Methods for improving bone growth by administering an IL-4R antagonist

Abstract

Methods for improving bone growth in a subject are provided. In one aspect, the methods include administering to a subject having a deficiency in bone growth one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed on November 22, 2023 as a PCT international patent application claiming priority to and benefit of U.S. Provisional Patent Application No. 63 / 384,816, filed on November 23, 2022, No. 63 / 480,717, filed on January 20, 2023, and No. 63 / 498,946, filed on April 28, 2023, the contents of each of which are incorporated herein by reference.

[0002] Reference to the array list XML This application contains a Sequence Listing that has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. The XML file was created on November 17, 2023, is named 40848_0118WOU1_SL.xml, and is 267,776 bytes in size.

[0003] The present disclosure relates to the use of interleukin-4 receptor (IL-4R) antagonists to improve bone growth. [Background technology]

[0004] Children with atopic dermatitis (AD) are at risk for low bone mineral density (BMD), which is associated with increased prevalence of osteopenia, osteoporosis, and fracture risk (Wu, et al., Ann Transl Med, 2021, 9:40. doi:10.21037 / atm-20-4708; Lowe, et al., J Allergy Clin Immunol, 2020, 145:563-571). Factors such as restricted nutrition, vitamin D deficiency, poor sleep, and corticosteroid use contribute to lower bone alkaline phosphatase (BALP) levels, a marker of bone mineralization, in children with moderate to severe AD compared with healthy children (Silverberg, Pediatr Allergy Immunol, 2015, 26:54-61).

[0005] A major determinant of lifetime risk for fracture and osteoporosis is the magnitude of peak bone mass achieved during early adolescence (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 may contribute to a higher prevalence of osteopenia and osteoporosis. Summary of the Invention

[0006] In one aspect, methods for improving bone growth are provided. In some embodiments, the methods include: Selecting a subject having a defect in bone growth, wherein the subject is a pediatric subject or an adolescent under the age of 18; and Administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist.

[0007] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or antigen-binding fragment thereof, comprising, for example, one or more CDR, HCVR, and / or LCVR sequences shown in Table 1. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0008] In some embodiments, the subject has atopic dermatitis (AD). In some embodiments, the subject has moderate to severe or severe AD.

[0009] In some embodiments, the subject is a pediatric subject having an age of less than 12 years. In some embodiments, the subject is between 6 and 11 years old. In some embodiments, the subject is between 6 months and 5 years old.

[0010] In some embodiments, the subject is an adolescent between the ages of 12 and 17 years.

[0011] In some embodiments, the subject has coexisting asthma.

[0012] In some embodiments, the selecting step comprises selecting a subject exhibiting a level of a bone turnover marker below a threshold, wherein the bone turnover marker is bone-specific alkaline phosphatase, carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I procollagen (PINP), insulin-like growth factor 1 (IGF-1), or osteocalcin. In some embodiments, the threshold is the mean level of the bone turnover marker for a population of healthy subjects of the same age as the selected pediatric or adolescent subject.

[0013] In some embodiments, the bone turnover marker is bone-specific alkaline phosphatase.

[0014] In some embodiments, 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 weekly (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 to 600 mg, followed by one or more subsequent doses of 50 to 300 mg, with each subsequent dose administered one to four weeks after the immediately preceding dose.

[0015] In some embodiments, the IL-4R antagonist is administered as an initial dose of 200 mg, followed by one or more subsequent doses of 200 mg.

[0016] In some embodiments, the IL-4R antagonist is administered as an initial dose of 300 mg, followed by one or more subsequent doses of 300 mg.

[0017] In some embodiments, the IL-4R antagonist is administered as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg.

[0018] In some embodiments, the IL-4R antagonist is administered as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg.

[0019] In some embodiments, the subject is a pediatric subject between the ages of 6 and 11 years or an adolescent between the ages of 12 and 17 years, the subject has a baseline body weight of ≥ 60 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W.

[0020] In some embodiments, the subject is an adolescent with a baseline weight <60 kg and the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

[0021] In some embodiments, the subject is a pediatric subject aged 6 to 11 years and having a baseline weight of ≧30 kg to <60 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

[0022] In some embodiments, the subject is a pediatric subject aged 6 to 11 years and having a baseline weight of ≥ 15 kg to < 30 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q4W.

[0023] In some embodiments, the subject is a pediatric subject aged 6 to 11 years with a baseline weight of ≧15 kg to <60 kg, and the IL-4R antagonist is administered subcutaneously 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 4 weeks after the dose on day 15.

