WO2024112935A1 - Procédés d'amélioration de la croissance osseuse par administration d'un antagoniste d'il-4r - Google Patents

Procédés d'amélioration de la croissance osseuse par administration d'un antagoniste d'il-4r Download PDF

Info

Publication number
WO2024112935A1
WO2024112935A1 PCT/US2023/080989 US2023080989W WO2024112935A1 WO 2024112935 A1 WO2024112935 A1 WO 2024112935A1 US 2023080989 W US2023080989 W US 2023080989W WO 2024112935 A1 WO2024112935 A1 WO 2024112935A1
Authority
WO
WIPO (PCT)
Prior art keywords
subject
seq
antagonist
administered
dose
Prior art date
Application number
PCT/US2023/080989
Other languages
English (en)
Inventor
Sara HAMON
Alan IRVINE
Sonya CYR
Peter Ehmann
Annamaria FARRELL
Original Assignee
Regeneron Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals, Inc. filed Critical Regeneron Pharmaceuticals, Inc.
Publication of WO2024112935A1 publication Critical patent/WO2024112935A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to the use of interleukin-4 receptor (IL-4R) antagonists for improving bone growth.
  • IL-4R interleukin-4 receptor
  • BMD bone mineral density
  • a major determinant for lifetime risk of fractures and osteoporosis is the magnitude of peak bone mass achieved during prepubescent years (Diemar, et al., Bone, 2021 , 146:115879. doi: 10.1016/j. bone.2021.115879).
  • Low BALP and BMD in children with moderate-to-severe AD could contribute to a higher prevalence of osteopenia and osteoporosis.
  • the method comprises: selecting a subject having a defect in bone growth, wherein the subject is a pediatric or adolescent subject less than 18 years old; and administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist.
  • IL-4R interleukin-4 receptor
  • the IL-4R antagonist is an anti-IL-4R antibody, or an antigenbinding fragment thereof, e.g., comprising one or more CDRs, HCVR, and/or LCVR sequences set forth in Table 1.
  • the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, that comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3, the HCDR2 comprises the amino acid sequence of SEQ ID NO:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence LGS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.
  • the subject has atopic dermatitis (AD). In some embodiments, the subject has moderate-to-severe or severe AD.
  • the subject is a pediatric subject having an age of less than 12 years old. In some embodiments, the subject is 6 years old to 11 years old. In some embodiments, the subject is 6 months old to 5 years old.
  • the subject is an adolescent aged 12 years old to 17 years old.
  • the subject has comorbid asthma.
  • the selecting step comprises selecting a subject who exhibits a level of a bone turnover marker that is below a threshold value, wherein the bone turnover marker is bone-specific alkaline phosphatase, carboxy-terminal cross-linked telopeptide of type I collagen (p-CTX), pro-collagen type I N-terminal propeptide (PINP), insulin-like growth factor 1 (IGF-1), or osteocalcin.
  • the threshold value is the average level of the bone turnover marker for a population of healthy subjects having the same age as the selected pediatric or adolescent subject.
  • the bone turnover marker is bone-specific alkaline phosphatase.
  • the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg. In some embodiments, the IL-4R antagonist is administered at a frequency of once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, the IL-4R antagonist is administered as an initial dose of 100-600 mg followed by one or more subsequent doses of 50-300 mg, wherein each subsequent dose is administered one week to four weeks after the immediately preceding dose.
  • the IL-4R antagonist is administered as an initial dose of 200 mg followed by one or more subsequent doses of 200 mg.
  • the IL-4R antagonist is administered as an initial dose of 300 mg followed by one or more subsequent doses of 300 mg.
  • the IL-4R antagonist is administered as an initial dose of 400 mg followed by one or more subsequent doses of 200 mg.
  • the IL-4R antagonist is administered as an initial dose of 600 mg followed by one or more subsequent doses of 300 mg.
  • the subject is a pediatric subject aged 6 years old to 11 years old or an adolescent aged 12 years old to 17 years old, and wherein the subject has a baseline weight > 60 kg, wherein the IL-4R antagonist is subcutaneously administered as an initial dose of 600 mg followed by one or more subsequent doses of 300 mg Q2W.
  • the subject is an adolescent having a baseline weight ⁇ 60 kg
  • the IL-4R antagonist is subcutaneously administered as an initial dose of 400 mg followed by one or more subsequent doses of 200 mg Q2W.
  • the subject is a pediatric subject having an age of 6 to 11 years old and having a baseline weight > 30 kg to ⁇ 60 kg, wherein the IL-4R antagonist is subcutaneously administered as an initial dose of 400 mg followed by one or more subsequent doses of 200 mg Q2W.
  • the subject is a pediatric subject having an age of 6 to 11 years old and having a baseline weight > 15 kg to ⁇ 30 kg, wherein the IL-4R antagonist is subcutaneously administered as an initial dose of 600 mg followed by one or more subsequent doses of 300 mg Q4W.
  • the subject is a pediatric subject having an age of 6 to 11 years old and having a baseline weight > 15 kg to ⁇ 60 kg, wherein the IL-4R antagonist is subcutaneously administered as an initial dose of 300 mg on Day 1 followed by 300 mg on Day 15, followed by one or more subsequent doses of 300 mg Q4W starting four weeks after the Day 15 dose.
  • the subject is a pediatric subject having an age of 6 months to 5 years old and having a baseline weight > 15 kg to ⁇ 30 kg, wherein the IL-4R antagonist is subcutaneously administered at a dose of 300 mg Q4W.
  • the subject is a pediatric subject having an age of 6 months to 5 years old and having a baseline weight > 5 kg to ⁇ 15 kg, wherein the IL-4R antagonist is subcutaneously administered at a dose of 200 mg Q4W.
  • the IL-4R antagonist is administered for at least 16 weeks.
  • the IL-4R antagonist is administered in combination with a topical AD medication.
  • the topical AD medication is a TCS.
  • treatment with the IL-4R antagonist results in an increase in bone growth in the subject as measured by an increase in a bone turnover marker selected from the group consisting of bone-specific alkaline phosphatase, p-CTX, PINP, IGF-1 , and osteocalcin.
  • a bone turnover marker selected from the group consisting of bone-specific alkaline phosphatase, p-CTX, PINP, IGF-1 , and osteocalcin.
  • the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2.
  • the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10.
  • the IL-4R antagonist is dupilumab.
  • the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an autoinjector. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in a pen delivery device. In some embodiments, the IL-4R antagonist is contained in an autoinjector.
  • compositions for improving bone growth are provided.
  • the pharmaceutical composition comprises an interleukin-4 receptor (IL-4R) antagonist.
  • the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, e.g., comprising one or more CDRs, HCVR, and/or LCVR sequences set forth in Table 1.
  • the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, that comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3, the HCDR2 comprises the amino acid sequence of SEQ ID N0:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence LGS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.
  • the pharmaceutical composition is for use in improving bone growth in a pediatric or adolescent subject, e.g., a pediatric or adolescent subject having atopic dermatitis.
  • interleukin-4 receptor (IL-4R) antagonists for the preparation of a medicament for improving bone growth.
  • the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, e.g., comprising one or more CDRs, HCVR, and/or LCVR sequences set forth in Table 1.
  • the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, that comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3, the HCDR2 comprises the amino acid sequence of SEQ ID NO:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence LGS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.
  • the medicament is for use in improving bone growth in a pediatric or adolescent subject, e.g., a pediatric or adolescent subject having atopic dermatitis.
  • FIG. 1 shows the geometric mean in bone alkaline phosphatase (BALP) (mcg/L) from baseline by visit for patients treated with placebo + topical corticosteroid (TCS), dupilumab 300 mg Q4W + TCS, or dupilumab 100 mg or 200 mg Q2W + TCS in a 16-week parent study (R668-AD-1652; “LIBERTY AD PEDS”) or subsequent open label extension study (R668-AD- 1434; “LIBERTY AD PED-OLE”). Visits at Week 8, 12, and 16 were from the parent study, and visits at Week 52 were from the open label extension study. Patients treated with placebo + TCS during the parent study were transitioned to dupilumab 100 mg or 200 mg Q2W or 300 mg Q4W for the open label extension study, ns, not significant; SE, standard error.
  • BALP placebo + topical corticosteroid
  • FIG. 2 shows osteocalcin levels (ng/mL) for patients treated with placebo + TCS or dupilumab (100/200mg Q2W or 300 mg Q4W) + TCS, at Week 8, Week 12, Week 16, or Week 52 of treatment.
  • Connecting lines represent data coming from the same subject.
  • Boxplots show median (middle horizontal line) and interquartile range (lower and upper bounds of the box), which correspond to the values at the top of the graph.
  • FIG. 3 shows pro-collagen type I N-terminal propeptide (PINP) levels(ng/ml_) for patients treated with placebo + TCS or dupilumab (100/200mg Q2W or 300 mg Q4W) + TCS, at Week 8, Week 12, Week 16, or Week 52 of treatment.
  • Connecting lines represent data coming from the same subject.
  • Boxplots show median (middle horizontal line) and interquartile range (lower and upper bounds of the box), which correspond to the values at the top of the graph.
  • FIG. 4 shows insulin-like growth factor 1 (IGF-1) levels (ng/mL) for patients treated with placebo + TCS or dupilumab (100/200mg Q2W or 300 mg Q4W) + TCS, at Week 8, Week 12, Week 16, or Week 52 of treatment.
  • Connecting lines represent data coming from the same subject.
  • Boxplots show median (middle horizontal line) and interquartile range (lower and upper bounds of the box), which correspond to the values at the top of the graph.
  • FIG. 5 shows carboxy-terminal cross-linked telopeptide of type I collagen ( -CTX) levels (pg/mL) for patients treated with placebo + TCS or dupilumab (100/200mg Q2W or 300 mg Q4W) + TCS, at Week 8, Week 12, Week 16, or Week 52 of treatment.
  • Connecting lines represent data coming from the same subject.
