin and Rajka criteria, which requires that three of four major criteria and three of twenty-three minor criteria be met. While comprehensive and often utilized in clinical trials, such a large number of criteria are unwieldy for use in clinical practice.
  • the current criteria for AD diagnosis is widely based on the Eichenfield revised criteria of Hanifin and Rajka as described in Eichenfield et al. (J Am Acad Dermatol. 70(2):338-351 , Epub Nov. 27, 2013). Specifically, the recommended criteria for the diagnosis of atopic dermatitis are shown in Table II of Eichenfield et al., and the strength of the recommendation is displayed in Table VI of Eichenfield et al. (both incorporated herein by reference).
  • the antibody is administered to the subject subcutaneously
  • the antibody is administered once a week (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every eight weeks (Q8W), once every twelve weeks (Q12W), or any intermittent PRN
  • each administration starting from the second dose, is separated from the immediate prior administration by the same number of days, preferably around the same time of the day of the administration.
  • the antibody is administered once every two weeks, preferably, each administration starting from the second dose is separated by 14 days from the immediate prior administration, preferably around the same time of the day of the administration.
  • the antibody is administered for 5-10 (e.g., 5, 6, 7, 8, 9, or 10) consecutive doses. In some embodiments, the antibody is administered for 5 consecutive doses. In some embodiments, the antibody is administered for 6 consecutive doses. In some embodiments, the antibody is administered for 7 consecutive doses. In some embodiments, the antibody is administered for 8 consecutive doses. In some embodiments, the antibody is administered for 9 consecutive doses. In some embodiments, the antibody is administered for 10 consecutive doses.
  • 5-10 e.g., 5, 6, 7, 8, 9, or 10 consecutive doses.
  • the antibody is administered for a period of up to 10 weeks, 13 weeks, 26 weeks, 52 weeks, 2 years, 3 years, 5 years, 10 years, or lifetime / permanently. In some embodiments, the antibody is administered as needed when there is AD symptom.
  • efficacy of treatment is measured by mean difference in percentage reduction from baseline level (just prior to commencement of treatment) of Eczema Area and Severity Index (EASI) score, at 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, and/or 24 weeks after the first dose at Week 0, for treatment vs. placebo / untreated control.
  • EASI Eczema Area and Severity Index
  • “just prior to” refers to within one day, 12 hrs, 6 hours, or 1 hour prior to the commencement of treatment, e.g., first dose at Week 0.
  • >50% , >75%, or >90% mean difference in percentage reduction from baseline level of EASI score is achieved at 4 weeks (Week 4), 8 weeks (Week 8), 12 weeks (Week 12), 16 weeks (Week 16), and/or 24 weeks (Week 24) after the first dose at Week 0, in the treated subject compared to placebo / untreated control.
  • efficacy of treatment is measured by mean percentage change from baseline level (just prior to commencement of treatment) in Scoring Atopic Dermatitis (SCORAD) score, at 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, and/or 24 weeks after the first dose at Week 0, for treatment vs. placebo / untreated control.
  • “just prior to” refers to within one day, 12 hrs, 6 hours, or 1 hour prior to the commencement of treatment, e.g., first dose at Week 0.
  • >50% , >75%, or >90% mean percentage change from baseline level in SCORAD score is achieved at 4 weeks (Week 4), 8 weeks (Week 8), 12 weeks (Week 12), 16 weeks (Week 16), and/or 24 weeks (Week 24) after the first dose at Week 0 in the treated subject compared to placebo / untreated control.
  • >50% , >75%, or >90% of all treated subject achieve EASI 50, EASI 75 and/or EASI 90 at Week 4, 8, 12, 14, 16, and/or 24.
  • >50% , >75%, or >90% of all treated subject achieve Validated Investigator Global Assessment for Atopic Dermatitis (v IGA- AD) score of 0 or 1 with at least 2 grades of reduction from Baseline at Week 4, 8, 12, 14, 16, and/or 24.
  • v IGA- AD Validated Investigator Global Assessment for Atopic Dermatitis
  • the antibody is formulated as 100 mg/mL solution in 20 mM histidine, 260 mM sucrose, and 0.05% (w/v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.
  • the antibody is administered to the subject based on a weight-based dosing regimen.
  • the antibody is administered to the subject at about 0.1 mg/kg - about 10 mg/kg per dose, about 0.2 mg/kg - about 8 mg/kg per dose, about 0.5 mg/kg - about 5 mg/kg per dose, about 1 mg/kg - about 4 mg/kg per dose, or about 2 mg/kg - about 3 mg/kg per dose.
  • the antibody is administered to the subject at about 0.2 mg/kg per dose, about 0.5 mg/kg per dose, about 1 mg/kg per dose, about 2 mg/kg per dose, about 3 mg/kg per dose, about 4 mg/kg per dose, about 5 mg/kg per dose, about 6 mg/kg per dose, about 7 mg/kg per dose, about 8 mg/kg per dose, about 9 mg/kg per dose, or about 10 mg/kg per dose.
  • the antibody is administered to the subject based on a body surface area (BSA)-based dosing regimen.
  • BSA body surface area
  • the dose for an adult male patient of any weight (in kg) and height (in cm) can be calculated / converted, based on a BSA Base Dose used for a standard male weight of 91 kg and height of 175 cm, to reach a dose of about 10 mg - about 800 mg per dose, about 20 mg - about 500 mg per dose, about 50 mg - about 300 mg per dose, about 100 mg - about 250 mg per dose.
  • the dose for an adult male patient of any weight (in kg) and height (in cm) can be calculated / converted, based on a BSA Base Dose used for a standard male weight of 91 kg and height of 175 cm, to reach a dose of about 25 mg per dose, about 50 mg per dose, about 100 mg per dose, about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, or about 350 mg per dose.
  • the dose for an adult female patient of any weight (in kg) and height (in cm) can be calculated / converted, based on a BSA Base Dose used for a standard female weight of 77.5 kg and height of 160 cm, to reach a dose of about 10 mg - about 800 mg per dose, about 20 mg - about 500 mg per dose, about 50 mg - about 300 mg per dose, or about 100 mg - about 250 mg per dose.
  • the dose for an adult female patient of any weight (in kg) and height (in cm) can be calculated / converted, based on a BSA Base Dose used for a standard female weight of 77.5 kg and height of 160 cm, to reach a dose of about 25 mg per dose, about 50 mg per dose, about 100 mg per dose, about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, or about 350 mg per dose.
  • the antibody is administered to the subject based on a fixed / flat dosing regimen.
  • the antibody is administered to the subject at about 10 mg - about 800 mg per dose, about 20 mg - about 500 mg per dose, about 50 mg - about 300 mg per dose, or about 100 mg - about 250 mg per dose.
  • the antibody is administered to the subject at about 25 mg per dose, about 50 mg per dose, about 100 mg per dose, about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, or about 350 mg per dose.
  • the antibody is administered to the subject based on a weight-banded dosing regimen, in which patients within certain ranges of weights (weightbands) are dosed a fixed amount for that specific weight band.
  • weightbands weight-bandsing regimen
  • patients within certain ranges of weights (weightbands) are dosed a fixed amount for that specific weight band.
  • patients with a body weight of about 10-25 kg are grouped in the same body weight band and given the same fixed dose.
  • patients with a body weight of about 25- 50 kg are grouped in the same body weight band and given the same fixed dose.
  • patients with a body weight of about 50-75 kg are grouped in the same body weight band and given the same fixed dose.
  • patients with a body weight of about 75-100 kg are grouped in the same body weight band and given the same fixed dose.
  • the fixed dose for each weight band is based on the average weight in the weight band (e.g., all patients in the weight band of 50-75 kg are dosed a fixed dose based on the dose for the middle weight - i.e., 62.5 kg for this weight band).
  • the fixed dose for the weight band 50-75 kg is about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 350 mg.
  • the antibody is administered to the subject based on a dosing regimen comprising a loading dose or an accelerated initial dosing schedule, followed by a maintenance dose, wherein the maintenance dose is administered according to any of the preceding weight-based dosing regimens, body surface area (BSA)-based dosing regimens, or fixed dose dosing regimens.
  • the loading dose comprises twice the dose of the maintenance dose (e.g., if the maintenance doses are administered once every two weeks (Q2W) as 200 mg fixed dose, the loading dose of 400 mg fixed dose may be administered once every two weeks (Q2W)).
  • an initial accelerated dosing schedule is used (e.g., if the 200 mg maintenance doses are administered once every two weeks (Q2W), the initial accelerated dosing schedule includes administering 200 mg once a week (Q1W) for two weeks).
  • the maintenance dose comprises infinite number of doses, which may be useful, for example, for management of a chronic condition such as atopic dermatitis.
  • the maintenance dose is administered intermittently (prn).
  • the subject has impaired renal function (e.g., mildly impaired renal function (such as a glomerular filtration rate ⁇ 60 mL/min and/or the presence of albuminuria >30 mg/d), moderately impaired renal function (such as a glomerular filtration rate ⁇ 45 mL/min), or severely impaired renal function (such as a glomerular filtration rate ⁇ 30 mL/min).
  • the subject is normal, e.g., normal with respect to renal function.
  • the subject is an adult (e.g., 18 years and older).
  • the subject is not an adult, or is a pediatric patient or an adolescent patient (e.g., a patient of under 18-year old, under 16-year old, under 14-year old, under 12-year old, under 10-year old, under 5-year old, under 3-year old, under 2-year old, under 1-year old, under 6-month old, or under 3-month old).
  • a pediatric patient or an adolescent patient e.g., a patient of under 18-year old, under 16-year old, under 14-year old, under 12-year old, under 10-year old, under 5-year old, under 3-year old, under 2-year old, under 1-year old, under 6-month old, or under 3-month old).
  • the subject is a Caucasian. In some embodiments, the subject is Asian. In some embodiments, the subject is African. In some embodiments, the subject is native American. In some embodiments, the subject is of mixed race or ethnic group. In some embodiments, the subject is biologic male. In some embodiments, the subject is biologic female.
  • the subject is further being treated by or has been treated by a second therapeutic agent effective to treat atopic dermatitis.
  • the second therapeutic agent comprises a topical immunomodulator (e.g., a calcineurin, PDE-4, and/or JAK inhibitor); a systemic steroid (corticosteroid); a topical corticosteroid; tacrolimus; pimecrolimus; phototherapy (narrow band ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet Al [UVA1], psoralen + ultraviolet A [PUVA]); allergen immunotherapy; a leukotriene inhibitor; or an oral chemical synthetic immunomodulator (e.g.
  • methotrexate mycophenolate mofetil, interferon (IFN)-y, azathioprine, cyclosporine, a systemic biologic (dupliumab, ustekinumab, tralokinumab, or nemolizumab), a systemic targeted synthetic JAK inhibitor (tofacitinib, ruxolitinib, upadacitinib, abrocitinib, and baricitinib), a topical synthetic JAK inhibitor (delgocitinib), or a PDE-4 inhibitor (crisaborole)).