[0024] In some embodiments, the subject is a pediatric subject aged between 6 months and 5 years and having a baseline weight of ≧15 kg to <30 kg, and the IL-4R antagonist is administered subcutaneously at a dose of 300 mg Q4W.

[0025] In some embodiments, the subject is a pediatric subject aged between 6 months and 5 years and having a baseline weight of ≧5 kg to <15 kg, and the IL-4R antagonist is administered subcutaneously at a dose of 200 mg Q4W.

[0026] In some embodiments, the IL-4R antagonist is administered for at least 16 weeks.

[0027] In some embodiments, the IL-4R antagonist is administered in combination with a topical AD medication. In some embodiments, the topical AD medication is TCS.

[0028] In some embodiments, treatment with an IL-4R antagonist results in an increase in bone growth in a subject as measured by an increase in a bone turnover marker selected from the group consisting of bone-specific alkaline phosphatase, β-CTX, PINP, IGF-1, and osteocalcin.

[0029] In some embodiments, 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 a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, 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 NO: 10. In some embodiments, the IL-4R antagonist is dupilumab.

[0030] In some embodiments, 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 auto-injector. 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 auto-injector.

[0031] In another aspect, a pharmaceutical composition for improving bone growth is provided. In some embodiments, the pharmaceutical composition comprises an interleukin-4 receptor (IL-4R) antagonist. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising one or more CDR, HCVR, and / or LCVR sequences, for example, as shown in Table 1. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the pharmaceutical composition is for use in improving bone growth in a pediatric or adolescent subject, for example, a pediatric or adolescent subject with atopic dermatitis.

[0032] In another aspect, provided herein is an interleukin-4 receptor (IL-4R) antagonist for the preparation of a medicament for improving bone growth. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or antigen-binding fragment thereof, comprising one or more CDR, HCVR, and / or LCVR sequences, e.g., as shown in Table 1. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the medicament is for use in improving bone growth in a pediatric or adolescent subject, for example, a pediatric or adolescent subject with atopic dermatitis.

[0033] Other embodiments will be apparent from consideration of the detailed description that follows. [Brief explanation of the drawings]

[0034] [Figure 1]Figure 1 shows the geometric means in bone alkaline phosphatase (BALP) (mcg / L) from baseline by visit for patients treated with placebo plus topical corticosteroids (TCS), dupilumab 300 mg Q4W plus TCS, or dupilumab 100 mg or 200 mg Q2W plus TCS in the 16-week parent study (R668-AD-1652; "LIBERTY AD PEDS") or subsequent open-label extension study (R668-AD-1434; "LIBERTY AD PED-OLE"). The week 8, week 12, and week 16 visits were from the parent study, and the week 52 visit was from the open-label extension study. Patients treated with placebo plus TCS during the parent study were crossed over to dupilumab 100 mg or 200 mg Q2W or 300 mg Q4W for the open-label extension study. ns, not significant; SE, standard error. [Figure 2] Figure 2 shows osteocalcin levels (ng / mL) at weeks 8, 12, 16, or 52 of treatment for patients treated with placebo plus TCS or dupilumab (100 / 200 mg Q2W or 300 mg Q4W) plus TCS. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper box limits), which correspond to the values ​​at the top of the graph. [Figure 3] Figure 3 shows procollagen type I N-terminal propeptide (PINP) levels (ng / mL) at weeks 8, 12, 16, or 52 of treatment for patients treated with placebo plus TCS or dupilumab (100 / 200 mg Q2W or 300 mg Q4W) plus TCS. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper box limits), which correspond to the values ​​at the top of the graph. [Figure 4]Figure 4 shows insulin-like growth factor 1 (IGF-1) levels (ng / mL) at weeks 8, 12, 16, or 52 of treatment for patients treated with placebo plus TCS or dupilumab (100 / 200 mg Q2W or 300 mg Q4W) plus TCS. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper box limits), which correspond to the values ​​at the top of the graph. [Figure 5] Figure 5 shows carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX) levels (pg / mL) at weeks 8, 12, 16, or 52 of treatment for patients treated with placebo plus TCS or dupilumab (100 / 200 mg Q2W or 300 mg Q4W) plus TCS. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper box limits), which correspond to the values ​​at the top of the graph. [Figure 6A] Figure 6A shows BALP geometric means over time for female patients in the 6-11 year old treatment group. a The dashed line represents the BALP reference range for females. b From week 16 onwards, these patients received active dupilumab treatment if enrolled in the LIBERTY AD PED-OLE trial. Week 8, 12, and 16 visits are from the LIBERTY AD PEDS trial, and the week 52 visit is from the LIBERTY AD PED-OLE trial. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, all vs. corresponding placebo + TCS. ns, not significant; SE, standard error. [Figure 6B]Figure 6B shows BALP geometric means over time for female (6A) and male (6B) patients in the 6-11 year old treatment group. a The dashed line represents the BALP reference range for males. b From week 16 onwards, these patients received active dupilumab treatment if enrolled in the LIBERTY AD PED-OLE trial. Week 8, 12, and 16 visits are from the LIBERTY AD PEDS trial, and the week 52 visit is from the LIBERTY AD PED-OLE trial. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, all vs. corresponding placebo + TCS. ns, not significant; SE, standard error. [Figure 7] Figure 7 shows BALP geometric means from baseline by visit for female (top row) and male (bottom row) patients in the 6-11 year old treatment group. The week 8, week 12, and week 16 visits are from the LIBERTY AD PEDS trial, and the week 52 visit is from the LIBERTY AD PED-OLE trial. Numbers below the gender and treatment regimen labels represent the group median and range from lower to upper quartile. a From week 16 onwards, these patients received active dupilumab treatment if enrolled in the LIBERTY AD PED-OLE trial. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001, all vs. corresponding baseline. DETAILED DESCRIPTION OF THE INVENTION