  • Boxplots show median (middle horizontal line) and interquartile range (lower and upper bounds of the box), which correspond to the values at the top of the graph.
  • FIGS. 6A and 6B show BALP geometric mean over time for female patients (6A) and male patients (6B) in the 6-11 year old treatment group.
  • a Dashed lines represent BALP reference intervals for females or males.
  • b After Week 16 these patients received active dupilumab treatment when enrolled in the LIBERTY AD PED-OLE trial. Visits at Weeks 8, 12, and 16 are from the LIBERTY AD PEDS trial and visits at Week 52 are from the LIBERTY AD PED-OLE trial.
  • FIG. 7 shows BALP geometric mean from baseline by visit for female (top panels) and male (bottom panels) patients in the 6-11 year old treatment group.
  • Visits at Weeks 8, 12, and 16 are from the LIBERTY AD PEDS trial and visits at Week 52 are from the LIBERTY AD PED- OLE trial.
  • the numbers below the gender and treatment regimen labels represent the group median and the range from lower quartile to upper quartile.
  • a After Week 16 these patients received active dupilumab treatment when enrolled in the LIBERTY AD PED-OLE trial.
  • the term "about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%.
  • the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1 , 99.2, 99.3, 99.4, etc.).
  • the terms “treat,” “treating,” or the like mean to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • the term "subject in need thereof” refers to a human or a non-human animal having a defect in bone growth.
  • a "defect in bone growth” refers to a decreased level of bone mineral density and/or a decreased level of a biomarker of bone formation or bone mineralization, e.g., as compared to a healthy subject or population of subjects.
  • the term "a subject in need thereof” refers to a pediatric patient who is ⁇ 12 years of age, e.g., a patent aged 6 months to 5 years old or a patient aged 6 to 11 years old.
  • the term "a subject in need thereof” refers to an adolescent patient who is > 12 and ⁇ 18 years of age.
  • the terms “subject” and “patient” are used interchangeably herein.
  • Atopic dermatitis or "AD”, as used herein, means an inflammatory skin disease characterized by intense pruritus (e.g., severe itch) and by scaly and dry eczematous lesions.
  • the term "atopic dermatitis” includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergy (e.g., allergy to certain foods, pollen, mold, dust mite, animals, etc.), radiation exposure, and/or asthma.
  • the present disclosure encompasses methods to treat patients with moderate-to-severe or severe AD.
  • “moderate-to- severe AD” is characterized by intensely pruritic, widespread skin lesions that are often complicated by persistent bacterial, viral or fungal infections.
  • Moderate-to-severe AD also includes chronic AD in patients.
  • the chronic lesions include thickened plaques of skin, lichenification and fibrous papules.
  • Patients affected by moderate-to-severe AD also, in general, have more than 20% of the body’s skin affected, or 10% of skin area in addition to involvement of the eyes, hands and body folds.
  • Moderate-to-severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids.
  • a patient may also be said to have moderate-to-severe AD when the patient is resistant or refractory to treatment by either a topical corticosteroid or a calcineurin inhibitor.
  • severe AD is characterized by the presence of widespread skin lesions, unremitting itching, or physically or emotionally disabling disease that significantly compromises a patient's quality of life. In some cases, patients with severe AD also exhibits one or more symptoms such as excoriation, extensive skin thickening, bleeding, oozing, and/or cracking of skin, and alteration of pigmentation. In some embodiments, severe AD is refractory to treatment by a topical therapy (e.g., a topical corticosteroid, calcineurin inhibitor, or crisaborole).
  • a topical therapy e.g., a topical corticosteroid, calcineurin inhibitor, or crisaborole.
  • TCS includes group I, group II, group III and group IV topical corticosteroids.
  • group I includes group I, group II, group III and group IV topical corticosteroids.
  • group II includes moderately potent (Group II) and potent (Group III) and very potent (Group IV), based on their activity as compared to hydrocortisone.
  • Group IV TCS very potent are up to 600 times as potent as hydrocortisone and include clobetasol propionate and halcinonide.
  • Group III TCS are 50 to 100 times as potent as hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate.
  • Group II TCS are 2 to 25 times as potent as hydrocortisone and include, but are not limited to, clobetasone butyrate, and triamcinolone acetonide.
  • Group I TCS (mild; also referred to interchangeably herein as "low potency”) includes hydrocortisone.
  • methods for improving bone growth in a subject are provided.
  • the subject has a defect in bone growth, e.g., a defect in bone formation or bone metabolism.
  • the methods comprise administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4Ra antibody or antigen-binding fragment thereof as disclosed herein.
  • IL-4R interleukin-4 receptor
  • the subject is a pediatric subject or adolescent subject less than 18 years old. In some embodiments, the subject is >6 months to ⁇ 18 years of age. In some embodiments, the subject is >6 years to ⁇ 18 years of age. In some embodiments, the subject is >12 years to ⁇ 18 years of age. In some embodiments, the subject is >6 years to ⁇ 12 years of age. In some embodiments, the subject is >6 months to ⁇ 12 years of age. In some embodiments, the subject is >6 months to ⁇ 6 years of age.
  • the subject is a pediatric or adolescent subject having a body weight ⁇ 60 kg at baseline. In some embodiments, the subject is a pediatric or adolescent subject having a body weight ⁇ 30 kg at baseline. In some embodiments, the subject has a body weight >5 kg and ⁇ 30 kg at baseline. In some embodiments, the subject has a body weight >5 kg and ⁇ 15 kg at baseline. In some embodiments, the subject has a body weight >15 kg and ⁇ 30 kg at baseline.
  • the subject has an atopic disease.
  • the subject has AD (e.g., moderate-to-severe AD or severe AD).
  • the subject has chronic atopic dermatitis diagnosed at least 6 months (e.g., at least 9 months or at least 1 year) prior to the start of treatment.
  • the subject has moderate-to-severe or severe AD that is inadequately responsive to topical therapies (e.g., TCS with or without topical calcineurin inhibitors (TCIs)) or for whom topical therapy is inadvisable (e.g., due to adverse side effects or safety risks).
  • the subject has moderate-to-severe or severe AD and is a candidate for systemic therapy.
  • the subject has AD (e.g., moderate to severe AD or severe AD) and has one or more concomitant allergic conditions (/.e., excluding AD).
  • AD e.g., moderate to severe AD or severe AD
  • concomitant allergic conditions /.e., excluding AD
  • the subject has a concurrent atopic or allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergy, non-food allergy, allergic conjunctivitis, hives, chronic rhinosinusitis, nasal polyps, and eosinophilic esophagitis.
  • the subject has a defect in bone growth.
  • the subject has abnormal bone metabolism relative to a healthy control or population of healthy control subjects.
  • the subject has decreased bone formation relative to a healthy control or population of healthy control subjects.
  • the subject has decreased bone mineral density relative to a healthy control or population of healthy control subjects.
  • the subject is at risk for skeletal fractures.
  • the subject has a history of skeletal fractures.
  • the subject has osteopenia.
  • the subject has osteoporosis (e.g., idiopathic juvenile osteoporosis or secondary osteoporosis).
  • the subject having a defect in bone growth has a history of treatment with a topical therapy (e.g., a topical corticosteroid, calcineurin inhibitor, or crisaborole).
  • a topical therapy e.g., a topical corticosteroid, calcineurin inhibitor, or crisaborole.
  • a subject having a defect in bone growth is selected based on the level of a bone-specific marker, e.g., a bone formation marker or bone turnover marker.
  • the marker is bone-specific alkaline phosphatase, carboxy-terminal crosslinked telopeptide of type I collagen (CTX-1), pro-collagen type I N-terminal propeptide (PINP), insulin-like growth factor 1 (IGF-1), or osteocalcin.
  • CTX-1 carboxy-terminal crosslinked telopeptide of type I collagen
  • PINP pro-collagen type I N-terminal propeptide
  • IGF-1 insulin-like growth factor 1
  • osteocalcin the subject is selected on the basis of exhibiting a level of a marker (e.g., bone turnover marker) that is below a threshold value.
  • a subject having a defect in bone growth is selected based on the subject's bone mineral density (BMD), e.g., a Z-score calculated for one or more skeletal sites.
  • BMD bone mineral density
  • the subject is selected on the basis of having a BMD Z-score that is below a threshold value.
  • the subject is identified as having a defect in bone growth if the subject has a BMD Z-score that is ⁇ -2.0, e.g., as measured for the lumbar spine, femur, hip, or another skeletal site.
  • the "threshold value" for a parameter or marker as disclosed herein is determined by reference to a population of healthy subjects having the same age as the selected pediatric or adolescent subject, or having a range of ages that encompasses the selected pediatric or adolescent subject.
  • a threshold value for a particular age or age range in view of knowledge in the art about the levels of the parameter or marker in a general population.
  • the threshold value is the lower value of a 95% reference interval for a bone turnover marker established for pediatric or adolescent patients, e.g., as shown in Table 3 of Diemar, et al., Bone, 2021, 146:115879 or as provided by Mayo Clinic Laboratories Pediatric Catalog (pediatric.testcatalog.org) (incorporated by reference herein).
  • the subject is selected on the basis of exhibiting a level of bone alkaline phosphatase that is below a threshold value, e.g., the lower value of a 95% reference interval for bone alkaline phosphatase established for a population of pediatric or adolescent patients.
  • a subject is selected if the subject has a serum bone alkaline phosphatase level ⁇ 70 pg/L, ⁇ 65 pg/L, ⁇ 60 pg/L, or ⁇ 55 pg/L.