  • IFN interferon
  • the antibody is administered to the subject at about 25, 50, 100, 150, 200, or 250 mg per dose; optionally, the doses of the antibody are administered to the subject once every two weeks, for a total of 10, 11, 12, 13, 14, or 15 doses.
  • the method reduces the measurement of an AD-associated biomarker after treatment (compared to before treatment).
  • the method further comprises detecting in the individual an AD-associated biomarker, either before or after treatment, or both.
  • the method prior to administering the subject anti-IL-7Ra antibody, antigen binding fragment thereof, or a pharmaceutically acceptable salt thereof, to the individual, the method further comprises selecting the individual based on a level of an AD- associated biomarker.
  • the administration of the subject anti-IL-7Ra antibody, antigen binding fragment thereof, or a pharmaceutically acceptable salt thereof results in a change in a level of an AD- associated biomarker in the individual.
  • the subject in need thereof satisfies one or more criteria in the inclusion criteria specified in Example 1. In some embodiments, the subject in need thereof satisfies all criteria in the inclusion criteria specified in Example 1.
  • the subject in need thereof does not satisfy (z.e., is not excluded by) any one criteria in the exclusion criteria specified in Example 1.
  • the method comprises administering the antibody e.g., one with the heavy chain sequence of SEQ ID NO: 23 and the light chain sequence of SEQ ID NO: 24) to the subject subcutaneously one dose every two weeks (Q2W), at about 200 mg per dose, for (at least) about 7 doses, (at least) about 8 doses, (at least) about 9 doses, (at least) about 10 doses, (at least) about 11 doses, (at least) about 12 doses, (at least) about 13 doses, or (at least) about 14 doses.
  • the antibody e.g., one with the heavy chain sequence of SEQ ID NO: 23 and the light chain sequence of SEQ ID NO: 24
  • a method of treating atopic dermatitis (AD) in a subject comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNS
  • HCVR heavy chain variable region
  • a related aspect provides a method of treating atopic dermatitis (AD) in a subject (e.g., a human) in need thereof, the method comprising administering an effective amount of a composition comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQF
  • compositions for use in treating atopic dermatitis (AD) in a subject comprising an antibody for IL-7Ra, wherein the antibody comprises: (a) a heavy chain variable region (HCVR) that comprises a VH CDR1 comprising the sequence of SEQ ID NO: 1 (DHAMH, such as any one of SEQ ID NOs: 7-22), a VH CDR2 sequence of SEQ ID NO: 2 (GISWNSRGIGYADSVKG), and a VH CDR3 sequence of SEQ ID NO: 3 (DEYSRGYYVLDV); and (b) a light chain variable region (LCVR) that comprises a VL CDR1 sequence of SEQ ID NO: 4 (RASQGISSALA), a VL CDR2 sequence of SEQ ID NO: 5 (DASSLES), and a VL CDR3 sequence of SEQ ID NO: 6 (QQFNSYPLWIT); wherein 200
  • the composition comprising the antibody is administered to the subject to maintain serum concentration of the antibody at >5 pg/mL throughout dosing.
  • Serum concentration of the antibody can be measured using any methods known in the art.
  • the level of the anti-IL-7Ra antibody in serum can be determined using a target capture approach. Specifically, the serum is flowed through a surface (e.g., column) pre-coated with a capture agent specific for the anti-IL-7Ra antibody (e.g., human IL-7R extracellular domain), and the antibody in the serum is captured onto the surface.
  • a capture agent specific for the anti-IL-7Ra antibody e.g., human IL-7R extracellular domain
  • a labeled secondary antibody that specifically binds to the anti-IL-7Ra antibody but does not compete for binding with the capture agent e.g., a labeled secondary antibody which binds to the Fc region of the anti-IL-7Ra antibody
  • the capture agent e.g., a labeled secondary antibody which binds to the Fc region of the anti-IL-7Ra antibody
  • Signal intensity from the labeled secondary antibody is proportional to the concentration of the anti- IL-7Ra antibody in the serum, and serum concentration of the antibody is determined by comparing its measured signal to signals produced by standards with known concentrations of the antibody.
  • serum concentration of the antibody can be measured using a Gyrolab® system which is a flow through immunoassay platform.
  • the antibody present in serum is captured on the columns in the Gyrolab® CD, which is pre-coated with biotinylated recombinant human IL-7R extracellular domain (target).
  • the bound anti-IL-7Ra antibody is detected with AlexaFluor®-647 labeled Cyno anti-human IgG Fc mAb (Pur Clone 10C7).
  • the immunofluorescence measured using the Gyrolab®’ s laser-induced fluorescence (LIF) detector is proportional to the concentration of the anti-IL-7Ra antibody in samples, standards, and controls.
  • LIF laser-induced fluorescence
  • serum concentration of the antibody can be measured using a Gyrolab® system, which is a flow through immunoassay platform.
  • the antibody present in serum is captured on the columns in the Gyrolab® CD which is pre-coated with biotinylated anti-idiotypic monoclonal antibody (mAb) that specifically bind to the anti-IL-7Ra antibody.
  • mAb biotinylated anti-idiotypic monoclonal antibody
  • the bound anti-IL-7Ra antibody is detected with AlexaFluor®-647 labeled mAb which is a non-competing clone but also binds to anti-IL- 7Ra antibody.
  • the immunofluorescence measured using the Gyrolab®’ s LIF detector is proportional to the concentration of the anti-IL-7Ra antibody in samples, standards, and controls.
  • the VH CDR1 comprises SEQ ID NO: 7 (GFTFDDHAMH).
  • the composition comprises 100 mg/ml of the antibody in 20 mM histidine, 260 mM sucrose, and 0.05% (w/v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.
  • the subject has an absolute lymphocyte count (ALC) of > 800 per microL.
  • ALC absolute lymphocyte count
  • administration of the antibody is stopped when the subject’s ALC is ⁇ 500 per microL.
  • the antibody is administered to the subject at about 200 mg per dose.
  • the antibody is administered once every two weeks (Q2W).
  • the antibody is administered for at least about 7 doses.
  • the antibody comprises an effectorless IgGl Fc.
  • a related aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody having two heavy chains and two light chains, wherein each said heavy chain has the amino acid sequence of SEQ ID NO: 23, and each said light chain has the amino acid sequence of SEQ ID NO: 24; and wherein the antibody is formulated in a pharmaceutically acceptable solution comprising about 50-200 mg/mL (e.g., about 100 mg/mL) of the antibody in about 15-25 mM (e.g., about 20 mM) histidine, 200-300 mM (e.g., about 260 mM) sucrose, and about 0.03-0.07% (w/v) (e.g., about 0.05% (w/v)) polysorbate 80 at pH 6.0.
  • a pharmaceutically acceptable solution comprising about 50-200 mg/mL (e.g., about 100 mg/mL) of the antibody in about 15-25 mM (e.g., about 20 mM) histidine, 200-300 mM (e.g.
  • the solution further comprises about 0.01-0.10 mM (e.g., about 0.05 mM) of pentetic acid.
  • the pharmaceutical composition comprises, consists essentially of, or consists of the antibody formulated as 100 mg/mL of the antibody in 20 mM histidine, 260 mM sucrose, and 0.05% (w/v) polysorbate 80 at pH 6.0.
  • the pharmaceutical composition comprises, consists essentially of, or consists of the antibody formulated as 100 mg/mL of the antibody in 20 mM histidine, 260 mM sucrose, 0.05 mM of pentetic acid, and 0.05% (w/v) polysorbate 80 at pH 6.0.
  • Yet another aspect provides a container (e.g., a polycarbonate bottle) containing about 2 mL of extractable volume of a pharmaceutical composition described herein.
  • a container e.g., a polycarbonate bottle
  • the container comprises about 2.26 mL of a pharmaceutical composition of described herein.
  • the term “about” is construed to include all values less than a full increment and greater than a full decrement of the least significant digit claimed.
  • the term “about,” as used herein is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error.
  • the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.
  • atopic dermatitis or “AD” or “atopic eczema” is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2-3% of adults, especially including those diagnosed under the Eichenfield revised criteria of Hanifin and Rajka (Eichenfield et al., Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 70(2):338-351, Epub Nov. 27, 2013 (incorporated herein by reference).
  • EASI Eczema Area and Severity Index
  • the area of involvement must be visually estimated in each of the 4 body regions separately (head and neck, upper extremities, trunk, and lower extremities) and assigned an area score: 1 (l%-9%), 2 (10%-29%), 3 (30%-49%), 4 (50%-69%), 5 (70%- 89%), and 6 (90%-100%).
  • the feet and buttocks are included as part of the lower extremities, whereas the axilla and groin are counted as part of the trunk.
  • each region is assessed separately for 4 signs: erythema, edema/papulation, excoriation, and lichenification. Each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe.
  • Half points may be used between points 1 and 3 (e.g., 1.5 and 2.5 but not 0.5) as any sign present should be treated as at least mild. It is important to note that only inflamed areas should be included in the assessment. Xerosis, ichthyosis, keratosis pilaris, urticaria, and postinflammatory pigment changes should not be included unless underlying eczema is present. Regions that present with varying severity of a particular sign should be roughly averaged across involved areas only; half units may be useful in this scenario. Each region is assigned an adult (>8 years old) or pediatric multiplier that reflects the relative contribution of that region to the total body surface area (BSA).
  • BSA body surface area
  • the region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region- specific multiplier.
  • the final EASI score is the summation of the 4 regional scores, ranging from 0 to 72. A score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease.
  • SCORAD is a clinical tool used to assess the extent and severity of eczema (SCORing Atopic Dermatitis). Dermatologists may use this tool before and after treatment to determine whether the treatment has been effective. Briefly, to determine extent in the various body areas, the sites affected by eczema are shaded on a drawing of a body. The rule of 9 is used to calculate the affected area (A) as a percentage of the whole body (Head and neck 9%; Upper limbs 9% each; Lower limbs 18% each; Anterior trunk 18%;
  • the score for each area is added up.
  • the total area is “A,” which has a possible maximum of 100%.
  • a representative area of eczema is selected. In this area, the intensity of each of the following signs is assessed as none (0), mild (1), moderate (2) or severe (3) - Redness, Swelling, Oozing/crusting, Scratch marks, Skin thickening (lichenification), and Dryness (this is assessed in an area where there is no inflammation).
  • the intensity scores are added together to give “B” (maximum 18).
  • itch and sleeplessness are each scored by the patient or relative using a visual analogue scale where 0 is no itch (or no sleeplessness) and 10 is the worst imaginable itch (or sleeplessness). These scores are added to give “C” (maximum 20). The total SCORAD score for that individual is A/5 + 7B/2 + C.
  • vIGA the “Validated Investigator Global Assessment for Atopic Dermatitis” or “vIGA” is an assessment scale used in clinical studies to determine severity of AD and clinical response to treatment based on a 5-point scale ranging from 0 (clear) to 4 (severe). See Simpson et al., The Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis. J Am Acad Dermatol.