[0035] definition Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0037] As used herein, the term "about," when used in reference to a specific recited numerical value, means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0038] As used herein, the terms "treat," "treating," and the like mean to relieve symptoms, eliminate the cause of symptoms either temporarily or permanently, or prevent or delay the onset of symptoms of the specified disorder or condition.

[0039] As used herein, the term "subject in need thereof" refers to a human or non-human animal having a defect in bone growth. In some embodiments, "defect in bone growth" refers to, for example, a reduced level of bone mineral density and / or a reduced level of a biomarker of bone formation or bone mineralization compared to a healthy subject or population of subjects. In some embodiments, the term "subject in need thereof" refers to a pediatric patient <12 years of age, e.g., a patent aged 6 months to 5 years, or a patient aged 6 to 11 years. In some embodiments, the term "subject in need thereof" refers to an adolescent patient ≥12 years of age and <18 years of age. The terms "subject" and "patient" are used interchangeably herein.

[0040] "Atopic dermatitis" or "AD," as used herein, refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaly, dry, eczematous lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epidermal barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, dust mites, animals, etc.), radiation exposure, and / or asthma. The present disclosure encompasses methods for treating patients with moderate to severe or severe AD. As used herein, "moderate to severe AD" is characterized by intensely pruritic, widespread skin lesions often complicated by persistent bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD in patients. In many cases, chronic lesions include thickened plaques of the skin, lichenification, and fibrous papules. Patients with moderate to severe AD also typically have more than 20% of their body's skin or more than 10% of their skin area affected, in addition to involvement of the eyes, hands, and flexors of the body. Moderate to severe AD is also considered to be present in patients who require frequent treatment with topical corticosteroids. Patients may also be said to have moderate to severe AD if they are resistant or refractory to treatment with either topical corticosteroids or calcineurin inhibitors. As used herein, "severe AD" is characterized by the presence of widespread skin lesions, constant itching, or physically or emotionally disabling disease that significantly impairs the patient's quality of life. In some cases, patients with severe AD also exhibit one or more symptoms, such as scratching, widespread skin thickening, bleeding, weeping, and / or cracking of the skin, and changes in pigmentation. In some embodiments, severe AD is refractory to treatment with topical treatments (e.g., topical corticosteroids, calcineurin inhibitors, or crisaborole).

[0041] The term "TCS," as used herein, includes topical corticosteroids of Groups I, II, III, and IV. According to the World Health Organization's Anatomical Therapeutic Classification System, corticosteroids are classified as weak (Group I), moderately potent (Group II), potent (Group III), and very potent (Group IV) based on their activity relative to hydrocortisone. Group IV TCS (very potent) are up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (potent) are 50 to 100 times more potent than 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 (moderately potent; also referred to interchangeably herein as "mid-potency") are 2-25 times more potent than hydrocortisone and include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (mild; also referred interchangeably herein as "low-potency") include hydrocortisone.

[0042] Although any methods and materials similar or equivalent to those described herein can be used in the practice of this disclosure, exemplary methods and materials are described herein. All publications mentioned herein are incorporated by reference in their entirety.