  • a subject is selected if the subject: is 8-9 years of age and has a serum bone alkaline phosphatase level ⁇ 53.4 pg/L (for female subjects) or ⁇ 46.2 pg/L (for male subjects); or is 10-11 years of age and has a serum bone alkaline phosphatase level ⁇ 50.6 pg/L (for female subjects) or ⁇ 52.7 pg/L (for male subjects); or is 12-13 years of age and has a serum bone alkaline phosphatase level ⁇ 54.6 pg/L (for female subjects) or ⁇ 49.5 pg/L (for male subjects); or is 14-15 years of age and has a serum bone alkaline phosphatase level ⁇ 14.2 pg/L (for female subjects) or ⁇ 30.1 pg/L (for male subjects); or is 16-17 years of age and has a serum bone alkaline phosphatase level ⁇ 12.3 pg/L (for
  • the subject is selected on the basis of exhibiting a level of osteocalcin that is below a threshold value, e.g., the lower value of a 95% reference interval for osteocalcin established for a population of pediatric or adolescent patients.
  • a threshold value e.g., the lower value of a 95% reference interval for osteocalcin established for a population of pediatric or adolescent patients.
  • a subject is selected if the subject: is 8-9 years of age and has a serum osteocalcin level ⁇ 68.5 pg/L (for female subjects) or ⁇ 54.1 pg/L (for male subjects); or is 10-11 years of age and has a serum osteocalcin level ⁇ 72.2 pg/L (for female subjects) or ⁇ 55.8 pg/L (for male subjects); or is 12-13 years of age and has a serum osteocalcin level ⁇ 82.9 pg/L (for female subjects) or ⁇ 58.7 pg/L (for male subjects); or is 14-15 years of age and has a serum osteocalcin level ⁇ 22.2 pg/L (for female subjects) or ⁇ 54.1 pg/L (for male subjects); or is 16-17 years of age and has a serum osteocalcin level ⁇ 18.8 pg/L (for female subjects) or ⁇ 61.5 pg/L (for male subjects).
  • the subject is selected on the basis of exhibiting a level of PINP that is below a threshold value, e.g., the lower value of a 95% reference interval for PINP established for a population of pediatric or adolescent patients.
  • a threshold value e.g., the lower value of a 95% reference interval for PINP established for a population of pediatric or adolescent patients.
  • a subject is selected if the subject: is 8-9 years of age and has a serum PINP level ⁇ 415 pg/L (for female subjects) or ⁇ 381 pg/L (for male subjects); or is 10-11 years of age and has a serum PINP level ⁇ 352 pg/L (for female subjects) or ⁇ 298 pg/L (for male subjects); or is 12-13 years of age and has a serum PINP level ⁇ 387 pg/L (for female subjects) or ⁇ 168 pg/L (for male subjects); or is 14-15 years of age and has a serum PINP level ⁇ 65 pg/L (for female subjects) or ⁇ 219 pg/L (for male subjects); or is 16-17 years of age and has a serum PINP level ⁇ 55 pg/L (for female subjects) or ⁇ 166 pg/L (for male subjects).
  • the subject is selected on the basis of exhibiting a level of p- CTX that is below a threshold value, e.g., the lower value of a 95% reference interval for p-CTX established for a population of pediatric or adolescent patients.
  • a threshold value e.g., the lower value of a 95% reference interval for p-CTX established for a population of pediatric or adolescent patients.
  • treatment with an IL-4R antagonist improves bone growth, improves or normalizes bone turnover, or reduces the severity of a bone defect (e.g., reducing the occurrence or severity of skeletal fractures, or reducing the severity of osteopenia or osteoporosis).
  • a bone-associated parameter is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the present disclosure.
  • a bone-associated parameter may be measured at day 1 , day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11 , day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71 , day 85; or at the end of week 1 , week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11 , week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21 , week 22, week 23, week 24, or longer, after the initial treatment with a pharmaceutical composition of the present disclosure.
  • the difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., a decrease) in the bone-associated parameter.
  • treatment with an IL-4R antagonist according to the methods of the present disclosure results in an increase in bone growth in the subject, as measured by an increase in a bone turnover marker selected from the group consisting of bone-specific alkaline phosphatase, p-CTX, PINP, IGF-1 , and osteocalcin.
  • treatment with an IL-4R antagonist results in an increase from baseline in the level of the marker by week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 after administration of the first dose of the IL-4R antagonist.
  • treatment with an IL-4R antagonist results in an increase of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% in the level of the marker, relative to baseline, by week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 after administration of the first dose of the IL-4R antagonist.
  • treatment with an IL-4R antagonist results in an increase of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% in the BMD Z-score, relative to baseline, by week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 after administration of the first dose of the IL-4R antagonist.
  • a type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Ra chain and a yc chain.
  • a type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Ra chain and an IL-13Ra1 chain.
  • Type 1 IL-4 receptors interact with and are stimulated by IL-4, while type 2 IL-4 receptors interact with and are stimulated by both IL-4 and IL-13.
  • the IL-4R antagonists that can be used in the methods of the present disclosure may function by blocking IL-4-mediated signaling, IL-13- mediated signaling, or both IL-4- and IL-13-mediated signaling.
  • IL-4R antagonists of the present disclosure may thus prevent the interaction of IL-4 and/or IL-13 with a type 1 or type 2 receptor.
  • categories of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody” molecules), “receptor-bodies” (e.g., engineered molecules comprising the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind human IL-4Ra.
  • IL-4R antagonists also include antigen-binding proteins that specifically bind IL-4 and/or IL-13.
  • the IL-4R antagonist is an anti-IL-4Ra antibody or antigen-binding fragment thereof.
  • antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM).
  • each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains, CH1 , CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V ) and a light chain constant region.
  • the light chain constant region comprises one domain (CL1).
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyterminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the FRs of the anti-IL-4R antibody are identical to the human germline sequences. In some embodiments, one or more FRs of the anti- IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.
  • antibody also includes antigen-binding fragments of full antibody molecules.
  • antigen-binding portion of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex.
  • Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains.
  • DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized.
  • the DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
  • Non-limiting examples of antigen-binding fragments include: (i) Fab fragments;
  • F(ab')2 fragments (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide.
  • CDR complementarity determining region
  • engineered molecules such as domain-specific antibodies, single domain antibodies, domain- deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment," as used herein.
  • SMIPs small modular immunopharmaceuticals
  • An antigen-binding fragment of an antibody will typically comprise at least one variable domain.
  • the variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences.
  • the VH and VL domains may be situated relative to one another in any suitable arrangement.
  • the variable region may be dimeric and contain VH- H, VH- L or L- L dimers.
  • the antigen-binding fragment of an antibody may contain a monomeric V H or V domain.
  • an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain.
  • variable and constant domains that may be found within an antigenbinding fragment of an antibody of the present disclosure include: (i) V H -C 1 ; (ii) V -C H 2; (iii) V H - CH3; (iv) VH-CH1-CH2; (V) VH-C H 1-C H 2-C H 3; (vi) VH-C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1 ; (ix) V L -C H 2; (x) V L -CH3; (xi) L -CH1-CH2; (xii) L -CH1-CH2-CH3; (xiii) L -CH2-CH3; and (xiv) V L -CL.
  • variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region.
  • a hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule.
  • an antigen-binding fragment of an antibody of the present disclosure may comprise a homodimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric V H or ⁇ Z domain (e.g., by disulfide bond(s)).
  • the constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity.
  • the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.
  • antibody also includes multispecific (e.g., bispecific) antibodies.
  • a multispecific antibody or antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen.
  • Any multispecific antibody format may be adapted for use in the context of an antibody or antigenbinding fragment of an antibody of the present disclosure using routine techniques available in the art.
  • the methods of the present disclosure comprise the use of bispecific antibodies wherein one arm of an immunoglobulin is specific for IL-4Ra or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety.
  • Exemplary bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into- holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, I gG 1 /I gG2, dual acting Fab (DAF)-lgG, and Mab 2 bispecific formats (see, e.g., Klein, et al., 2012, mAbs, 4:6, 1-11, and references cited therein, for a review of the foregoing formats).
  • Bispecific antibodies can also be constructed using peptide/nucleic acid conjugation, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates which then self-assemble into multimeric complexes with defined composition, valency and geometry.
  • peptide/nucleic acid conjugation e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates which then self-assemble into multimeric complexes with defined composition, valency and geometry.
  • the antibodies used in the methods of the present disclosure are human antibodies.
  • the term “human antibody,” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies of the disclosure may nonetheless 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), for example in the CDRs and in particular CDR3.
  • the term “human antibody,” as used herein 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.
  • the antibodies used in the methods of the present disclosure may be recombinant human antibodies.
  • the term "recombinant human antibody,” as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor, et al., (1992) Nucl.
  • Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • an "isolated antibody” refers to an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an “isolated antibody.” An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • the antibodies used in the methods of the present disclosure specifically bind IL-4Ra.