  • BSA Body Surface Area Involvement of Atopic Dermatitis
  • Peak Pruritis Numerical Rating Scale refers to an 11- point scale to evaluate itch intensity. Subjects are asked to rate the overall severity of their itch in the past 24 hours using a scale described in Yosipovitch et al. (Br J Dermatol. 181(4):761-769, Epub 2019 May 1 2019, incorporated herein by reference).
  • Patient- Oriented Eczema Measure is a self-assessed, repeatable measurement tool for measuring atopic dermatitis (AD) severity. Patients will answer questions about the frequency of seven symptoms: itch, sleep disturbance, skin bleeding, skin weeping/oozing, skin cracking, skin flaking, and skin dryness/roughness over the last week. The total score from this assessment reflects overall disease activity.
  • the POEM utilizes a 5-point Likert scale for each question. POEM scores can range from 0 to 28 where lower total scores reflect lower disease activity and higher scores reflect higher disease activity (Charman et al., Arch Dermatol.
  • the “Dermatology Life Quality Index (DLQI)” refers to a selfadministered questionnaire designed to measure the health-related quality of life of adult patients suffering from a skin disease.
  • the DLQI consists of 10 questions concerning symptoms and feelings, daily activities, leisure, work, and school, personal relationships and treatment. Each question is answered by a tick box: “not at all”, “a little”, “a lot” or “very much”. Each question is scored from 0 to 3 and the scores summed, giving a range from 0 (no impairment of life quality) to 30 (maximum impairment). All questions relate “to the last week.” See Lewis and Finlay, 10 years experience of the Dermatology Life Quality Index (DLQI). J Investig Dermatol Symp Proc. 9(2): 169- 180, 2004, incorporated herein by reference).
  • ADCT Atopic Dermatitis Control Tool
  • PROMIS Sleep Disturbance (SD) and Sleep Related Impairment (SRI) assesses perceptions of alertness, sleepiness, and tiredness during usual waking hours, and the perceived functional impairments during wakefulness associated with sleep problems or impaired alertness. These instruments were previously validated and found to strongly correlate with both objective and other PRO measures of sleep quality. See Li et al. (Sleep Disturbance and Sleep-Related Impairment in Adults With Atopic Dermatitis: A Cross- sectional Study. Dermatitis. 29(5):270-277, 2018, incorporated herein by reference).
  • AD-associated biomarker means any biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule which is present or detectable in an AD patient at a level or amount that is different from (e.g., greater than or less than) the level or amount of the marker present or detectable in a non-AD patient.
  • the term “AD-associated biomarker” also includes a gene or gene probe known in the art which is differentially expressed in a subject with AD as compared to a subject without AD. Alternatively, “AD- associated biomarker” also includes genes which are down regulated due to AD.
  • AD-associated biomarkers include one or more of: total eosinophil count, total IgE (e.g., high total serum IgE levels), CCL17 (Thymus and Activation- Regulated Chemokine (TARC)), CCL18 (PARC), LDH (lactate dehydrogenase), serum levels of CD30, Macrophage-Derived Chemoattractant (MDC), interleukins (IL)-12, IL-16, IL- 18, IL-31, and filaggrin gene null mutations.
  • total IgE e.g., high total serum IgE levels
  • CCL17 Thymus and Activation- Regulated Chemokine (TARC)
  • CCL18 PARC
  • LDH lactate dehydrogenase
  • CD30 CD30
  • MDC Macrophage-Derived Chemoattractant
  • IL interleukins
  • AD-associated biomarkers include one or more of: total eosinophil count, total IgE, CCL17 (TARC), CCL18 (PARC), and/or LDH.
  • AD-associated biomarker include the SCORing Atopic Dermatitis (SCORAD) index and other severity scales known in the art.
  • the biomarker comprises total eosinophil count. In some embodiments, the biomarker comprises total IgE. In some embodiments, the biomarker comprises CCL17. In some embodiments, the biomarker comprises CCL18. In some embodiments, the biomarker comprises LDH.
  • the biomarker is assessed using histology. In some embodiments, the biomarker is assessed using RNAseq. In some embodiments, the biomarker is assessed using proteomic analysis. In some embodiments, the biomarker is assessed using enzyme-linked immunosorbent assay. In some embodiments, the biomarker is assessed using mass spectrometry. In some embodiments, the biomarker is assessed using a blood sample. In some embodiments, the biomarker will be assessed using a serum sample. In some embodiments, the biomarker will be assessed using a plasma sample. In some embodiments, the biomarker is assessed using a tissue sample. In some embodiments, the biomarker will be assessed using a punch biopsy. [0112] In some embodiments, the biomarker is a gene expression signature.
  • biomarkers for monitoring disease reversal with the administration of the subject antibody, or a pharmaceutically acceptable formulation thereof are known in the art; kits for measuring such AD-associated biomarkers are available from various commercial sources; and various commercial diagnostic laboratories offer services which provide measurements of such biomarkers as well.
  • TSLP refers to a growth factor that closely resembles IL-7 and plays a role in the maturation and activation of myeloid cells (e.g., monocytes and dendritic cells).
  • myeloid cells e.g., monocytes and dendritic cells.
  • TSLP is produced by various cell types, such as fibroblasts, epithelial cells, and stromal cells. Elevated levels of TSLP have been associated with diseases, such as asthma, atopic dermatitis, and inflammatory arthritis, which are also known to be associated with abnormal regulation of IL-7.
  • the term “antibody” refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH).
  • VH heavy chain variable region
  • CH heavy chain constant region
  • the heavy chain constant region is comprised of a hinge and three domains, CHI, CH2 and CH3.
  • each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain (abbreviated herein as CL).
  • CL The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system e.g., effector cells) and the first component (Clq) of the classical complement system.
  • a heavy chain may have the C- terminal lysine or not.
  • the amino acids in the variable regions are numbered using the Rabat numbering system and those in the constant regions are numbered using the EU system.
  • “Antibody” includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human and nonhuman antibodies and wholly synthetic antibodies.
  • IgG antibody e.g., a human IgGl, IgG2, IgG3 and IgG4 antibody, as used herein, has, in some embodiments, the structure of a naturally occurring IgG antibody, i.e., it has the same number of heavy and light chains and disulfide bonds as a naturally occurring IgG antibody of the same subclass.
  • an anti-IL-7R IgGl, IgG2, IgG3 or IgG4 antibody consists of two heavy chains (HCs) and two light chains (LCs), wherein the two heavy chains and light chains are linked by the same number and location of disulfide bridges that occur in naturally occurring IgGl, IgG2, IgG3 and IgG4 antibodies, respectively (unless the antibody has been mutated to modify the disulfide bridges).
  • Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (KD) of 10' 5 to 10' 11 M or less. Any KD greater than about 10' 4 M is generally considered to indicate nonspecific binding.
  • KD dissociation constant
  • the anti-IL-7Ra antibody used or useful for the method described herein specifically binds to IL-7Ra, such as binding specifically with a KD of 10' 5 to 10' 11 M or less (e.g., 10' 5 M or less, 10' 6 M or less, 10' 7 M or less, 10' 8 M or less, 10' 9 M or less, IO' 10 M or less, or 10' 11 M or less).
  • a KD of 10' 5 to 10' 11 M or less e.g., 10' 5 M or less, 10' 6 M or less, 10' 7 M or less, 10' 8 M or less, 10' 9 M or less, IO' 10 M or less, or 10' 11 M or less.
  • the anti-IL-7Ra antibody used or useful for the method described herein binds specifically to IL-7Ra (such as human IL-7Ra) with a KD of 10' 7 M or less, 10' 8 M or less, 5 x 10' 9 M or less, or between 10' 8 M and IO' 10 M or less, but does not bind with high affinity to unrelated antigens.
  • IL-7Ra such as human IL-7Ra
  • an antigen is “substantially identical” to a given antigen if it exhibits a high degree of sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the sequence of the given antigen.
  • an antibody that binds specifically to human IL-7Ra can, in some embodiments, also have cross-reactivity with IL-7Ra antigens from certain primate species (e.g., cynomolgus IL-7Ra), but cannot cross-react with IL-7Ra antigens from other species or with an antigen other than IL-7Ra.
  • isotype refers to the antibody class (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE antibody) that is encoded by the heavy chain constant region genes.
  • the IgG isotype is divided in subclasses in certain species: IgGl, IgG2, IgG3 and IgG4 in humans, and IgGl, IgG2a, IgG2b and IgG3 in mice.
  • the anti-IL-7R antibodies described herein are of the IgGl isotype.
  • Immunoglobulins e.g., IgGl
  • allotype refers to naturally occurring variants within a specific isotype group, wherein the variants differ in a few amino acids.
  • Anti-IL-7R antibodies described herein can be of any allotype.
  • antibodies referred to as “IgGlf,” “IgGl. If,” or “IgG1.3f” isotype are IgGl, effectorless IgGl.l, and effectorless IgG1.3 antibodies, respectively, of the allotype “f,” i.e.. having 214R, 356E and 358M according to the EU index as in Kabat, as shown, e.g., in SEQ ID NO: 23.
  • antigen-binding portion of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human IL-7Ra). It has been shown that the antigen -binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment (fragment from papain cleavage) or a similar monovalent fragment consisting of the VL, VH, LC and CHI domains; (ii) a F(ab')2 fragment (fragment from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fa fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VE and VH domains of a single arm of an antibody, (v) a dAb fragment which consists of a VH domain; (vi) an isolated complementarity determining region (CDR) and (vii) a combination of two or more isolated CDRs which can optionally be joined by a synthetic linker.
  • a Fab fragment fragment from papain cleavage
  • VE and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VE and VH regions pair to form monovalent molecules (known as single chain Fv (scFv).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.
  • the term “monoclonal antibody,” as used herein, refers to an antibody from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprised in the population are substantially similar and bind the same epitope(s) (e.g., the antibodies display a single binding specificity and affinity), except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • human monoclonal antibody refers to an antibody from a population of substantially homogeneous antibodies that display(s) a single binding specificity and which has variable and optional constant regions derived from human germline immunoglobulin sequences.
  • human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, (b) antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
  • variable and constant regions that utilize particular human germline immunoglobulin sequences are encoded by the germline genes, but include subsequent rearrangements and mutations which occur, for example, during antibody maturation.
  • the variable region contains the antigen binding domain, which is encoded by various genes that rearrange to form an antibody specific for a foreign antigen.
  • the variable region can be further modified by multiple single amino acid changes (referred to as somatic mutation or hypermutation) to increase the affinity of the antibody to the foreign antigen.
  • the constant region will change in further response to an antigen (i.e., isotype switch).
  • the rearranged and somatically mutated nucleic acid molecules that encode the light chain and heavy chain immunoglobulin polypeptides in response to an antigen cannot have sequence identity with the original nucleic acid molecules, but instead will be substantially identical or similar (i.e., have at least 80% identity).
  • a “human” antibody refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the anti- IL-7R antibodies described herein can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site- specific mutagenesis in vitro or by somatic mutation in vivo).
  • human antibody is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • human antibodies and “fully human” antibodies are used synonymously.
  • a “humanized” antibody refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen.
  • a “humanized” antibody retains an antigenic specificity similar to that of the original antibody.