[0043] Treatment method In one aspect, methods are provided for improving bone growth in a subject. In some embodiments, the subject has a defect in bone growth, e.g., a defect in bone formation or bone metabolism. In some embodiments, the method includes administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4Rα antibody or antigen-binding fragment thereof disclosed herein.

[0044] In some embodiments, the subject is a pediatric or adolescent subject under 18 years of age. 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.

[0045] In some embodiments, the subject is a pediatric or adolescent subject with a baseline weight of <60 kg. In some embodiments, the subject is a pediatric or adolescent subject with a baseline weight of <30 kg. In some embodiments, the subject has a baseline weight of ≥5 kg and <30 kg. In some embodiments, the subject has a baseline weight of ≥5 kg and <15 kg. In some embodiments, the subject has a baseline weight of ≥15 kg and <30 kg.

[0046] In some embodiments, the subject has an atopic disease. In some embodiments, the subject has AD (e.g., moderate to severe AD or severe AD). In some embodiments, 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 initiation of treatment. In some embodiments, the subject has moderate to severe or severe AD that has responded poorly to topical treatment (e.g., TCS with or without a topical calcineurin inhibitor (TCI)) or for which topical treatment is not advisable (e.g., due to adverse side effects or safety risks). In some embodiments, the subject has moderate to severe or severe AD and is a candidate for systemic treatment.

[0047] In some embodiments, the subject has AD (e.g., moderate to severe AD or severe AD) and one or more concomitant allergic conditions (i.e., excluding AD). In some embodiments, the subject has concurrent atopic dermatitis or an allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergies, non-food allergies, allergic conjunctivitis, urticaria, chronic rhinosinusitis, nasal polyps, and eosinophilic esophagitis.

[0048] In some embodiments, the subject has a deficiency in bone growth. In some embodiments, the subject has abnormal bone metabolism compared to a healthy control or a population of healthy control subjects. In some embodiments, the subject has decreased bone formation compared to a healthy control or a population of healthy control subjects. In some embodiments, the subject has decreased bone mineral density compared to a healthy control or a population of healthy control subjects. In some embodiments, the subject is at risk for skeletal fracture. In some embodiments, the subject has a history of skeletal fracture. In some embodiments, the subject has osteopenia. In some embodiments, the subject has osteoporosis (e.g., idiopathic juvenile osteoporosis or secondary osteoporosis). In some embodiments, the subject with a deficiency in bone growth has a history of treatment with a topical treatment (e.g., a topical corticosteroid, a calcineurin inhibitor, or crisaborole).

[0049] In some embodiments, subjects with defects in bone growth are selected based on the level of a bone-specific marker, such as a bone formation marker or a bone turnover marker. In some embodiments, the marker is bone-specific alkaline phosphatase, carboxy-terminal cross-linked telopeptide of type I collagen (CTX-1), N-terminal propeptide of type I procollagen (PINP), insulin-like growth factor 1 (IGF-1), or osteocalcin. In some embodiments, subjects are selected based on exhibiting a level of the marker (e.g., a bone turnover marker) below a threshold value.

[0050] In some embodiments, subjects having a deficiency in bone growth are selected based on the subject's bone mineral density (BMD), e.g., a Z-score calculated for one or more skeletal sites. In some embodiments, subjects are selected based on having a BMD Z-score below a threshold. In some embodiments, a subject is identified as having a deficiency in bone growth if the subject has a BMD Z-score of ≦−2.0, e.g., measured for the spine, femur, hip, or another skeletal site.

[0051] In some embodiments, threshold values ​​for a parameter or marker disclosed herein, such as a bone turnover marker or BMD Z-score, are determined by reference to a population of healthy subjects having the same age as, or an age range that encompasses, the selected pediatric or adolescent subject. For a given parameter or marker, one skilled in the art can determine the threshold value for a particular age or age range upon review of knowledge in the art about the levels of the parameter or marker in the general population. For example, methods for calculating mean BMD Z-scores for different age ranges of pediatric and adolescent subjects with AD or healthy control subjects have been described in Leung, et al., Hong Kong Med J, 2017, 23:470-479; Pedreira, et al., Pediatr Dermatol, 2007, 24:613-620; Penterich, et al., J Pediatr Endocrinol Metab, 2018, 31:247-260; Silverberg, et al., J Allergy Clin Immunol, 2013, 132:1132-1138; Silverberg, et al., Pediatr Allergy Immunol, 2015;26:54-61; and Wu, et al., Ann Transl Med, 2021, 9:40. doi:10.21037 / atm-20-4708. Methods for calculating average levels for bone formation / bone turnover markers, including bone alkaline phosphatase, osteocalcin, PINP, IGF-1, and β-CTX, are disclosed in Diemar, et al., Bone, 2021, 146:115879; Penterich, et al., J Pediatr Endocrinol Metab, 2018, 31:247-260; Silverberg, et al., Pediatr Allergy Immunol, 2015, 26:54-61; and Tobiume, et al., J Clin Endocrinol Metab, 1997, 82:2056-2061.In some embodiments, the threshold value is the lower value of the 95% reference range for an established bone turnover marker for pediatric or adolescent patients, for example, as shown in Table 3 of Diemar et al. Bone, 2021, 146:115879, or as provided by the Mayo Clinic Laboratories Pediatric Catalog (pediatric.testcatalog.org), incorporated herein by reference.