  • the term "specifically binds,” as used herein, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.
  • an antibody that "specifically binds" IL-4Ra binds to IL-4Ra or a portion thereof with an equilibrium dissociation constant (K D ) of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM or less than about 0.05 nM, as measured in a surface plasmon resonance assay (e.g., BIAcoreTM, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).
  • K D equilibrium dis
  • an antibody that specifically binds to a target antigen can also specifically bind to another antigen, e.g., an ortholog of the target antigen.
  • a target antigen e.g., IL-4Ra
  • another antigen e.g., an ortholog of the target antigen.
  • an isolated antibody that specifically binds human IL-4Ra exhibits cross-reactivity to other antigens, such as IL-4Ra molecules from other (non-human) species.
  • the IL-4R antagonist is an anti-IL-4Ra antibody, or antigenbinding fragment thereof, comprising a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-4R antibodies as set forth in US Patent No. 7,608,693, incorporated by reference herein.
  • HCVR heavy chain variable region
  • LCVR light chain variable region
  • CDRs complementarity determining regions
  • the IL-4R antagonist is an anti-IL-4Ra antibody or antigen-binding fragment thereof that comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2.
  • HCDRs heavy chain complementarity determining regions
  • LCDRs light chain complementarity determining regions of a light chain variable region
  • the IL-4R antagonist is an anti-IL-4Ra antibody or antigen-binding fragment thereof that comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence GFTFRDYA (SEQ ID NO:3), the HCDR2 comprises the amino acid sequence ISGSGGNT (SEQ ID NO:4), the HCDR3 comprises the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO:5), the LCDR1 comprises the amino acid sequence QSLLYSIGYNY (SEQ ID NO:6), the LCDR2 comprises the amino acid sequence LGS, and the LCDR3 comprises the amino acid sequence MQALQTPYT (SEQ ID NO:8).
  • HCDR1 comprises the amino acid sequence GFTFRDYA (SEQ ID NO:3)
  • the HCDR2 comprises the amino acid sequence ISGSGGNT (SEQ ID NO:4)
  • the HCDR3 comprises the
  • the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCDR1 comprising the amino acid sequence GFTFRDYA (SEQ ID NO:3), an HCDR2 comprising the amino acid sequence ISGSGGNT (SEQ ID NO:4), an HCDR3 comprising the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO:5), an LCDR1 comprising the amino acid sequence QSLLYSIGYNY (SEQ ID NO:6), an LCDR2 comprising the amino acid sequence LGS, and an LCDR3 comprising the amino acid sequence MQALQTPYT (SEQ ID NO:8), and further comprises an HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO:1 and an LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%,
  • the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10 is the fully human anti-IL-4R antibody known as dupilumab.
  • the methods of the present disclosure comprise the use of dupilumab.
  • dupilumab also includes bioequivalents of dupilumab.
  • bioequivalent refers to anti-IL-4R antibodies or IL-4R-binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and/or extent of absorption do not show a significant difference with that of dupilumab when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose.
  • the term refers to antigen-binding proteins that bind to IL-4R which do not have clinically meaningful differences with dupilumab in their safety, purity and/or potency.
  • WQ2020/096381 WO 2020/182197, WQ2020/239134, WO 2021/213329, WQ2022/052974, WQ2022/136669, or WQ2022/136675, the contents of each of which are incorporated by reference herein.
  • an anti-IL-4Ra antibody or antigen-binding fragment thereof for use in the methods of the present disclosure comprises one or more CDR, HCVR, and/or LCVR sequences set forth in Table 1 below.
  • an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:32 (SCB-VH-59), SEQ ID NO:33 (SCB-VH-60), SEQ ID NO:34 (SCB-VH-61), SEQ ID NO:35 (SCB-VH-62), SEQ ID NO:36 (SCB-VH-63), SEQ ID NO:37 (SCB-VH-64), SEQ ID NO:38 (SCB-VH-65), SEQ ID NO:39 (SCB-VH-66), SEQ ID NQ:40 (SCB-VH-67), SEQ ID NO:41 (SCB-VH-68), SEQ ID NO:42 (SCB-VH-
  • the anti-IL-4Ra antibody comprises an HCVR comprising the amino acid sequence of SEQ ID NO:64 (SCB-VH-91) and an LCVR comprising the amino acid sequence of SEQ ID NO:17 (SCB-VL-44), SEQ ID NO:27 (SCB-VL-54), or SEQ ID NO:28 (SCB-VL-55).
  • an anti-IL-4Ra antibody comprises an amino acid sequence pair selected from the group consisting of: SEQ ID NOs:67/68 (MEDI-1-VH/MEDI-1-VL); SEQ ID NQs:69/70 (MEDI-2-VH/MEDI-2-VL); SEQ ID NOs:71/72 (MEDI-3-VH/MEDI-3-VL); SEQ ID NOs:73/74 (MEDI-4-VH/MEDI-4-VL); SEQ ID NOs:75/76 (MEDI-5-VH/MEDI-5-VL); SEQ ID NOs:77/78 (MEDI-6-VH/MEDI-6/VL); SEQ ID NQs:79/80 (MEDI-7-VH/MEDI-7-VL); SEQ ID NOs:81/82 (MEDI-8-VH/MEDI-8-VL); SEQ ID NOs:83/84 (MEDI-9-VH/MEDI-9-VL); SEQ ID NOs:
  • an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:153 (AJOU-1-VH), SEQ ID NO:154 (AJOU-2-VH), SEQ ID NO: 155 (AJOU-3-VH), SEQ ID NO: 156 (AJOU-4-VH), SEQ ID NO: 157 (AJOU-5-VH), SEQ ID NO:158 (AJOU-6-VH), SEQ ID NO:159 (AJOU-7-VH), SEQ ID NO:160 (AJOU-8-VH), SEQ ID NO:161 (AJOU-9-VH), SEQ ID NO:162 (AJQU-10-VH), SEQ ID NO:163 (AJOU-69-VH), SEQ ID NO:164 (AJQU-70-VH), SEQ ID NO:165 (AJOU-71-VH), SEQ ID NO:166 (AJOU-72-VH), or SEQ ID NO: 167 (AJOU-83-VH);
  • an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:188 (REGN-VH-3), SEQ ID NO:189 (REGN-VH-19), SEQ ID NO:190 (REGN-VH-35), SEQ ID NO:191 (REGN-VH-51), SEQ ID NO:192 (REGN-VH-67), SEQ ID NO:193 (REGN-VH-83), SEQ ID NO:194 (REGN-VH-99), SEQ ID NO:195 (REGN-VH- 115), SEQ ID NO:196 (REGN-VH-147), or SEQ ID NO:197 (REGN-VH-163); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:198 (REGN-VL-11), SEQ ID NO:199 (REGN-VL-27), SEQ ID N0:200 (REGN-VL-43), SEQ ID NO:201 (REGN
  • an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NQ:208 (STSA-C27-VH), SEQ ID NQ:209 (STSA-C27-6-33- VH), SEQ ID NO:210 (STSA-C27-7-33-VH), SEQ ID NO:211 (STSA-C27-24-56-VH), SEQ ID NO:212 (STSA-C27-47-56-VH), SEQ ID NO:213 (STSA-C27-33-33-VH), SEQ ID NO:214 (STSA-C27-56-56-VH), SEQ ID NO:215 (STSA-C27-78-78-VH), SEQ ID NO:216 (STSA-C27- 82-58-VH), SEQ ID NO:217 (STSA-C27-54-54-VH), SEQ ID NO:218 (STSA-C27-36-36-VH), SEQ
  • an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:244 (Y0188-1 VH), SEQ ID NO:245 (Y0188-2 VH), SEQ ID NO:246 (Y0188-3 VH), SEQ ID NO:247 (Y0188-4 VH), SEQ ID NO:248 (Y0188-6 VH), SEQ ID NO:249 (Y0188-8 VH), SEQ ID NQ:250 (Y0188-9 VH), SEQ ID NO:251 (Y0188-10 VH), SEQ ID NO:252 (Y0188-14 VH), SEQ ID NO:253 (HV3-15-14 VH), SEQ ID NO:254 (HV3-48-14 VH), SEQ ID NO:255 (HV3-73*2-14 VH), SEQ ID NO:256 (HV3-72-14 VH), SEQ ID NO:257 (Y01-14 VH), SEQ ID NO:258
  • an anti-IL-4Ra antibody used in the methods of the present disclosure can have pH-dependent binding characteristics.
  • an anti-IL-4Ra antibody for use as disclosed herein may exhibit reduced binding to IL-4Ra at acidic pH as compared to neutral pH.
  • an anti-IL-4Ra antibody for use as disclosed herein may exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH.
  • acidic pH includes pH values less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1 , 5.05, 5.0, or less.
  • neutral pH means a pH of about 7.0 to about 7.4.
  • neutral pH includes pH values of about 7.0, 7.05, 7.1 , 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.
  • "reduced binding to IL-4Ra at acidic pH as compared to neutral pH” is expressed in terms of a ratio of the KD value of the antibody binding to IL-4Ra at acidic pH to the K D value of the antibody binding to IL-4Ra at neutral pH (or vice versa).
  • an antibody or antigen-binding fragment thereof may be regarded as exhibiting "reduced binding to IL-4Ra at acidic pH as compared to neutral pH” for purposes of the present disclosure if the antibody or antigen-binding fragment thereof exhibits an acidic/neutral KD ratio of about 3.0 or greater.
  • the acidic/neutral KD ratio for an antibody or antigen-binding fragment of the present disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or greater.
  • Antibodies with pH-dependent binding characteristics may be obtained, e.g., by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH as compared to neutral pH. Additionally, modifications of the antigen-binding domain at the amino acid level may yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an antigen-binding domain (e.g., within a CDR) with a histidine residue, an antibody with reduced antigen-binding at acidic pH relative to neutral pH may be obtained.
  • the VELOCIMMUNE® technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation.
  • the DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions.
  • the DNA is then expressed in a cell capable of expressing the fully human antibody.
  • lymphatic cells such as B-cells
  • the lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest.
  • DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain.
  • Such an antibody protein may be produced in a cell, such as a CHO cell.
  • DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.
  • high affinity chimeric antibodies are isolated having a human variable region and a mouse constant region.
  • the antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art.
  • the mouse constant regions are replaced with a desired human constant region to generate the fully human antibody of the disclosure, for example wild-type or modified IgG 1 or lgG4. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
  • the antibodies that can be used in the methods of the present disclosure possess high affinities, as described above, when measured by binding to antigen either immobilized on solid phase or in solution phase.
  • the mouse constant regions are replaced with desired human constant regions to generate the fully human antibodies of the disclosure. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
  • a human antibody or antigen-binding fragment thereof that specifically binds IL-4R and that can be used in the methods disclosed herein comprises the three heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO:1 , and the three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO:2.
  • Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, and the AbM definition.
  • the Kabat definition is based on sequence variability
  • the Chothia definition is based on the location of the structural loop regions
  • the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani, et al., J. Mol. Biol., 273:927-948 (1997); and Martin, et al., Proc. Natl. Acad. Sci. USA, 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within an antibody.