  • a “chimeric antibody” refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
  • an antibody recognizing an antigen and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”
  • an “isolated antibody,” as used herein, is intended to refer to an antibody which is substantially free of other proteins and cellular material.
  • an antibody that “inhibits binding of IL-7 to IL-7Ra” is intended to refer to an antibody that inhibits the binding of IL-7Ra to its ligand, e.g., interleukin-7 (IL- 7), e.g., in binding assays using T cells from whole blood that express IL-7Ra, with an EC50 of about 1 pg/mL or less, such as about 0.9 pg/mL or less, about 0.85 pg/mL or less, about 0.8 pg/mL or less, about 0.75 pg/mL or less, about 0.7 pg/mL or less, about 0.65 pg/mL or less, about 0.6 pg/mL or less, about 0.55 pg/mL or less, about 0.5 pg/mL or less, about 0.45 pg/mL or less, about 0.4 pg/mL or less, about 0.35 pg/mL or
  • effector function refers to the interaction of an antibody Fc region with an Fc receptor or ligand, or a biochemical event that results therefrom.
  • exemplary “effector functions” include Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, FcyR-mediated effector functions such as ADCC and antibody dependent cell- mediated phagocytosis (ADCP), and downregulation of a cell surface receptor (e.g., the B cell receptor; BCR).
  • CDC complement dependent cytotoxicity
  • FcyR-mediated effector functions such as ADCC and antibody dependent cell- mediated phagocytosis (ADCP)
  • ADCP antibody dependent cell- mediated phagocytosis
  • BCR B cell receptor
  • Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain).
  • Fc receptor or “FcR” is a receptor that binds to the Fc region of an immunoglobulin.
  • FcRs that bind to an IgG antibody comprise receptors of the FcyR family, including allelic variants and alternatively spliced forms of these receptors.
  • the FcyR family consists of three activating (FcyRI, FcyRIII, and FcyRIV in mice; FcRIA, FcRIIA, and FcyRIIIA in humans) and one inhibitory (FcyRIIB) receptor.
  • FcyRIIB inhibitory receptor
  • NK cells selectively express one activating Fc receptor (FcyRIII in mice and FcyRIIIA in humans) but not the inhibitory FcyRIIB in mice and humans.
  • Human IgGl binds to most human Fc receptors and is considered equivalent to murine IgG2a with respect to the types of activating Fc receptors that it binds to.
  • an “Fc region” fragment crystallizable region or “Fc domain” or “Fc” refers to the C-terminal region of the heavy chain of an antibody that mediates the binding of the immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (e.g., effector cells) or to the first component (Clq) of the classical complement system.
  • an Fc region comprises the constant region of an antibody excluding the first constant region immunoglobulin domain (e.g., CHI or CF).
  • the Fc region comprises two identical protein fragments, derived from the second (CH2) and third (CH3) constant domains of the antibody's two heavy chains; IgM and IgE Fc regions comprise three heavy chain constant domains (CH domains 2-4) in each polypeptide chain.
  • the Fc region comprises immunoglobulin domains CH2 and CH3 and the hinge between CHI and CH2 domains.
  • the human IgG heavy chain Fc region is defined to stretch from an amino acid residue D221 for IgGl, V222 for IgG2, F221 for IgG3 and P224 for IgG4 to the carboxy-terminus of the 1 heavy chain, wherein the numbering is according to the EU index as in Kabat.
  • the CH2 domain of a human IgG Fc region extends from amino acid 237 to amino acid 340, and the CH3 domain is positioned on C-terminal side of a CH2 domain in an Fc region, i.e., it extends from amino acid 341 to amino acid 447 or 446 (if the C-terminal lysine residue is absent) or 445 (if the C-terminal glycine and lysine residues are absent) of an IgG.
  • the Fc region can be a native sequence Fc, including any allotypic variant, or a variant Fc (e.g., a non-naturally occurring Fc).
  • Fc can also refer to this region in isolation or in the context of an Fc-comprising protein polypeptide such as a “binding protein comprising an Fc region,” also referred to as an “Fc fusion protein” (e.g., an antibody or immunoadhesion).
  • a “native sequence Fc region” or “native sequence Fc” comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature.
  • Native sequence human Fc regions include a native sequence human IgGl Fc region; native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.
  • Native sequence Fc include the various allotypes of Fes.
  • epitopes refers to a site on an antigen (e.g., IF-7Ra) to which an immunoglobulin or antibody specifically binds, e.g., as defined by the specific method used to identify it.
  • Epitopes can be formed both from contiguous amino acids (usually a linear epitope) or noncontiguous amino acids juxtaposed by tertiary folding of a protein (usually a conformational epitope). Epitopes formed from contiguous amino acids are typically, but not always, retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
  • An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids in a unique spatial conformation.
  • Methods for determining what epitopes are bound by a given antibody i.e.. epitope mapping
  • epitope mapping include, for example, immunoblotting and immunoprecipitation assays, wherein overlapping or contiguous peptides from (e.g., from IF-7Ra) are tested for reactivity with a given antibody (e.g., anti-IF-7R antibody).
  • Methods of determining spatial conformation of epitopes include techniques in the art and those described herein, for example, x-ray crystallography, antigen mutational analysis, 2- dimensional nuclear magnetic resonance and HDX-MS.
  • KD is intended to refer to the dissociation constant, which is obtained from the ratio of kd to ka (i.e.. kd/ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. Available methods for determining the KD of an antibody include surface plasmon resonance, a biosensor system such as a BIACORE® system or flow cytometry and Scatchard analysis.
  • high affinity for an IgG antibody refers to an antibody having a KD of 10' 8 M or less, 10' 9 M or less, or IO' 10 M or less for a target antigen.
  • “high affinity” binding can vary for other antibody isotypes.
  • “high affinity” binding for an IgM isotype refers to an antibody having a KD of IO' 10 M or less, or 10' 8 M or less.
  • EC50 in the context of an in vitro or in vivo assay using an antibody or antigen binding fragment thereof, refers to the concentration of an antibody or an antigenbinding portion thereof that induces a response that is 50% of the maximal response, i.e., halfway between the maximal response and the baseline.
  • autoimmune disease refers to a disease or disorder in which the immune system produces an immune response (e.g., a B cell or a T cell response) against an antigen that is part of the normal host (i.e., an autoantigen), with consequent injury to tissues.
  • an autoantigen may be derived from a host cell, or may be derived from a commensal organism such as the micro-organisms (known as commensal organisms) that normally colonize mucosal surfaces.
  • inflammation refers to a complex series of events, including dilatation of arterioles, capillaries and venules, with increased permeability and blood flow, exudation of fluids, including plasma proteins and leukocyte migration into the inflammatory focus. Inflammation may be measured by many methods well known in the art, such as the number of leukocytes, the number of polymorphonuclear neutrophils (PMN), a measure of the degree of PMN activation, such as luminal enhanced-chemiluminescence, or a measure of the amount of proinflammatory cytokines (e.g., IL-6 or TNF-a) present.
  • PMN polymorphonuclear neutrophils
  • a measure of the degree of PMN activation such as luminal enhanced-chemiluminescence
  • proinflammatory cytokines e.g., IL-6 or TNF-a
  • the term “regulatory T cells” refer to a population of T cells with the ability to reduce or suppress the induction and proliferation of effector T cells, and thereby, modulate an immune response.
  • Tregs can suppress an immune response by secreting anti-inflammatory cytokines, such as IL- 10, TGF-b, and IL- 35, which can interfere with the activation and differentiation of naive T cells into effector T cells.
  • Tregs can also produce cytolytic molecules, such as Granzyme B, which can induce the apoptosis of effector T cells.
  • the regulatory T cells are natural regulatory T cells (nTregs) (i.e...
  • the regulatory T cells are induced regulatory T cells (iTregs) (i.e., naive T cells that differentiate into Tregs in the peripheral tissue upon exposure to certain stimuli).
  • iTregs induced regulatory T cells
  • Methods for identifying Tregs are known in the art.
  • Tregs express certain phenotypic markers (e.g., CD25, Foxp3, or CD39) that can be measured using flow cytometry.
  • the Tregs are CD45RA- CD39+ T cells.
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Different routes of administration for the anti-IL-7R antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation.
  • an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • the terms “inhibits” or “blocks” are used interchangeably and encompass both partial and complete inhibition/blocking.
  • the anti-IL- 7R antibody inhibits binding of IL-7 to IL-7Ra by at least about 50%, for example, about 60%, 70%, 80%, 90%, 95%, 99%, or 100%, determined, e.g., as further described herein.
  • treat refers to any type of intervention or process performed on, or administering an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease or enhancing overall survival. These terms do not include prophylatic intervention.
  • the term “prophylatic intervention” refers to treating a subject who does not yet have a disease for preventive purpose.
  • the term “effective dose” or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve a desired effect.
  • a “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a therapeutically effective amount or dosage of a drug includes a “prophylactic ally effective amount” or a “prophylactically effective dosage,” which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease.
  • a therapeutic agent to promote disease regression or inhibit the development or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials (including the methods described in the examples), in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • the term “patient” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment. In some embodiments, the patient is a human.
  • the term “subject” includes any human or non-human animal.
  • the methods and compositions described herein can be used to treat a subject having cancer.
  • the term “non-human animal” includes all vertebrates, e.g., mammals and nonmammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
  • weight-based” dose or dosing as referred to herein means that a dose that is administered to a patient is calculated based on the weight of the patient. For example, when a patient with 60 kg body weight requires 3 mg/kg of an anti-IL-7R antibody, one can calculate and use the appropriate amount of the anti-IL-7Ra antibody (z.e., 180 mg) for administration.
  • atopic dermatitis the method comprising administering to a subject in need thereof an isolated antibody or antigen binding portion thereof, which specifically binds to an alpha-chain of a human IL-7 receptor (“anti- IL-7Ra antibody,” or “anti-IL-7R antibody” for short), comprising a heavy chain CDR1, CDR2, and CDR3, and a light chain CDR1, CDR2, and CDR3, respectively, wherein the antibody (a) is capable of binding to T cells (CD4 + CD45RA + , CD4 + CD45RA", CD8 + CD45RA + , and/or CD8 + CD45RA”) in whole blood with an EC50 of about 5 nM or less (e.g., less than about 3 nM);
  • (b) is not capable of binding to non-T cells in whole blood
  • (c) does not agonize IL-7 receptor signaling upon binding to the IL-7 receptor, e.g., minimal pSTAT5 activation; or
  • the heavy chain CDR3 of the subject anti-IL-7Ra antibody comprises the amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV).