[0052] In some embodiments, subjects are selected based on exhibiting a bone alkaline phosphatase level below a threshold, e.g., a value lower than the 95% reference range for bone alkaline phosphatase established for a pediatric or adolescent patient population, hi some embodiments, subjects are selected if they have a serum bone alkaline phosphatase level <70 μg / L, <65 μg / L, <60 μg / L, or <55 μg / L.

[0053] In some embodiments, the subject is Age 8 to 9 years and have a serum bone alkaline phosphatase level of <53.4 μg / L (for female subjects) or <46.2 μg / L (for male subjects); or 10 to 11 years of age and have a serum bone alkaline phosphatase level of <50.6 μg / L (for female subjects) or <52.7 μg / L (for male subjects); or 12 to 13 years of age and have a serum bone alkaline phosphatase level of <54.6 μg / L (for female subjects) or <49.5 μg / L (for male subjects); or 14 to 15 years of age and have a serum bone alkaline phosphatase level of <14.2 μg / L (for female subjects) or <30.1 μg / L (for male subjects); or Subjects were selected if they were 16-17 years of age and had a serum bone alkaline phosphatase level of <12.3 μg / L (for female subjects) or <25.7 μg / L (for male subjects).

[0054] In some embodiments, the subject is selected based on exhibiting a level of osteocalcin below a threshold, e.g., a value lower than the 95% reference range for osteocalcin established for a pediatric or adolescent patient population. Age 8-9 years and have a serum osteocalcin level <68.5 μg / L (for female subjects) or <54.1 μg / L (for male subjects); or 10 to 11 years of age and have a serum osteocalcin level of <72.2 μg / L (for female subjects) or <55.8 μg / L (for male subjects); or 12 to 13 years of age and have a serum osteocalcin level of <82.9 μg / L (for female subjects) or <58.7 μg / L (for male subjects); or 14 to 15 years of age and have a serum osteocalcin level of <22.2 μg / L (for female subjects) or <54.1 μg / L (for male subjects); or Subjects were selected if they were 16-17 years of age and had a serum osteocalcin level of <18.8 μg / L (for female subjects) or <61.5 μg / L (for male subjects).

[0055] In some embodiments, the subject is selected based on exhibiting a level of PINP below a threshold, e.g., a value lower than the 95% reference range for PINP established for a population of pediatric or adolescent patients. Age 8-9 years and have a serum PINP level <415 μg / L (for female subjects) or <381 μg / L (for male subjects); or 10 to 11 years of age with a serum PINP level of <352 μg / L (for female subjects) or <298 μg / L (for male subjects); or 12 to 13 years of age with a serum PINP level <387 μg / L (for female subjects) or <168 μg / L (for male subjects); or 14 to 15 years of age and have a serum PINP level <65 μg / L (for female subjects) or <219 μg / L (for male subjects); or Subjects are selected if they are 16-17 years of age and have a serum PINP level of <55 μg / L (for female subjects) or <166 μg / L (for male subjects).

[0056] In some embodiments, the subject is selected based on exhibiting a level of β-CTX below a threshold, e.g., a value lower than the 95% reference range for β-CTX established for a population of pediatric or adolescent patients. Age 8-9 years and have a serum β-CTX level <1030ng / L (for female subjects) or <1080ng / L (for male subjects); or 10 to 11 years of age and have a serum β-CTX level of <1103 ng / L (for female subjects) or <1140 ng / L (for male subjects); or 12 to 13 years of age with a serum β-CTX level of <960 ng / L (for female subjects) or <1100 ng / L (for male subjects); or Age 14-15 years with a serum β-CTX level <330ng / L (for female subjects) or <1000ng / L (for male subjects); or Patients are selected if they are 16-17 years of age and have a serum β-CTX level of <290 ng / L (for female subjects) or <1060 ng / L (for male subjects).