  • the present disclosure provides methods that comprise administering an IL-4R antagonist to a subject, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained within a pharmaceutical composition that comprises one or more pharmaceutically acceptable vehicle, carriers, and/or excipients.
  • a pharmaceutical composition that comprises one or more pharmaceutically acceptable vehicle, carriers, and/or excipients.
  • Various pharmaceutically acceptable carriers and excipients are well-known in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.
  • the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
  • a pharmaceutical composition as disclosed herein is administered intravenously.
  • a pharmaceutical composition as disclosed herein is administered subcutaneously.
  • the pharmaceutical composition comprises an injectable preparation, such as a dosage form for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc.
  • injectable preparations may be prepared by known methods.
  • the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
  • aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glycol
  • a nonionic surfactant e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil
  • oily medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • the dose of antibody administered to a subject according to the methods of the present disclosure may vary depending upon the age and the size of the subject, symptoms, conditions, route of administration, and the like.
  • the dose is typically calculated according to body weight or body surface area.
  • Effective dosages and schedules for administering pharmaceutical compositions comprising anti-IL-4R antibodies may be determined empirically; for example, subject progress can be monitored by periodic assessment, and the dose adjusted accordingly.
  • interspecies scaling of dosages can be performed using well-known methods in the art (e.g., Mordenti, et al., 1991 , Pharmaceut. Res., 8:1351).
  • Specific exemplary doses of anti-IL4R antibodies, and administration regimens involving the same, that can be used in the context of the present disclosure are disclosed elsewhere herein.
  • an IL-4R antagonist or a pharmaceutical composition of the present disclosure is contained within a container.
  • containers comprising an IL-4R antagonist or a pharmaceutical composition as disclosed herein are provided.
  • a pharmaceutical composition is contained within a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an autoinjector.
  • a pharmaceutical composition of the present disclosure is delivered, e.g., subcutaneously or intravenously, with a standard needle and syringe.
  • the syringe is a pre-filled syringe.
  • a pen delivery device or autoinjector is used to deliver a pharmaceutical composition of the present disclosure (e.g., for subcutaneous delivery).
  • a pen delivery device can be reusable or disposable.
  • a reusable pen delivery device utilizes a replaceable cartridge that contains a pharmaceutical composition. Once the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused.
  • Suitable pen and autoinjector delivery devices include, but are not limited to AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and Co., Indianapolis, IN), NOVOPENTM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROTM, OPTIPEN STARLETTM, and OPTICLIKTM (sanofi-aventis, Frankfurt, Germany).
  • Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTARTM pen (sanofi-aventis), the FLEXPENTM (Novo Nordisk), and the KWIKPENTM (Eli Lilly), the SURECLICKTM Autoinjector (Amgen, Thousand Oaks, CA), the PENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRATM Pen (Abbott Labs, Abbott Park IL).
  • the pharmaceutical composition is delivered using a controlled release system.
  • a pump may be used (see Langer, supra, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201).
  • polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida.
  • a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138).
  • a pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system as described in Table 1 of section 5.2 of ISO 11608-1 :2014(E).
  • a drug delivery device that is a needle-based injection system as described in Table 1 of section 5.2 of ISO 11608-1 :2014(E).
  • needle-based injection systems may be broadly distinguished into multi-dose container systems and single-dose (with partial or full evacuation) container systems.
  • the container may be a replaceable container or an integrated non-replaceable container.
  • a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).
  • Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).
  • a single-dose container system may involve a needle-based injection device with a replaceable container.
  • each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation).
  • each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).
  • a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container.
  • each container holds a single dose, whereby the entire deliverable volume is expelled (full evacuation).
  • each container holds a single dose, whereby a portion of the deliverable volume is expelled (partial evacuation).
  • An exemplary sleeve-triggered auto-injector with manual needle insertion is described in International Publication WO2015/004052.
  • Exemplary audible end-of-dose feedback mechanisms are described in International Publications WO2016/193346 and WO2016/193348.
  • An exemplary needle-safety mechanism after using an auto-injector is described in International Publication WO2016/193352.
  • An exemplary needle sheath remover mechanism for a syringe auto-injector is described in International Publication WO2016/193353.
  • An exemplary support mechanism for supporting an axial position of a syringe is described in International Publication WO2016/193355.
  • compositions for use as described herein are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
  • dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
  • compositions comprising an anti-IL-4R antibody that can be used in the context of the present disclosure are disclosed, e.g., in US Patent No. 8,945,559.
  • an IL-4R antagonist e.g., anti-IL-4R antibody
  • a subject e.g., a subject having a defect in bone growth
  • the phrase "therapeutically effective amount” means an amount of IL-4R antagonist that results in one or more of: (a) an improvement in bone formation; (b) an improvement in bone mineralization and/or bone mineral density; (c) a reduction in bone loss; (d) an improvement or normalization (e.g., relative to a healthy control value) in one or more biomarkers of bone formation or bone turnover (such as, but not limited to, bone-specific alkaline phosphatase, carboxy-terminal cross-linked telopeptide of type I collagen, pro-collagen type I N-terminal propeptide, insulin-like growth factor 1 , or osteocalcin); and/or (e) a reduction in the occurrence of osteopenia, osteoporosis, or fracture (e.g., relative to a healthy control value).
  • biomarkers of bone formation or bone turnover such as, but not limited to, bone-specific alkaline phosphatase, carboxy-terminal cross-linked telopeptide of type I collagen, pro-collagen
  • a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg,
  • a therapeutically effective amount is from about 50 mg to about 600 mg, or from about 100 mg to about 600 mg, or from about 200 mg to about 600 mg.
  • 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg of an anti-IL-4R antibody is administered to a subject.
  • the amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of subject body weight (/.e., mg/kg).
  • the IL-4R antagonist may be administered to a subject at a dose of about 0.0001 to about 10 mg/kg of subject body weight, e.g., at a dose of about 1 mg/kg to about 10 mg/kg, at a dose of about 2 mg/kg to about 9 mg/kg, or at a dose of about 3 mg/kg to about 8 mg/kg.
  • the IL-4R antagonist may be administered to a subject at a dose of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, or 10 mg/kg.
  • the methods disclosed herein comprise administering an IL-4R antagonist to a subject at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved.
  • the methods disclosed herein comprise administering an IL-4R antagonist to a subject once every week, once every two weeks, once every three weeks, or once every four weeks.
  • the methods disclosed herein comprise administering an IL-4R antagonist to a subject once a month or twice a month.
  • multiple doses of an IL-4R antagonist are administered to a subject over a defined time course.
  • the methods of the present disclosure comprise sequentially administering to a subject multiple doses of an IL-4R antagonist.
  • sequentially administering means that each dose of IL-4R antagonist is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).
  • the methods of the disclosure comprise sequentially administering to the patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of the IL- 4R antagonist, and optionally followed by one or more tertiary doses of the IL-4R antagonist.
  • the terms "initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the IL-4R antagonist.
  • the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the "loading dose”);
  • the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses.
  • the initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of IL-4R antagonist contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, one or more (e.g., 1 , 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").
  • the initial or loading dose and the one or more secondary or maintenance doses each contain the same amount of the IL-4R antagonist.
  • the initial dose comprises a first amount of the IL-4R antagonist
  • the one or more secondary doses each comprise a second amount of the IL-4R antagonist.
  • the first amount of the IL-4R antagonist can be 1 ,5x, 2x, 2.5x, 3x, 3.5x, 4x or 5x or more than the second amount of the IL-4R antagonist.
  • one or more maintenance doses of the IL-4R antagonist are administered without a loading dose.
  • a loading dose is a "split dose" that is administered as two or more doses (e.g., 2, 3, 4, or 5 doses) that are administered on separate days.
  • a loading dose is administered as a split dose wherein the two or more doses are administered at least about one week apart.
  • a loading dose is administered as a split dose wherein the two or more doses are administered about 1 week, 2 weeks, 3 weeks, or 4 weeks apart.
  • the loading dose is split evenly over the two or more doses (e.g., half of the loading dose is administered as the first portion and half of the loading dose is administered as the second portion).