  • the anti-IL-7Ra antibody has one or more properties selected from the group consisting of:
  • (a) is capable of selectively binding to an alpha-chain of a human and cynomolgus IL- 7 receptor (IL-7R);
  • (b) is capable of binding to an alpha-chain of soluble and membrane bound IL-7R;
  • (c) is capable of blocking an expansion and/or survival of pathogenic T cells when administered to a subject in need thereof;
  • (d) is capable of restoring a T regulatory cell (Treg) function and/or promoting a Treg survival when administered to a subject in need thereof;
  • (f) is capable of blocking inflammation and mucosal damage, e.g., induced by pathogenic T cells, within an intestinal tissue of a subject in need thereof;
  • (g) is capable of decreasing a frequency of T effector cells in the mesenteric lymph nodes (MLN) and/or lamina intestinal (LP) in a subject in need thereof;
  • (h) is capable of reducing or inhibiting IL-7 mediated pSTAT activation in T cells e.g., CD4 + CD45RA + );
  • (i) is capable of blocking expansion of IL- 17 and/or ILN-gamma producing cells
  • (j) is capable of treating a subject with an inflammatory disease (e.g., inflammatory bowel disease).
  • an inflammatory disease e.g., inflammatory bowel disease
  • the subject anti-IL-7Ra antibody comprises a heavy chain CDR1, wherein the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (DHAMH), such as any one of amino acid sequences set forth in SEQ ID NOs: 7 to 22.
  • an anti-IL-7Ra antibody comprises a heavy chain CDR2, wherein the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2 (GISWNSRGIGYADSVKG).
  • an anti-IL-7Ra antibody comprises a heavy chain CDR3, wherein the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV).
  • an anti-IL-7Ra antibody comprises a light chain CDR1, wherein the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 4 (RASQGISSALA).
  • an anti- IL-7Ra antibody comprises a light chain CDR2, wherein the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 5 (DASSLES).
  • an anti- IL-7Ra antibody comprises a light chain CDR3, wherein the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6 (QQFNSYPLWIT).
  • the subject anti-IL-7Ra antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 (e.g., any one of SEQ ID NOs: 7-22, such as SEQ ID NO: 7 (GFTFDDHAMH)); a heavy chain CDR2 of the amino acid sequence set forth in SEQ ID NO: 2 (GISWNSRGIGYADSVKG); a heavy chain CDR3 of the amino acid sequence set forth in SEQ ID NO: 3 (DEYSRGYYVLDV); a light chain CDR1 of the amino acid sequence set forth in SEQ ID NO: 4 (RASQGISSALA); a light chain CDR2 of the amino acid sequence set forth in SEQ ID NO: 5 (DASSLES); and a light chain CDR3 of the amino acid sequence set forth in SEQ ID NO: 6 (QQFNSYPLWIT).
  • SEQ ID NO: 1 e.g., any one of SEQ ID NOs: 7-22, such as SEQ ID NO: 7 (GFTF
  • the subject anti-IL-7Ra antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence which is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 25.
  • the VL comprises an amino acid sequence which is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 26.
  • the subject anti-IL-7Ra antibody disclosed herein specifically binds to the alpha-chain of the human IL-7 receptor at an epitope selected from the group consisting of: 24 SQLEVNGSQHSLTCAF 39 (SEQ ID NO: 27); 73 FIETKKFLLIGKSNIC 88 (SEQ ID NO: 28); 89 VKVGEKSLTCKKIDLTT 105 (SEQ ID NO: 29); 136 QKKYVKVLMHDVAY 149 (SEQ ID NO: 30); 181 YEIKVRSIPDHYFKGF 196 (SEQ ID NO: 31); and combinations thereof.
  • an anti-IL-7Ra antibody specifically binds to the alphachain of the human IL-7 receptor at an epitope comprising one or more amino acid residues selected from the group consisting of H33, E75, F79, 182, K84, M144, R186, H191, Y192, and combinations thereof.
  • an anti-IL-7R antibody of is selected from the group consisting of an IgGl, IgG2, IgG3, IgG4, and a variant thereof.
  • an IL-7R antibody is an IgGl antibody.
  • an anti-IL-7R antibody comprises an effectorless IgGl Fc.
  • the subject anti-IL-7Ra antibody or antigen binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 25 and the VL comprises the amino acid sequence set forth in SEQ ID NO: 26.
  • VH heavy chain variable region
  • VL light chain variable region
  • the subject anti-IL-7Ra antibody or antigen binding portion thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 23 and wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 24.
  • an anti-IL-7Ra antibody binds to the alpha-chain of the human IL-7 receptor with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.3 nM), as measured by surface plasmon resonance.
  • an anti-IL-7Ra antibody binds to the alpha-chain of the cynomolgus IL-7 receptor with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.7 nM), as measured by surface plasmon resonance.
  • the binding to the alpha-chain of the human IL-7 receptor or the alpha-chain of the cynomolgus IL-7 receptor is pH-dependent.
  • an anti-IL-7Ra antibody binds to the alpha-chain of the human IL-7 receptor with a KD of about 1.3 nM at pH 7.4 and with a KD of about 5.3 nM at pH 6. In some embodiments, an anti-IL-7Ra antibody binds to the alphachain of the cynomolgus IL-7 receptor with a KD of about 1.7 nM at pH 7.4 and with a KD of about 7.0 nM at pH 6.
  • the anti-IL-7Ra antibody binds to the alpha-chain of the human IL-7 7Ra with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.3 nM), as measured by surface plasmon resonance.
  • an anti-IL-7Ra antibody binds to the alpha-chain of the cynomolgus IL-7 receptor with a KD of less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM (e.g., 1.7 nM), as measured by surface plasmon resonance.
  • the binding to the alpha-chain of the human IL-7 receptor or the alpha-chain of the cynomolgus IL-7 receptor is pH-dependent.
  • an anti- IL-7Ra antibody binds to the alpha-chain of the human IL-7 receptor with a KD of about 1.3 nM at pH 7.4 and with a KD of about 5.3 nM at pH 6. In some embodiments, an anti-IL-7R antibody binds to the alphachain of the cynomolgus IL-7 receptor with a KD of about 1.7 nM at pH 7.4 and with a KD of about 7.0 nM at pH 6.
  • an anti-IL-7Ra antibody is formulated for administration to the subject at a flat dose or a body weight-based dose. In some embodiments, an anti-IL-7Ra antibody is formulated for administration to the subject at a body weight-based dose (e.g., mg/kg). In some embodiments, an anti-IL-7Ra antibody is formulated for administration intravenously, subcutaneously, intramuscularly, intradermally, or intraperitoneally. In some embodiments, an anti-IL-7Ra antibody is formulated for administration intravenously (z.v.) or subcutaneously (s.c.).
  • compositions comprising an anti-IL-7Ra antibody or antigenbinding portion thereof described herein having the desired degree of purity in a physiologically acceptable carrier, excipient or stabilizer.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum album
  • compositions comprise an antibody or antigen binding portion thereof, a bispecific molecule, or a immunoconjugate described herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier.
  • pharmaceutical compositions comprise an effective amount of an antibody or antigen-binding portion thereof described herein, and optionally one or more additional prophylactic of therapeutic agents, in a pharmaceutically acceptable carrier.
  • the antibody is the only active ingredient included in the pharmaceutical composition.
  • compositions described herein can be useful in modulating (e.g., reducing or inhibiting) IL-7 activity in a T cell (e.g., pathogenic T cell) and treating a disease or disorder, such as an inflammatory disease, e.g., inflammatory bowel disease.
  • a T cell e.g., pathogenic T cell
  • a disease or disorder such as an inflammatory disease, e.g., inflammatory bowel disease.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound i.e., antibody, immunoconjugate, or bispecific molecule
  • the pharmaceutical formulation disclosed herein comprises: (a) an anti-IL-7R antibody; (b) a buffering agent; (c) a stabilizing agent; (d) a salt; (e) a bulking agent; and/or (f) a surfactant.
  • the pharmaceutical formulation is stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years or more. In some embodiments, the formulation is stable when stored at 4°C, 25°C, or 40°C.
  • Buffering agents can be a weak acid or base used to maintain the acidity (pH) of a solution near a chosen value after the addition of another acid or base.
  • Suitable buffering agents can maximize the stability of the pharmaceutical formulations by maintaining pH control of the formulation. Suitable buffering agents can also ensure physiological compatibility or optimize solubility. Rheology, viscosity and other properties can also dependent on the pH of the formulation.
  • Common buffering agents include, but are not limited to, histidine, citrate, succinate, acetate and phosphate.
  • a buffering agent comprises histidine (e.g., L-histidine) with isotonicity agents and potentially pH adjustment with an acid or a base known in the art.
  • the buffering agent is L- histidine.
  • the pH of the formulation is maintained between about 2 and about 10, or between about 4 and about 8.
  • Stabilizing agents are added to a pharmaceutical product in order to stabilize that product. Such agents can stabilize proteins in a number of different ways. Common stabilizing agents include, but are not limited to, amino acids such as glycine, alanine, lysine, arginine, or threonine, carbohydrates such as glucose, sucrose, trehalose, raffmose, or maltose, polyols such as glycerol, mannitol, sorbitol, cyclodextrins or dextrans of any kind and molecular weight, or PEG. In some embodiments, the stabilizing agent is chosen in order to maximize the stability of FIX polypeptide in lyophilized preparations. In some embodiments, the stabilizing agent is sucrose and/or arginine.
  • Bulking agents can be added to a pharmaceutical product in order to add volume and mass to the product, thereby facilitating precise metering and handling thereof.
  • Common bulking agents include, but are not limited to, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, or magnesium stearate.
  • Surfactants are amphipathic substances with lyophilic and lyophobic groups.
  • a surfactant can be anionic, cationic, zwitterionic, or nonionic.
  • nonionic surfactants include, but are not limited to, alkyl ethoxylate, nonylphenol ethoxylate, amine ethoxylate, polyethylene oxide, polypropylene oxide, fatty alcohols such as cetyl alcohol or oleyl alcohol, cocamide MEA, cocamide DEA, polysorbates, or dodecyl dimethylamine oxide.
  • the surfactant is polysorbate 20 or polysorbate 80.
  • the pharmaceutical formulation comprises: (a) about 0.25 mg/mL to 250 mg/mL (e.g., 10 to 200 mg/mL) of an anti-IL-7Ra antibody; (b) about 20 mM histidine; (c) about 260 mM sucrose; (d) about 0.5 mM DTPA; and (e) about 0.05% Tween- 80; optionally further comprising 0.05 mM pentetic acid.
  • the pharmaceutical formulation comprises about 100 mg/mL of an anti-IL-7Ra antibody in 20 mM histidine, 260 mM sucrose, and 0.05% (w/v) polysorbate 80 at pH 6.0, with an optional 0.05 mM pentetic acid.
  • the formulation can further comprise one or more of a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer and/or a surfactant, as well as various combinations thereof.
  • a buffer system a preservative, a tonicity agent, a chelating agent, a stabilizer and/or a surfactant, as well as various combinations thereof.
  • preservatives, isotonic agents, chelating agents, stabilizers and surfactants in pharmaceutical compositions is well-known to the skilled person.
  • the pharmaceutical formulation is an aqueous formulation.
  • aqueous formulation is typically a solution or a suspension, but may also include colloids, dispersions, emulsions, and multi-phase materials.
  • aqueous formulation is defined as a formulation comprising at least 50% w/w water.