[0057] In some embodiments, the subject is selected based on exhibiting a level of IGF-1 below a threshold, e.g., a value lower than the 95% reference range for IGF-1 established for a pediatric or adolescent patient population. <1 year of age and have a serum IGF-1 level <14 ng / mL (for female subjects) or <18 ng / mL (for male subjects); or 1 year of age and have a serum IGF-1 level <23 ng / mL (for female subjects) or <14 ng / mL (for male subjects); or 2 years of age and have a serum IGF-1 level <28 ng / mL (for female subjects) or <16 ng / mL (for male subjects); or 3 years of age and have a serum IGF-1 level <31 ng / mL (for female subjects) or <22 ng / mL (for male subjects); or 4 years of age and have a serum IGF-1 level <33 ng / mL (for female subjects) or <30 ng / mL (for male subjects); or 5 years of age and have a serum IGF-1 level <36 ng / mL (for female subjects) or <39 ng / mL (for male subjects); or 6 years of age and have a serum IGF-1 level <39 ng / mL (for female subjects) or <47 ng / mL (for male subjects); or 7 years of age and have a serum IGF-1 level <44 ng / mL (for female subjects) or <54 ng / mL (for male subjects); or Age 8 years and have a serum IGF-1 level <51 ng / mL (for female subjects) or <61 ng / mL (for male subjects); or 9 years of age and have a serum IGF-1 level <61 ng / mL (for female subjects) or <67 ng / mL (for male subjects); or 10 years of age and have a serum IGF-1 level <73 ng / mL (for female subjects) or <73 ng / mL (for male subjects); or 11 years of age and have a serum IGF-1 level <88 ng / mL (for female subjects) or <79 ng / mL (for male subjects); or 12 years of age and have a serum IGF-1 level <104 ng / mL (for female subjects) or <84 ng / mL (for male subjects); or 13 years of age and have a serum IGF-1 level <120 ng / mL (for female subjects) or <90 ng / mL (for male subjects); or 14 years of age and have a serum IGF-1 level <136 ng / mL (for female subjects) or <95 ng / mL (for male subjects); or 15 years of age and have a serum IGF-1 level <147 ng / mL (for female subjects) or <99 ng / mL (for male subjects); or 16 years of age and have a serum IGF-1 level <153 ng / mL (for female subjects) or <104 ng / mL (for male subjects); or 17 years of age and have a serum IGF-1 level <149 ng / mL (for female subjects) or <107 ng / mL (for male subjects); or Subjects are selected if they are 16-17 years of age and have a serum IGF-1 level of <55 μg / L (for female subjects) or <166 μg / L (for male subjects).

[0058] In some embodiments, treatment with an IL-4R antagonist improves bone growth, improves or normalizes bone turnover, or reduces the severity of bone defects (e.g., reduces the incidence or severity of skeletal fractures or reduces the severity of osteopenia or osteoporosis).

[0059] In some embodiments, treatment with an IL-4R antagonist improves one or more bone-related parameters in a subject. Examples of "bone-related parameters" include, but are not limited to, bone formation or bone turnover markers, such as bone-specific alkaline phosphatase, β-CTX, PINP, IGF-1, and osteocalcin; and bone mass density, measured, for example, by dual-energy X-ray absorptiometry (DEXA). "Improvement in bone-related parameters" refers to an improvement (e.g., increase or normalization) from baseline in one or more of the parameters. The term "baseline," as used in reference to bone-related parameters, refers to the value of the bone-related parameter for a subject before or at the start of administration of a pharmaceutical composition disclosed herein.

[0060] To determine whether a bone-related parameter is "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the present disclosure. For example, bone-related parameters 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 more after initial treatment with a pharmaceutical composition of the present disclosure. The difference between the value of the parameter at a particular time point after the start 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-related parameter.

[0061] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an increase in bone growth in a subject as measured by an increase in a bone turnover marker selected from the group consisting of bone-specific alkaline phosphatase, β-CTX, PINP, IGF-1, and osteocalcin. In some embodiments, treatment with an IL-4R antagonist results in an increase from baseline in the level of the marker by 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 30 weeks, 36 weeks, 48 ​​weeks, or 52 weeks after administration of a first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% increase in the level of the marker compared to baseline by 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 30 weeks, 36 weeks, 48 ​​weeks, or 52 weeks after administration of the first dose of the IL-4R antagonist.