  • the loading dose is split unevenly over the two or more doses (e.g., more than half of the loading dose is administered as the first portion and less than half of the loading dose is administered as the second portion).
  • each secondary and/or tertiary dose is administered 1 to 14 (e.g., 1 , 1 %, 2, 2/2, 3, 3 1 / 2 , 4, 4 1 / 2 , 5, 5 1 / 2 , 6, 6 1 / 2 , 7, 7%, 8, 8 1 / 2 , 9, 9 1 / 2 , 10, 10 1 / 2 , 11 , 1 1%, 12, 12 1 / 2 , 13, 13%, 14, 14%, or more) weeks after the immediately preceding dose.
  • the phrase "the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of IL-4R antagonist which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
  • the methods of the disclosure may comprise administering to a patient any number of secondary and/or tertiary doses of an IL-4R antagonist.
  • any number of secondary and/or tertiary doses of an IL-4R antagonist may comprise administering to a patient any number of secondary and/or tertiary doses of an IL-4R antagonist.
  • only a single secondary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient.
  • only a single tertiary dose is administered to the patient.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
  • each secondary dose is administered at the same frequency as the other secondary doses.
  • each secondary dose may be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose.
  • each tertiary dose is administered at the same frequency as the other tertiary doses.
  • each tertiary dose may be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose.
  • the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
  • a therapeutically effective amount of an IL-4R antagonist comprises 300 mg administered every two weeks (Q2W).
  • a therapeutically effective amount of an IL-4R antagonist comprises a loading dose of 600 mg followed by one or more subsequent doses of 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 200 mg administered every two weeks (Q2W).
  • a therapeutically effective amount of an IL-4R antagonist comprises a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 300 mg administered every four weeks (Q4W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., anti-IL-4R antibody) comprises a loading dose of 600 mg followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W).
  • a therapeutically effective amount of an IL-4R antagonist comprises a split loading dose of 600 mg (e.g., in which 300 mg is administered on Day 1 and 300 mg is administered on Day 15) followed by one or more subsequent doses of 300 mg administered Q4W starting four weeks after the Day 15 dose. In some embodiments, no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 200 mg administered every four weeks (Q4W).
  • a therapeutically effective amount of an IL-4R antagonist comprises a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every four weeks (Q4W). In some embodiments, no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 300 mg administered every two weeks (Q2W), if the subject is >60 kg in weight.
  • the subject is administered a loading dose of 600 mg followed by one or more subsequent doses of 300 mg administered every two weeks (Q2W), if the subject is >60 kg in weight.
  • no loading comprises 300 mg administered every two weeks (Q2W), if the subject is >60 kg in weight.
  • a therapeutically effective amount of an IL-4R antagonist comprises 200 mg administered every two weeks (Q2W), if the subject is ⁇ 60 kg in weight.
  • the subject is administered a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W), if the subject is ⁇ 60 kg in weight.
  • no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 200 mg administered every two weeks (Q2W), if the subject is >30 kg to ⁇ 60 kg in weight.
  • the subject is administered a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W), if the subject is >30 kg to ⁇ 60 kg in weight. In some embodiments, no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 200 mg administered every two weeks (Q2W)
  • a therapeutically effective amount of an IL-4R antagonist comprises 300 mg administered every four weeks (Q4W), if the subject is >15 kg to ⁇ 60 kg in weight.
  • the subject is administered a loading dose of 600 mg followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W), if the subject is >15 kg to ⁇ 60 kg in weight.
  • the subject is administered a split loading dose of 600 mg (e.g., in which 300 mg is administered on Day 1 and 300 mg is administered on Day 15) followed by one or more subsequent doses of 300 mg administered Q4W starting four weeks after the Day 15 dose.
  • no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 300 mg administered every four weeks (Q4W), if the subject is >15 kg to ⁇ 30 kg in weight.
  • the subject is administered a loading dose of 600 mg followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W), if the subject is >15 kg to ⁇ 30 kg in weight.
  • the subject is administered a split loading dose of 600 mg (e.g., in which 300 mg is administered on Day 1 and 300 mg is administered on Day 15) followed by one or more subsequent doses of 300 mg administered Q4W starting four weeks after the Day 15 dose.
  • no loading dose is administered.
  • a therapeutically effective amount of an IL-4R antagonist comprises 200 mg administered every four weeks (Q4W), if the subject is >5 kg to ⁇ 15 kg in weight.
  • the subject is administered a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every four weeks (Q4W), if the subject is >5 kg to ⁇ 15 kg in weight.
  • the subject is administered a split loading dose of 400 mg (e.g., in which 200 mg is administered on Day 1 and 200 mg is administered on Day 15) followed by one or more subsequent doses of 200 mg administered Q4W starting four weeks after the Day 15 dose.
  • no loading dose is administered.
  • the methods of the present disclosure comprise administering to the subject (e.g., a pediatric or adolescent subject having a defect in bone growth) an IL-4R antagonist according to the disclosure (e.g., an anti-IL-4R antibody) in combination with one or more additional therapeutic agents.
  • the additional therapeutic agent is a topical therapeutic agent, e.g., a TCS or a topical nonsteroidal medication such as a TCI or crisaborole.
  • the additional therapeutic agent is a systemic agent, e.g., cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, a Janus kinase (JAK) inhibitor, or interferon-gamma.
  • systemic agent e.g., cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, a Janus kinase (JAK) inhibitor, or interferon-gamma.
  • the additional therapeutic agent is an immunobiologic such as a tumor necrosis factor alpha (TNFa) inhibitor (e.g., an anti-TNFa antibody such as infliximab), a CD11a inhibitor (e.g., an anti-CD11a antibody such as efalizumab), an IgE inhibitor (e.g., omalizumab), or a CD20 inhibitor (e.g., rituximab).
  • TNFa tumor necrosis factor alpha
  • CD11a inhibitor e.g., an anti-CD11a antibody such as efalizumab
  • IgE inhibitor e.g., omalizumab
  • CD20 inhibitor e.g., rituximab
  • the expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrent with the IL-4R inhibitor.
  • the term “in combination with” also includes sequential or concomitant administration of IL-4R inhibitor and the additional therapeutic agent.
  • the additional therapeutic agent when administered "before" the pharmaceutical composition comprising the IL-4R antagonist, may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the pharmaceutical composition comprising the IL-4R antagonist.
  • the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the pharmaceutical composition comprising the IL-4R antagonist.
  • Administration "concurrent" or with the pharmaceutical composition comprising the IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than about 10 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the IL-4R antagonist, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.
  • the additional therapeutic agent is a TCS.
  • the TCS is a medium-potency TCS.
  • the TCS is a low- potency TCS.
  • the additional therapeutic agent is a TCI.
  • the additional therapeutic agent is crisaborole.
  • Example 1 Dupilumab Treatment of Children With Moderate-to-Severe Atopic Dermatitis Increases Bone Alkaline Phosphatase, a Marker of Bone Mineralization
  • the objective of this analysis is to report the impact of dupilumab treatment on markers of bone formation in children aged > 6 to ⁇ 12 years with moderate-to-severe AD.
  • LIBERTY AD PEDS a double-blind, 16-week, phase 3 trial, children aged 6 to ⁇ 12 years were randomized 1 :1 :1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w for patients with baseline weight ⁇ 30 kg, and 200 mg q2w for those with baseline weight > 30 kg), or placebo; with concomitant medium-potency topical corticosteroids (TCS).
  • TCS medium-potency topical corticosteroids
  • BALP levels were significantly increased vs baseline (placebo vs placebo transitioned to dupilumab: 64.2[1.04]pg/L vs 82.9[1.04]pg/L, P ⁇ 0.0001 ; 100/200mg q2w: 62.0[ 1.05] pg/L vs 83.8[1.03]pg/L, P ⁇ 0.0001 ; 300mg q4w: 64.1 [1.04] pg/L vs 78.7[1.04]pg/L, P ⁇ 0.0001), and also increased within reference intervals (Diemar, et al., Bone, 2021 , 146:115879).
  • dupilumab Treatment with dupilumab increased BALP levels to reference intervals for both female and male patients and reflected this gender difference. At 16 weeks, dupilumab treatment led to a rapid and significant increase in geometric mean (standard error) levels of BALP in girls and boys compared with patients in the placebo group (girls: 80.0 (1.04) pg/L vs 70.1 (1.06) pg/L, P - 0.0018; boys: 75.7 (1.03) pg/L vs 60.4 (1.07) pg/L, P ⁇ 0.0001). Dupilumab treatment led to increases in levels of BALP in all treated children, reaching levels up to 90.5 pg/L in girls and 86.6 pg/L in boys. See, Figures 6-7.
  • dupilumab treatment led to a rapid and significant increase in geometric mean (standard error) levels of BALP in children with moderate-to-severe AD at 16 weeks compared with patients in the placebo group (with asthma: 76.8 [1.04]
  • jg/L vs 59.1 [1.07] pg/L, P ⁇ 0.0001 ; without asthma: 78.5 [1.03] pg/L vs 70.7 [1.05] pg/L, P 0.0024).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés d'amélioration de la croissance osseuse chez un sujet. Selon un aspect, les procédés comprennent l'administration au sujet ayant un défaut dans la croissance osseuse d'une ou plusieurs doses d'un antagoniste du récepteur de l'interleukine-4 (IL-4R), tel qu'un anticorps anti-IL-4R ou un fragment de liaison à l'antigène de celui-ci.
PCT/US2023/080989 2022-11-23 2023-11-22 Procédés d'amélioration de la croissance osseuse par administration d'un antagoniste d'il-4r WO2024112935A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202263384816P 2022-11-23 2022-11-23
US63/384,816 2022-11-23
US202363480717P 2023-01-20 2023-01-20
US63/480,717 2023-01-20
US202363498946P 2023-04-28 2023-04-28
US63/498,946 2023-04-28