  • aqueous solution is defined as a solution comprising at least 50 % w/w water
  • aqueous suspension is defined as a suspension comprising at least 50 % w/w water.
  • the pharmaceutical formulation is a freeze-dried formulation, to which the physician or the patient adds solvents and/or diluents prior to use.
  • Pharmaceutical compositions described herein also can be administered in combination therapy, i.e., combined with other agents.
  • the combination therapy can include an IL-7R antibody described herein combined with at least one other therapeutic agent.
  • therapeutic agents that can be used in combination therapy can include other compounds, drugs, and/or agents used for the treatment of a disease or disorder (e.g., an inflammatory disorder).
  • Such compounds, drugs, and/or agents can include, for example, anti-inflammatory drugs or antibodies that block or reduce the production of inflammatory cytokines.
  • therapeutic agents can include an anti -IP- 10 antibody, an anti-TNF-a antibody (e.g., adalimumab (HUMIRA®), golimumab (SIMPONI®), infliximab (REMICADE®), certolizumab pegol (CIMZIA®)), interferon beta-la (e.g., AVONEX®, REBIF®), interferon beta- lb (e.g., BETASERON®, EXT AVIA®), glatiramer acetate (e.g., COPAXONE®, GLATOPA®), mitoxantrone (e.g., NOVANTRONE®), non-steroidal antiinflammatory drugs (NSAIDs), analgesics, corticosteroids, and combinations thereof.
  • an anti-TNF-a antibody e.g., adalimumab (HUMIRA®), golimumab (SIMPONI®), infliximab (
  • therapeutic agents can include compounds, drugs, and/or agents that can induce the generation of regulatory T cells (e.g., induced regulatory T cells).
  • regulatory T cells e.g., induced regulatory T cells
  • Non-limiting examples of such therapeutic agents include TGF-b, IL- 10, IL-2, and combinations thereof.
  • the pharmaceutical compounds described herein can include one or more pharmaceutically acceptable salts.
  • a "pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms can be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions described herein is contemplated.
  • a pharmaceutical composition can comprise a preservative or can be devoid of a preservative. Supplementary active compounds can be incorporated into the compositions.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfdtration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • some methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent of active ingredient, from about 0.1 percent to about 70 percent, or from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms described herein are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dosage range for each dose is from about 10 mg - about 800 mg per dose, about 20 mg - about 500 mg per dose, about 50 mg - about 300 mg per dose, or about 100 mg - about 250 mg per dose.
  • the anti-IL-7Ra antibody is administered to the subject at about 25, 50, 100, 150, 200, 250, 300, or 350 mg per dose.
  • the anti-IL-7Ra antibody is administered at a dose based on body weight.
  • the dosage ranges from about 0.1 mg/kg - about 10 mg/kg per dose, about 0.2 mg/kg - about 8 mg/kg per dose, about 0.5 mg/kg - about 5 mg/kg per dose, about 1 mg/kg - about 4 mg/kg per dose, or about 2 mg/kg - about 3 mg/kg per dose.
  • the anti-IL-7Ra antibody is administered to the subject at about 0.2 mg/kg per dose, about 0.5 mg/kg per dose, about 1 mg/kg per dose, about 2 mg/kg per dose, about 3 mg/kg per dose, about 4 mg/kg per dose, about 5 mg/kg per dose, about 6 mg/kg per dose, about 7 mg/kg per dose, about 8 mg/kg per dose, about 9 mg/kg per dose, or about 10 mg/kg per dose.
  • the anti-IL-7Ra antibody is administered at a fixed dose with another antibody.
  • Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, bi-weekly (z.e., once every two weeks), monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient.
  • An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • the anti-IL-7Ra antibody e.g., those described herein, is administered once a week.
  • the anti-IL-7Ra antibody e.g., those described herein, is administered once every two weeks.
  • the treatment comprises 5-10 e.g., 5, 6, 7, 8, 9, or 10) consecutive doses, administered once every two weeks.
  • the treatment may comprise 5, 6, 7, 8, 9, or 10 consecutive doses, with each dose administered every two weeks apart.
  • the antibody is administered for a period of up to 10 weeks, 13 weeks, 26 weeks, 52 weeks, 2 years, 3 years, 5 years, 10 years, or lifetime / permanently. In some embodiments, the antibody is administered as needed when there is AD symptom.
  • two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated.
  • dosage is adjusted to achieve a plasma antibody concentration of about 0.1 - about 10 pg/mL, about 0.2 - about 9 pg/mL, about 0.5 - about 8 pg/mL, about 1 - about 7 pg/mL, about 2 - about 6 pg/mL, about 4 - about 5 pg/mL or about 5 - about 10 pg/mL.
  • dosage is adjusted to achieve a plasma antibody concentration of about 2 pg/mL, about 3 pg/mL, about 4 pg/mL, about 5 pg/mL, about 6 pg/mL, about 7 pg/mL, or about 8 pg/mL.
  • An antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the halflife of the antibody in the patient. In general, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a maintenance regime.
  • compositions described herein can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions described herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a composition described herein can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. Routes of administration for the anti-IL-7R antibodies described herein can include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
  • an antibody described herein could potentially be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • a non-parenteral route such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poly lactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art.
  • compositions can be administered with medical devices known in the art.
  • a therapeutic composition described herein can be administered with a needleless hypodermic injection device.
  • implants and modules for use with anti-IL-7R antibodies described herein include an implantable micro-infusion pump for dispensing medication at a controlled rate; a therapeutic device for administering medicaments through the skin; a medication infusion pump for delivering medication at a precise infusion rate; a variable flow implantable infusion apparatus for continuous drug delivery; an osmotic drug delivery system having multichamber compartments; and an osmotic drug delivery system.
  • Many other such implants, delivery systems, and modules are known to those skilled in the art.
  • the method described herein comprises administering to the mammalian subject a second / additional therapeutic agent effective for treating AD.
  • the second / additional therapeutic agent comprises a topical immunomodulator.
  • the topical immunomodulator comprises a calcineurin inhibitor.
  • the topical immunomodulator comprises a PDE- 4 inhibitor.
  • the topical immunomodulator comprises a JAK inhibitor (such as tofacitinib, ruxolitinib, upadacitinib, abrocitinib, and baricitinib).
  • the topical immunomodulator comprises one or more of calcineurin inhibitor, PDE-4 inhibitor, and JAK inhibitor.
  • the second / additional therapeutic agent comprises a systemic steroid, such as corticosteroid.
  • the second / additional therapeutic agent comprises a topical corticosteroid.
  • the second / additional therapeutic agent comprises tacrolimus and/or pimecrolimus.
  • the second / additional therapeutic agent comprises phototherapy.
  • the phototherapy comprises narrow band ultraviolet B [NBUVB].
  • the phototherapy comprises ultraviolet B [UVB].
  • the phototherapy comprises ultraviolet Al [UVA1].
  • the phototherapy comprises psoralen and ultraviolet A [PUVA].
  • the second / additional therapeutic agent comprises an allergen immunotherapy.
  • the second / additional therapeutic agent comprises a leukotriene inhibitor.
  • the second / additional therapeutic agent comprises an oral chemical synthetic immunomodulator.
  • the oral chemical synthetic immunomodulator may comprises one or more of: methotrexate, mycophenolate mofetil, interferon (IFN)-y, azathioprine, cyclosporine, a systemic biologic, a systemic targeted synthetic JAK inhibitor, a topical synthetic JAK inhibitor, or a PDE-4 inhibitor.
  • the systemic biologic comprises one or more of dupliumab, ustekinumab, tralokinumab, and nemolizumab.
  • the systemic targeted synthetic JAK inhibitor comprises one or more of tofacitinib, ruxolitinib, upadacitinib, abrocitinib, and/or baricitinib.
  • the topical synthetic JAK inhibitor comprises delgocitinib.
  • the PDE-4 inhibitor comprises crisaborole.
  • patients receiving treatment e.g., baseline COMPOUND A group
  • placebo control e.g., patients receiving placebo
  • the treatment also evaluates a number of Secondary and Exploratory Objectives and Endpoints, including:
  • SRI Sleep Related Impairment
  • PK Pharmacokinetics
  • immunogenicity of COMPOUND A in treated patients are also characterized to be desirable, based on assays including serum COMPOUND A concentrations based on Schedule of Assessments (SoA), and anti-drug antibody (ADA) rate.
  • SoA Schedule of Assessments
  • ADA anti-drug antibody
  • COMPOUND A safety and tolerability of COMPOUND A are evaluated, including acceptable numbers or percentages of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) including injection site tolerability, in view of laboratory evaluations, physical examinations, vital signs, and 12-lead electrocardiogram (ECG).
  • AEs adverse events
  • SAEs serious adverse events
  • AESIs adverse events of special interest
  • Changes in disease-specific biomarkers which may include but are not limited to total eosinophil count, total IgE, CCL17 (TARC), CCL18 (PARC), and LDH
  • RNA and DNA are collected and stored for potential future assessment of biomarkers related to COMPOUND A treatment responses and/or AD disease biomarkers
  • the clinical study was designed as a Phase 2a, multicenter, placebo controlled, proof-of-concept trial to assess the preliminary efficacy, safety, tolerability, PK, and PD of COMPOUND A in in adult subjects with persistent moderate to severe AD.
  • COMPOUND A or matching placebo is administered subcutaneously in the clinic setting post-randomization and every 2 weeks for a total of 7 doses.
  • Subjects with chronic AD (duration of disease >3 years) as diagnosed by the Eichenfield revised criteria of Hanifin and Rajka (Eichenfield et al 2014, incorporated herein by reference) who have moderate to severe disease activity at the time of enrollment, and who has a history of inadequate response to previous therapy are eligible for treatment.
  • Steady-state is predicted to occur by approximately 10 weeks following initiation of dosing every 2 weeks; predicted steady-state exposures at 2 mg/kg fall within the range of exposures previously tested in healthy subjects in Phase 1 study, while 3 mg/kg exposures are up to approximately 40% higher than previously tested.
  • Predicted observed maximum serum concentration after administration (Cmax) and area under the concentration time curve (AUC) are >120 times and >40 times lower than exposures observed at the no observed adverse effect level (NOAEL) of 150 mg/kg/week SC COMPOUND A in cynomolgus monkeys.
  • the trial is a two-part, Phase 2a, randomized, double-blind, placebo-controlled, multi-center proof of concept study in adult subjects with persistent moderate to severe AD.
  • Both Part A and Part B of the study have three periods: Screening up to 4 weeks, treatment with COMPOUND A or placebo for 12 weeks, and follow-up for 12 weeks.
  • COMPOUND A or matching placebo is administered subcutaneously (e.g., in the abdomen or anterior thigh) in the clinic setting post-randomization and every 2 weeks for a total of 7 doses.
  • Subjects with chronic AD (duration of disease >3 years) as diagnosed by the Eichenfield revised criteria of Hanifin and Rajka (Eichenfield et al 2014) who have moderate to severe disease activity at the time of consent and who have a history of inadequate response to previous therapy are eligible for the study.
  • subjects are screened for eligibility for up to 4 weeks before enrollment in the study.