[0062] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an increase in bone mass in a subject, as measured by bone mineral density (BMD) Z-score. In some embodiments, treatment with an IL-4R antagonist results in an improvement or normalization in the subject's BMD Z-score compared to baseline by 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 30 weeks, 36 weeks, 48 ​​weeks, or 52 weeks after administration of a first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in an increase in BMD Z-score 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% compared to baseline by 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks, 30 weeks, 36 weeks, 48 ​​weeks, or 52 weeks after administration of the first dose of the IL-4R antagonist.

[0063] Interleukin-4 receptor antagonist In some embodiments, the methods of the present disclosure include administering an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist to a subject in need thereof (e.g., a subject having a defect in bone growth). As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor," "IL-4R blocker," or "IL-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, while type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, 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 signaling mediated by both IL-4 and IL-13. IL-4R antagonists of the present disclosure may thus prevent the interaction of IL-4 and / or IL-13 with the type 1 or type 2 receptor.

[0064] Non-limiting examples of 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 containing the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0065] Anti-IL-4Rα antibodies and their antigen-binding fragments In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody," as used herein, includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or VL). H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (herein referred to as LCVR or V L The light chain constant region comprises one domain (C L 1) V H Area and V L The regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.

[0066] The term "antibody," as used herein, also includes antigen-binding fragments of intact antibody molecules. The terms "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 to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived from intact antibody molecules using any suitable standard techniques, such as proteolytic or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, e.g., phage antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to place one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0067] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) 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 amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other 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.

[0068] Antigen-binding fragments of antibodies typically contain at least one variable domain, which may be of any size or amino acid composition and generally comprises at least one CDR adjacent to, or in frame with, one or more framework sequences. L V associated with domain H In an antigen-binding fragment having a domain, V H Domain and V L The domains can be positioned relative to each other in any suitable configuration. For example, the variable region is a dimer, V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a dimer of monomeric V H or V L It may also include a domain.

[0069] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) a V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v) V H -C H 1-C H 2-C H 3;(vi)V H -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 -C H3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present disclosure may be linked to each other and / or to one or more monomeric V H or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above in non-covalent association (e.g., via disulfide bonds) of the domains.

[0070] The constant region of an antibody is important in the antibody's ability to fix complement and mediate cell-dependent cytotoxicity. Thus, in some embodiments, the antibody isotype may be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0071] The term "antibody," as used herein, also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of the antibodies or antigen-binding fragments of antibodies of the present disclosure using routine techniques available in the art. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα 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 invention include, without limitation, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knob-into-hole, common light chain (e.g., common light chain with knob-into-hole), CrossMab, CrossFab, (SEED) body, leucine zipper, duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include bispecific antibodies (see, e.g., Klein, et al., 2012, mAbs, 4:6, 1-11, and references cited therein for a review of the aforementioned formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, e.g., using unnatural amino acids with orthogonal chemical reactivity to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valency, and geometry (see, e.g., Kazane, et al., J. Am. Chem. Soc. [Epub: December 4, 2012]).

[0072] In some embodiments, 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. Human antibodies of the present disclosure may nevertheless 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, particularly CDR3. However, 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.

[0073] The antibody used in the methods of the present disclosure may be a recombinant human antibody. The term "recombinant human antibody," as used herein, is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, e.g., 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) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means, including splicing human immunoglobulin gene sequences into other DNA sequences. 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 animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis), thus modifying the V of the recombinant antibody. H Area and V L The amino acid sequence of the region is human germline V H Sequence and V LThese are sequences that, while derived from and related to sequences, may not naturally occur within the human antibody germline repertoire in vivo.

[0074] 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 the tissue or cell in which it is naturally present or produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has 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.

[0075] According to certain embodiments, the antibody used in the methods of the present disclosure specifically binds to IL-4Rα. As used herein, the term "specifically binds" means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological 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. In some embodiments, an antibody that "specifically binds" to IL-4Rα has an equilibrium dissociation constant (K) 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 for IL-4Rα or a portion thereof. D), as measured in a surface plasmon resonance assay (e.g., BIAcore™, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) can also specifically bind to another antigen, e.g., an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds to human IL-4Rα exhibits cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0076] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) comprising any of the amino acid sequences of the anti-IL-4R antibodies set forth in U.S. Patent No. 7,608,693, which is incorporated herein by reference. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody, or an antigen-binding fragment thereof, comprising a heavy chain complementarity-determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence GFTFRDYA (SEQ ID NO: 3), HCDR2 comprises the amino acid sequence ISGSGGNT (SEQ ID NO: 4), HCDR3 comprises the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO: 5), LCDR1 comprises the amino acid sequence QSLLYSIGYNY (SEQ ID NO: 6), LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence MQALQTPYT (SEQ ID NO: 8).