Publications (1)

Publication Number Publication Date
WO2024112935A1 true WO2024112935A1 (fr) 2024-05-30

Family

ID=89474536

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/080989 WO2024112935A1 (fr) 2022-11-23 2023-11-22 Procédés d'amélioration de la croissance osseuse par administration d'un antagoniste d'il-4r

Country Status (1)

Country Link
WO (1) WO2024112935A1 (fr)

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US7186809B2 (en) 2000-05-26 2007-03-06 Immunex Corporation Methods and compositions relating to anti-interleukin-4 receptor antibodies
US7605237B2 (en) 2006-10-02 2009-10-20 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to human IL-4 receptor
US7608693B2 (en) 2006-10-02 2009-10-27 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to human IL-4 receptor
US7638606B2 (en) 2003-11-07 2009-12-29 Immunex Corporation Antibodies that bind interleukin-4 receptor
US8092804B2 (en) 2007-12-21 2012-01-10 Medimmune Limited Binding members for interleukin-4 receptor alpha (IL-4Rα)-173
WO2015004052A1 (fr) 2013-07-09 2015-01-15 Sanofi-Aventis Deutschland Gmbh Auto-injecteur
US8945559B2 (en) 2010-10-06 2015-02-03 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies
WO2016193346A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Indicateur sonore pour dispositif d'administration de médicament
WO2016193353A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Préhenseur de protecteur d'aiguille, capuchon, auto-injecteur et procédé de production d'un préhenseur
WO2016193352A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Verrou de protection
WO2016193348A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Indicateur sonore
WO2016193355A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Support de seringue et auto-injecteur
WO2020096381A1 (fr) 2018-11-09 2020-05-14 아주대학교 산학협력단 Anticorps humain présentant une affinité élevée vis-à-vis du récepteur alpha d'il -4 humain, et son utilisation
US10774141B2 (en) 2016-06-08 2020-09-15 Suzhou Connect Biopharmaceuticals, Ltd. Antibody for binding to interleukin 4 receptor
WO2020182197A1 (fr) 2019-03-13 2020-09-17 苏州康乃德生物医药有限公司 Composition liquide comprenant un anticorps du récepteur alpha de l'interleukine 4 humaine
WO2020239134A1 (fr) 2019-05-29 2020-12-03 山东博安生物技术有限公司 Anticorps anti-récepteur de l'interleukine 4 et son application
WO2021213329A1 (fr) 2020-04-24 2021-10-28 苏州康乃德生物医药有限公司 LIAISON D'ANTICORPS AVEC UN ÉPITOPE SPÉCIFIQUE DANS UNE IL-4Rα HUMAINE ET APPLICATION DE L'ANTICORPS
WO2022052974A1 (fr) 2020-09-10 2022-03-17 Staidson (Beijing) Biopharmaceuticals Co., Ltd. Anticorps reconnaissant de manière spécifique le récepteur alpha de l'interleukine 4 et leurs utilisations
WO2022136669A1 (fr) 2020-12-23 2022-06-30 Numab Therapeutics AG Anticorps multispécifiques ayant une spécificité pour il-4r et il-31
WO2022136675A1 (fr) 2020-12-23 2022-06-30 Numab Therapeutics AG Domaines variables d'anticorps se liant à il-4r