  • BSA, EASI, IGA, and other specified qualifying measures of AD disease activity are performed to determine eligibility.
  • the pre-randomization assessments constitute the baseline reference measures. All subjects use an additive free bland emollient twice daily for 7 days or more before baseline and during the study. Subjects continue the same emollient throughout the study. Subjects who are not compliant with specified AD therapeutic exclusions for any reason during the screening period are not enrolled.
  • Efficacy, PK, PD, and immunology assessments are conducted at scheduled visits throughout the study.
  • Clinical laboratory assessments, vital signs and physical examination, 12-lead ECG, and AE assessments are conducted at scheduled visits throughout the study.
  • the study schema is provided in FIG. 1.
  • Part A the intent is to demonstrate initial safety and generate confirmatory PK/PD data in AD subjects to support the use of a safe and pharmacologically active dose for Part B.
  • Up to 20 eligible subjects are enrolled.
  • Study conduct in Part A are the same as in Part B with the following exceptions:
  • Part A Cohort 1 on Day -1, a minimum of 6 subjects are randomized in a 2:1 fashion to either COMPOUND A at a dose of 2 mg/kg or placebo administered subcutaneously every 2 weeks for a total of 7 doses. Safety data from the first 6 subjects who have completed a minimum of 2 weeks of study participation are reviewed by the Safety Review Committee (SRC) to support a recommendation regarding initiation of Cohort 2.
  • SRC Safety Review Committee
  • a minimum of 6 subjects are randomized in a 2: 1 fashion to either COMPOUND A at a dose of 3 mg/kg or placebo administered subcutaneously every 2 weeks for a total of 7 doses.
  • an additional cohort (Cohort 3) is opened to evaluate COMPOUND A administered SC Q2W for a total of 7 doses, at an intermediate or lower weight-based dose with respect to Cohorts 1 and 2, or at a fixed dose with predicted exposures ⁇ those at 3 mg/kg. Consistent with the other Part A cohorts, a minimum of 6 subjects are randomized to receive either COMPOUND A or placebo in a 2: 1 fashion. Safety and available PK/PD data from all subjects who have completed a minimum of 2 weeks of study participation are reviewed by the SRC prior to initiation of Cohort 3.
  • Part B subjects are randomized in a 1:1 ratio to COMPOUND A or matching placebo at the dose finalized in Part A (e.g., 200 mg COMPOUND A administered as a single 2-mL subcutaneous injection every 2 weeks) . Approximately 82 subjects are enrolled. For Part B, randomization is stratified by disease severity (EASI Score ⁇ 30, >30) at baseline, using block randomization.
  • EASI Score ⁇ 30, >30
  • An additional cohort may be enrolled to investigate COMPOUND A administered SC every 2 weeks, at a lower or intermediate weight-based dose with respect to Cohorts 1 and 2, or a fixed dose with predicted exposures ⁇ those at 3 mg/kg Q2W Dose for Part B will be dependent on Part A data. See FIG. 1.
  • This dosing regimen (z.e., 200 mg of COMPOUND A administered s.c. Q2W) is expected to result in steady- state serum trough concentrations >5 pg/mL, and maximum RO on circulating T cells in >90% of subjects throughout dosing. Additionally, exposures after 200 mg are predicted to fall within the range of previously tested exposures at 3 mg/kg, and is expected to be safe and well tolerated. [0267] Specifically, following COMPOUND A doses of 2 to 3 mg/kg administered every 2 weeks, median effective half-life is approximately 17 days (95% prediction interval 7 to 40 days). Model-predicted IL-7Ra RO on circulating CD3+ T cells for the dosing regimens show complete return to baseline by Study Week 20. Therefore, considering the duration and magnitude of lymphocyte reductions observed in toxicology studies and COMPOUND A clinical study and the PK/RO model projections, the 12-week follow-up period in the Phase 2a study is considered appropriate.
  • Skin tape and optional skin biopsy samples are collected for potential analysis of biomarkers related to COMPOUND A treatment responses and/or AD disease biomarkers, which may include but not limited to protein, gene expression and immunohistochemical (biopsy only) analyses of biomarkers related to COMPOUND A treatment effects and/or AD disease biomarkers.
  • a DNA sample is collected for exploratory research related to AD disease activity and/or the response to COMPOUND A. Genetic polymorphism in genes encoding drug targets or the downstream pathways may affect the efficacy and safety of the study treatment. In the event of an unusual response or observation of unexplained AEs, DNA samples are used to determine if there are any pharmacogenetic associations with drug response. As the understanding of the role of IL-7 and TSLP pathways in AD increases, additional genetic analyses may be warranted to refine the knowledge of the molecular basis of the disease, drug response, and to advance the development of novel therapeutics.
  • COMPOUND A (the antibody having the heavy chain amino acid sequence of SEQ ID NO: 23 and the light chain amino acid sequence of SEQ ID NO: 24) was formulated as 100 mg/mL drug product in 20 mM histidine, 260 mM sucrose, and 0.05% (w/v) polysorbate 80 at pH 6.0. Based on ongoing long-term stability studies, this formulation has a shelf life of about 24 months when stored at -20°C ( ⁇ 5°C) away from direct light.
  • Formulation characterization studies were performed on the COMPOUND A bulk drug substance (BDS) excipients and formulation including photostability, thermal, agitation, and freeze-thaw in 2R glass vials. The studies were performed in 2R glass vials to generate formulation data in drug product container closures.
  • BDS bulk drug substance
  • the buffer histidine and excipient sucrose were shown to have good conformational stability in comparison to other buffers such as citrate, phosphate and excipients arginine and sodium chloride at pH ranges of 5.5 to 6.5.
  • Conformation stability assessment utilized differential scanning fluorimetry to evaluate unfolding temperature and dynamic light scattering to evaluate hydrodynamic radius.
  • polysorbate 80 as a stabilizing surfactant in the COMPOUND A BDS was evaluated in agitation and freeze thaw studies at a protein concentration of 60 mg/mL. The study showed that agitation stress up to one week had no observable effect on aggregation or significant increase of subvisible particulates in both formulations with and without polysorbate 80.
  • the dose for Part B was selected as 200 mg COMPOUND A administered as a single 2-mL subcutaneous injection every 2 weeks (Q2W).
  • the dose selected for Part B was based on the totality of available data for COMPOUND A as described above and also considering:
  • Preliminary population PK simulations project that a dose of 200 mg administered Q2W will result in a median steady-state serum trough concentration of 20.0 pg/mL and the majority of subjects maintaining concentrations >5 pg/mL throughout dosing.
  • Fey receptors are found on hematopoietic cells and mediate antibody- antigen- induced effector functions. These include antibody-dependent cell-mediated cytotoxicity and antibody dependent cellular phagocytosis. The binding of specific non-variable regions of IgGl with FcyRs expressed on immune cells mediates effector functions of the antigenantibody complexes.
  • COMPOUND A ClGM/2hIgGl
  • the precursor of COMPOUND A was tested for its binding to human and monkey Fey receptors (types I, II, and III) by surface plasma resonance (SPR).
  • the FcyRs screened included FcyRI (hCD64 and cynoCD64), FcyRII (hCD32a-H131 and hCD32a-R131, hCD32b, cynoCD32a, and cynoCD32b), and FcyRIII (hCD16a-V158, hCD16b-NA2, and cynoCD16) subtypes.
  • the ClGM/2hIgGl antibody demonstrated the expected binding profiles for human and cynomolgus monkey FcyRI, FcyRII and FcyRIII (data not shown)
  • COMPOUND A Three amino acid substitutions were engineered into the Fc chain of the precursor CICM/2hGl to attenuate effector function, arriving at COMPOUND A.
  • COMPOUND A was expressed in HEK293 and CHO cells.
  • COMPOUND A (1 pM) was purified from cell supernatants and assessed for binding to human and cynomolgus monkey FcyRs by SPR.
  • the FcyRs screened included FcyRI (hCD64 and cynoCD64), FcyRII (hCD32a-H131, hCD32a-R131, hCD32b, cynoCD32a, and cynoCD32b), and FcyRIII (hCD16a-V158, hCD16b-NA2, and cynoCD16) subtypes.
  • Clq binding to the Fc domain of IgGl antibodies can mediate complement- mediated cell lysis.
  • the ability of COMPOUND A to bind Clq was evaluated using an ELISA assay. Briefly, microtiter plates were coated with human IL-7Ra, and COMPOUND A from 2 different lots were added at varying concentrations to the coated plates, followed by a saturating concentration of Clq purified from human serum. Bound Clq was detected with a sheep anti-human Clq antibody. Positive control included human IgGl. Positive control IgGl showed the expected affinity for Clq; however, neither lot of COMPOUND A showed any measurable binding to Clq at concentrations of up to 1000 ng/mL (6.7 nM).
  • Neonatal Fc receptor (FcRn), expressed on endothelial and bone marrow-derived cells, extends the half-life of IgGs by facilitating their transport out of epithelial cell endosomes (pH 6.0) where they would otherwise be degraded, and back into the bloodstream as functional immunoglobulins (pH 7.4). Endosomal recycling is facilitated by a pH shift (tight binding at pH 6.0 and low binding/high dissociation at pH 7.4) in the IgG-FcRn interaction.
  • COMPOUND A was evaluated for binding to purified recombinant human and cynomolgus monkey IL-7Ra via SPR.
  • the Kd of COMPOUND A for human IL-7Ra is 1.3 nM and for cynomolgus monkey IL-7Ra is 1.7 nM at pH 7.4.
  • the binding affinity of COMPOUND A for both human and cynomolgus monkey IL-7Ra was 4-fold weaker at pH 6.0, with Kd values of 5.3 nM for human IL-7Ra (hIL-7Ra), and 7.0 nM for cynomolgus monkey IL-7Ra (cIL-7Ra ) (see Table 3 below).
  • Table 3 Binding Affinity of COMPOUND A to Human and Cynomolgus Monkey IL- 7Ra
  • Kd receptor binding affinity dissociation constant
  • SPR surface plasmon resonance
  • COMPOUND A was evaluated with prophylactic treatment in a humanized non- obese diabetic severe combined immune deficiency-mice with a humanized immune system (NOD-SCID-ILZry" 1111 [Hu-NSG]) mouse model of GvHD.
  • NSG mice are immunodeficient due to the lack of mature murine lymphocytes and natural killer (NK) cells, which allows human peripheral blood mononuclear cells (PBMCs) to engraft with high efficiency.
  • PBMCs peripheral blood mononuclear cells
  • NSG mice were injected intravenously (IV) with human PBMCs that engrafted and led to the development of a robust xenogeneic-GvHD response, reproducing many aspects of the human disease.
  • A3312F tested in the same study, showed comparable efficacy to COMPOUND A.
  • CTLA4-Ig a different inhibitor of T cell activation, CTLA4-Ig, did not exhibit efficacy in that disease model using the same treatment strategy (data not shown), thus demonstrating a clear differentiation between anti-IL-7Ra mAb and CTLA4-Ig treatment, and highlighting the potential for a durable, drug-free response with IL-7Ra mAb treatment.