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7186809B2 (en) 2000-05-26 2007-03-06 Immunex Corporation Methods and compositions relating to anti-interleukin-4 receptor antibodies
US8679487B2 (en) 2000-05-26 2014-03-25 Immunex Corporation Anti-interleukin-4 receptor antibodies
US6596541B2 (en) 2000-10-31 2003-07-22 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US7638606B2 (en) 2003-11-07 2009-12-29 Immunex Corporation Antibodies that bind interleukin-4 receptor
US7605237B2 (en) 2006-10-02 2009-10-20 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to human IL-4 receptor
US7608693B2 (en) 2006-10-02 2009-10-27 Regeneron Pharmaceuticals, Inc. High affinity human antibodies to human IL-4 receptor
US8092804B2 (en) 2007-12-21 2012-01-10 Medimmune Limited Binding members for interleukin-4 receptor alpha (IL-4Rα)-173
US8877189B2 (en) 2007-12-21 2014-11-04 Medimmune Limited Binding members for interleukin-4 receptor alpha (IL-4Rα) - 173
US8945559B2 (en) 2010-10-06 2015-02-03 Regeneron Pharmaceuticals, Inc. Stabilized formulations containing anti-interleukin-4 receptor (IL-4R) antibodies
WO2015004052A1 (fr) 2013-07-09 2015-01-15 Sanofi-Aventis Deutschland Gmbh Auto-injecteur
WO2016193346A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Indicateur sonore pour dispositif d'administration de médicament
WO2016193353A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Préhenseur de protecteur d'aiguille, capuchon, auto-injecteur et procédé de production d'un préhenseur
WO2016193352A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Verrou de protection
WO2016193348A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Indicateur sonore
WO2016193355A1 (fr) 2015-06-03 2016-12-08 Sanofi-Aventis Deutschland Gmbh Support de seringue et auto-injecteur
US10774141B2 (en) 2016-06-08 2020-09-15 Suzhou Connect Biopharmaceuticals, Ltd. Antibody for binding to interleukin 4 receptor
WO2020096381A1 (fr) 2018-11-09 2020-05-14 아주대학교 산학협력단 Anticorps humain présentant une affinité élevée vis-à-vis du récepteur alpha d'il -4 humain, et son utilisation
WO2020182197A1 (fr) 2019-03-13 2020-09-17 苏州康乃德生物医药有限公司 Composition liquide comprenant un anticorps du récepteur alpha de l'interleukine 4 humaine
WO2020239134A1 (fr) 2019-05-29 2020-12-03 山东博安生物技术有限公司 Anticorps anti-récepteur de l'interleukine 4 et son application
WO2021213329A1 (fr) 2020-04-24 2021-10-28 苏州康乃德生物医药有限公司 LIAISON D'ANTICORPS AVEC UN ÉPITOPE SPÉCIFIQUE DANS UNE IL-4Rα HUMAINE ET APPLICATION DE L'ANTICORPS
WO2022052974A1 (fr) 2020-09-10 2022-03-17 Staidson (Beijing) Biopharmaceuticals Co., Ltd. Anticorps reconnaissant de manière spécifique le récepteur alpha de l'interleukine 4 et leurs utilisations
WO2022136669A1 (fr) 2020-12-23 2022-06-30 Numab Therapeutics AG Anticorps multispécifiques ayant une spécificité pour il-4r et il-31
WO2022136675A1 (fr) 2020-12-23 2022-06-30 Numab Therapeutics AG Domaines variables d'anticorps se liant à il-4r

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
AL-LAZIKANI ET AL., J. MOL. BIOL., vol. 273, 1997, pages 927 - 948
CORREN ET AL., AM J RESPIR CRIT CARE MED., vol. 181, no. 8, 2010, pages 788 - 796
DIEMAR ET AL., BONE, vol. 146, 2021, pages 115879
GOODSON, MEDICAL APPLICATIONS OF CONTROLLED RELEASE, vol. 2, 1984, pages 115 - 138
IRVINE ALAN D ET AL: "P93 Dupilumab treatment in children with moderateto-severe atopic dermatitis increases levels of bone mineralization biomarkers", 1 June 2023 (2023-06-01), XP093143715, Retrieved from the Internet <URL:https://academic.oup.com/bjd/article/188/Supplement_4/ljad113.121/7207210> *
KAZANE ET AL., J. AM. CHEM. SOC., 4 December 2012 (2012-12-04)
KLEIN ET AL., MABS, vol. 4, no. 6, 2012, pages 1 - 11
LANGER, SCIENCE, vol. 249, 1990, pages 1527 - 1533
LEUNG ET AL., HONG KONG MED J, vol. 23, 2017, pages 470 - 479
LOWE ET AL., J ALLERGY CLIN IMMUNOL, vol. 145, 2020, pages 563 - 571
LOWE KATHERINE E ET AL: "Atopic eczema and fracture risk in adults: A population-based cohort study", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 145, no. 2, 19 November 2019 (2019-11-19), pages 563, XP086000366, ISSN: 0091-6749, [retrieved on 20191119], DOI: 10.1016/J.JACI.2019.09.015 *
MARTIN ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 9268 - 9272
MORDENTI ET AL., PHARMACEUT. RES., vol. 8, 1991, pages 1351
NCT03345914: "Study to Investigate the Efficacy and Safety of Dupilumab Administered With Topical Corticosteroids (TCS) in Participants >=6 to <12 Years With Severe Atopic Dermatitis (AD)", 13 August 2020 (2020-08-13), XP093143631, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT03345914> *
PEDREIRA ET AL., PEDIATR DERMATOL, vol. 24, 2007, pages 613 - 620
PENTERICH ET AL., J PEDIATR ENDOCRINOL METAB, vol. 31, 2018, pages 247 - 260
SIEGFRIED ELAINE C. ET AL: "Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized, Placebo-Controlled, Phase 3 Clinical Trial", AMERICAN JOURNAL OF CLINICAL DERMATOLOGY, vol. 22, no. 2, 3 March 2021 (2021-03-03), US, pages 243 - 255, XP093143648, ISSN: 1175-0561, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973645/pdf/40257_2020_Article_583.pdf> DOI: 10.1007/s40257-020-00583-3 *
SILVERBERG ET AL., J ALLERGY CLIN IMMUNOL, vol. 132, 2013, pages 1132 - 1138
SILVERBERG ET AL., PEDIATR ALLERGY IMMUNOL, vol. 26, 2015, pages 54 - 61
SILVERBERG, PEDIATR ALLERGY IMMUNOL., vol. 26, 2015, pages 54 - 61
TAYLOR ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 6287 - 6295
TOBIUME ET AL., J CLIN ENDOCRINOL METAB, vol. 82, 1997, pages 2056 - 2061
WU DI ET AL: "Bone mineral density, osteopenia, osteoporosis, and fracture risk in patients with atopic dermatitis: a systematic review and meta- analysis", ANNALS OF TRANSLATIONAL MEDICINE, vol. 9, no. 1, 1 January 2021 (2021-01-01), US, pages 40 - 40, XP093143598, ISSN: 2305-5839, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859773/pdf/atm-09-01-40.pdf> DOI: 10.21037/atm-20-4708 *
WU ET AL., ANN TRANSL MED, vol. 9, 2021, pages 40
WU ET AL., J. BIOL. CHEM., vol. 262, 1987, pages 4429 - 4432

Similar Documents

Publication Publication Date Title
AU2019204577B2 (en) Methods for treating allergy and enhancing allergen-specific immunotherapy by administering an IL-4R inhibitor
US11655291B2 (en) Compositions and methods for increasing muscle mass and muscle strength by specifically antagonizing GDF8 and or activin A
TW201329099A (zh) 經投與前蛋白轉化酶枯草桿菌素克新－９之抑制劑以降低脂蛋白濃度的方法
JP7164530B2 (ja) Ｉｌ－４ｒ阻害剤を投与することによって重度のアトピー性皮膚炎を処置するための方法
JP2022543815A (ja) Ｉｌ－４ｒアンタゴニストを投与することによりアレルギーを治療しアレルゲン特異的免疫療法を増強するための方法
US20230102151A1 (en) Methods for treating atopic dermatitis by administering an il-4r antagonist
US20220119514A1 (en) Methods for altering body composition by administering a gdf8 inhibitor and an activin a inhibitor
WO2024112935A1 (fr) Procédés d&#39;amélioration de la croissance osseuse par administration d&#39;un antagoniste d&#39;il-4r
RU2789047C2 (ru) Способы лечения аллергии и повышения эффективности аллерген- специфической иммунотерапии путем введения ингибитора ил-4р
WO2023130010A1 (fr) Méthodes pour atténuer la marche atopique par administration d&#39;un antagoniste d&#39;il-4/il-13
WO2024097714A1 (fr) Méthodes de traitement de la dermatite de la main et du pied par administration d&#39;un antagoniste d&#39;il-4r
WO2023212586A1 (fr) Procédés de sélection de patients pour le traitement avec un antagoniste du ngf