  • COMPOUND A and A3312F were administered by IV injection at doses of 0 (vehicle), 0.1 (low dose), 0.5 (mid dose), or 3.0 (high dose) mg/kg to groups of 1 or 2 monkeys per sex.
  • Criteria for PD evaluation included total and soluble IL-7R levels in blood and plasma, inhibition of IL-7-induced pSTAT5, receptor occupancy (RO), and peripheral lymphocyte phenotyping.
  • Pharmacokinetic endpoints included AUC, Cmax, and T ma x and immunogenicity endpoint included anti-drug antibody (ADA).
  • Cynomolgus monkey IL-7-induced pSTAT5 was strongly inhibited by both COMPOUND A and A3312F.
  • the low dose of 0.1 mg/kg showed notable inhibition of pSTAT5 (>80%) at early time points (Days 1-3) with COMPOUND A being slightly more effective than A3312F.
  • the intermediate dose of 0.5 mg/kg COMPOUND A was more effective than A3312F at maintaining complete inhibition of pSTAT5 through Day 5, with an approximate 4-fold higher suppression on Day 5.
  • complete inhibition of pSTAT5 activity was sustained through Day 8 with COMPOUND A treatment, while A3312F treatment demonstrated lesser inhibition of pSTAT5 over the same time period.
  • COMPOUND A at Day 11 continued to substantially inhibit IL-7 induced pSTAT5 while A3312F exhibited a complete loss of this inhibitory activity.
  • AUCs Mean exposures (AUCs) at 3 mg/kg in the first week, before anti-drug antibody (ADA) formation, were higher for COMPOUND A compared to A3312F with a mean AUC from 0 extrapolated to infinity (AUCinf) ⁇ 287 pg*day/mL and AUCinf ⁇ 135 pg*day/mL, respectively) (see Table 6).
  • ADA formation was accompanied by concomitant accelerated decline of serum concentrations, RO, and inhibition of pSTAT5 for COMPOUND A and A3312F.
  • AUCinf area under the concentration-time curve from 0 extrapolated to infinity
  • Cmax maximum plasma concentration
  • CL clearance
  • IV intravenous
  • PK pharmacokinetic
  • Tmax time of maximum plasma concentration
  • ADAs were detected in all monkeys dosed with COMPOUND A. ADAs were detected in 3, 3, and 2 of 3 monkeys dosed with A3312F at 0.1, 0.5, and 3 mg/kg, respectively, by Day 11. The presence of ADAs led to generally lower serum COMPOUND A and A3312F concentrations and lower individual COMPOUND A and A3312F systemic exposures on and after Day 11 (240 hours post dose) in all monkeys.
  • COMPOUND A and A3312F were well tolerated by monkeys after single IV doses of up to 3 mg/kg. There were no drug-related clinical observations or effects on body weight observed during the study. Good correlation was observed between the inhibition pSTAT5 in the CD4+CD45RA+ T cell population and serum concentration of antihuman IL-7R antibodies. More than 95% RO resulted in 90% inhibition of pSTAT5. The inhibition of pSTAT5 levels, a proximal biomarker of IL-7R signaling, by COMPOUND A was similar but more prolonged than that by A3312F and suggests that COMPOUND A exhibits improved PK, but similar in vivo potency compared to A3312F.
  • COMPOUND A was well tolerated by monkeys after a single SC dose ⁇ 30 mg/kg (AUCo-336h ⁇ 61,314 pg*h/mL).
  • COMPOUND A-related PD activity was noted at all doses, as demonstrated by inhibition of IL-7-induced pSTAT5, and generally correlated with IL-7 RO and COMPOUND A exposure, which was decreased due to the presence of ADAs in all monkeys by Day 11.
  • Decreased lymphocyte subpopulations observed as early as on Day 8 was consistent with hematology findings of decreased lymphocytes (at >3 mg/kg SC).
  • ADAs Despite the impact of ADAs on COMPOUND A’s concentration, meaningful exposure and evaluation of toxicological endpoints were achieved.
  • COMPOUND A was administered SC once weekly at doses of 0 (vehicle), 2, 10, or 50 mg/kg to groups of 5 monkeys per sex. Scheduled necropsies were conducted after 6 weeks of dosing (7 doses) (3/sex/group) and after an 8-week recovery period (2/sex/group).
  • At all doses near-complete (>95%) inhibition of IL-7 induced pSTAT5 on CD3+ T cells (PD activity) and near-complete (>98%) IL-7 RO on CD3+ T cells (target engagement) were observed at 4 hours post dose on Day 1 through Day 8.
  • T cell subset counts returned to baseline levels by Day 22 with the exception of the highest dose group of 50 mg/kg in which drug levels remained in circulation. In the 50 mg/kg dose group, the decreases in T cell subsets were maintained through the end of the recovery period (Day 97/99) and consistent with drug maintained in circulation.
  • COMPOUND A was well tolerated by monkeys for 6 weeks at SC, once weekly doses of 2, 10, or 50 mg/kg. SC toxikinetic profile was approximately doseproportional on Day 1 across the dose range tested but was later affected by the development of ADA in most animals. High-dose animals maintained exposure, albeit variable, allowing for meaningful interpretation of toxicological endpoints and the definition of a NOAEL. At all doses, PD activity (inhibition of IL-7 induced pSTAT5) generally correlated with IL-7 RO (target engagement) and COMPOUND A exposure and was decreased due to high levels of ADAs (more prominently at the lower doses). Three-month repeat dose toxicity study of COMPOUND A by subcutaneous injection with a 6-month recovery period
  • COMPOUND A was administered SC weekly at doses of 0 (vehicle), 25, 50, and 150 mg/kg to groups of sexually mature and not sexually mature monkeys. Scheduled necropsy was conducted after 6 months of dosing (27 doses) (2-4/sex/group) and after an 8- month recovery period (1-2/sex/group). All doses were administered at 1 mL/kg in a vehicle/carrier consisting of 20 mM histidine, 260 mM sucrose, and 0.05% PS80, pH 6, which is consistent with the clinical formulation.
  • lymphoid cellularity was observed in the thymus of sexually mature males administered >25 mg/kg (mild to moderate), and sexually mature females and not sexually mature males and females administered >50 mg/kg (moderate to marked), correlating with decreased thymus weights (absolute and relative to body and brain weights), small thymus size noted macroscopically, and decreases in lymphocyte counts.
  • the COMPOUND A-related decreased lymphoid cellularity observed in the thymus and associated hematology effects during the dosing phase of the study were considered non- adverse because of the low incidence and severity of the changes. There were no significant differences between the findings noted in not sexually mature and sexually mature animals.
  • Example 8 Phase 1, double-blind, placebo-controlled, single and multiple ascending dose study to assess the safety, PK, and PD of COMPOUND A after SC administration in healthy subjects
  • COMPOUND A is safe and well tolerated in healthy human subjects (male and female subjects aged 18 to 50 years old). Further, PK studies based on the data collected in these healthy human subjects show that COMPOUND A can be administered at relatively low doses and still achieve high receptor occupancy (RO) with respect to the IL-7R receptor. Additional analysis revealed that COMPOUND A administration in healthy human subjects led to minimal ADA host response due to the low immunogenecity of COMPOUND A.
  • MAD multiple ascending dose
  • the protocol defined up to 3 cohorts of 8 subjects per cohort. In each cohort, subjects were to be randomly assigned in a 3:1 ratio to receive either COMPOUND A or matching placebo. In the end, MAD Cohorts 2 and 3 were not enrolled per termination decision due to COVID-19 caseload and COVID-19 operational concerns where the study was being conducted.
  • the assay Given the ability to detect low titer antibodies in the presence of circulating drug, the assay can detect both clinically relevant and irrelevant anti-COMPOUND A antibodies. The impact of ADA on COMPOUND A exposure and PD activity was also evaluated.
  • Phase 1 data indicates that dose up to 4 mg/kg is well tolerated in healthy human volunteers, with no observable impact on pharmacology or safety by ADA. Doses less than 3 mg/kg SC was observed to achieve full RO, and multiple administration of COMPOUND A at 1 mg/kg SC every two weeks also achieved full RO and pSTAT5 inhibition. A total lymphocyte count of ⁇ 0.5 x 10 9 /L, a prespecified protocol stopping criterion, was not observed in any of the study subjects during the study. There were no cases of lymphopenia as defined by the Common Terminology Criteria for Adverse Events (CTCAE) guidance.
  • CCAE Common Terminology Criteria for Adverse Events
  • the interim cutoff date for this analysis resulted in inclusion of data of at least 98 days (14 weeks) or 14 days (2 weeks) postdose for PK.
  • Analyses were performed by an external unblinded pharmacometrician and results were reblinded for the Sponsor. To maintain blinding, time points or groups with N ⁇ 2 were not included in the analysis. Nominal doses and nominal times of dosing and sampling were used in the analyses.
  • COMPOUND A has an acceptable safety profile at doses up to 3 mg/kg every 2 weeks in subjects with AD. All adverse events (AEs) were assessed as mild or moderate, and there were no reported severe AEs. Reductions in lymphocyte count below 1000/pL, consistent with the mechanism of action, were observed in 5 subjects across both cohorts. The minimum lymphocyte count observed was 750/pL and no adverse sequelae were reported; the subject’s lymphocyte count returned to normal upon retesting approximately 1 week later with no further reduction below normal values observed. No dose-dependent reduction in lymphocyte count was observed. The lymphocyte count reductions were generally transient and trended to within normal limits at follow-up visits. No CTCAE Grade >3 lymphopenia or associated AEs or infections were observed. No doses were delayed due to TEAEs or due to a subject’s absolute lymphocyte count (ALC) being ⁇ 800/pL (as per protocol). No other clinically significant findings in laboratory values related to COMPOUND A have been observed.
  • ALC absolute lymphocyte count
  • both 2 and 3 mg/kg dose groups maintained target PK threshold > 5 pg/mL (dose expected to achieve full target engagement in tissue). Maximal RO (>90%) was achieved in all subjects of both dose groups by day 3 and maintained through the entire dosing period. Safety profile is also acceptable at these two doses; particularly, no lymphopenia- associated AEs, including viral infections, have been observed.
  • a dose of 200 mg ( ⁇ 2.7 mg/kg) administered SC Q2W is expected to result in steady-state serum trough concentrations >5 pg/mL and maximum RO on circulating T cells in >90% of subjects throughout dosing, while expected to cause no or only minimal lymphopenia.
  • predicted median C ma x,ss and AUCtau.ss after a dose of 200 mg SC administered Q2W are > 100-fold and >50-fold lower, respectively, than exposures at the NOAEL of 150 mg/kg/week SC in cynomolgus monkeys from the 6-month GLP toxicology study (Example 7).

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Abstract

L'invention concerne des composés, des compositions et des méthodes de traitement de la dermatite atopique (DA) chez des patients en ayant besoin.
PCT/US2024/040285 2023-07-31 2024-07-31 Traitement de la dermatite atopique Pending WO2025029859A2 (fr)

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