[0077] In some embodiments, 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 HCDR3 comprising the amino acid sequence MQALQTPYT (SEQ ID NO: 8). and further comprises a 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 a LCVR 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: 2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO:2.

[0078] In some embodiments, 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.

[0079] 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 NO:10 is the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure include the use of dupilumab. As used herein, "dupilumab" also includes bioequivalents of dupilumab. The term "bioequivalent," as used herein with reference to dupilumab, refers to anti-IL-4R antibodies or IL-4R binding proteins, or fragments thereof, that are pharmaceutical equivalents or pharmaceutical substitutes and that exhibit no significant difference in rate and / or extent of absorption from dupilumab when administered at the same molar dose under similar experimental conditions, either in single or multiple doses. In some embodiments, the term refers to antigen-binding proteins that bind to IL-4R that have no clinically meaningful differences from dupilumab in their safety, purity, and / or potency.

[0080] Other anti-IL-4Rα antibodies that can be used in the context of the disclosed methods include, for example, the antibody referred to as AMG317 (Corren, et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) and known in the art, or MEDI 9314, or any of the anti-IL-4Rα antibodies set forth in U.S. Pat. Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, 8,877,189, 10,774,141, or International Patent Publications WO2020 / 096381, WO2020 / 182197, WO2020 / 239134, WO2021 / 213329, WO2022 / 052974, WO2022 / 136669, or WO2022 / 136675, the contents of each of which are incorporated herein by reference.

[0081] In some embodiments, anti-IL-4Rα antibodies or antigen-binding fragments thereof for use in the methods of the disclosure comprise one or more CDR, HCVR, and / or LCVR sequences shown in Table 1 below.

[0082] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) 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 NO: 40 (SCB-VH-67), SEQ ID NO: 41 (SCB-VH-68), SEQ ID NO: 42 (SCB-VH-69), SEQ ID NO: 43 (SCB-VH-70), SEQ ID NO: 44 (SCB-VH-71), SEQ ID NO: 45 (SCB-VH-72), SEQ ID NO: 46 (SCB-VH-73), SEQ ID NO: 47 (SCB-VH-74), SEQ ID NO: 48 (SCB-VH-75), SEQ ID NO: 49 9 (SCB-VH-76), SEQ ID NO: 50 (SCB-VH-77), SEQ ID NO: 51 (SCB-VH-78), SEQ ID NO: 52 (SCB-VH-79), SEQ ID NO: 53 (SCB-VH-80), SEQ ID NO: 54 (SCB-VH-81), SEQ ID NO: 55 (SCB-VH-82), SEQ ID NO: 56 (SCB-VH-83), SEQ ID NO: 57 (SCB-VH-84), SEQ ID NO: 58 (SCB - a HCVR comprising the amino acid sequence of SCB-VH-85), SEQ ID NO: 59 (SCB-VH-86), SEQ ID NO: 60 (SCB-VH-87), SEQ ID NO: 61 (SCB-VH-88), SEQ ID NO: 62 (SCB-VH-89), SEQ ID NO: 63 (SCB-VH-90), SEQ ID NO: 64 (SCB-VH-91), SEQ ID NO: 65 (SCB-VH-92), or SEQ ID NO: 66 (SCB-VH-93);and (ii) SEQ ID NO:12 (SCB-VL-39), SEQ ID NO:13 (SCB-VL-40), SEQ ID NO:14 (SCB-VL-41), SEQ ID NO:15 (SCB-VL-42), SEQ ID NO:16 (SCB-VL-43), SEQ ID NO:17 (SCB-VL-44), SEQ ID NO:18 (SCB-VL-45), SEQ ID NO:19 (SCB-VL-46), SEQ ID NO:20 (SCB-VL-47), SEQ ID NO:21 (SCB-VL-48), SEQ ID NO:22 (SCB-VL-49), SEQ ID NO:23 (SCB-VL-50), SEQ ID NO:24 (SCB-VL-51), SEQ ID NO:25 (SCB-VL-52), SEQ ID NO:26 (SCB-VL-53), SEQ ID NO:27 (SCB-VL-54), SEQ ID NO:28 (SCB-VL-55), SEQ ID NO:29 (SCB-VL-56), SEQ ID NO:30 (SCB-VL-57), or SEQ ID NO:31 (SCB-VL-58). In some embodiments, the anti-IL-4Rα 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).

[0083] In some embodiments, the anti-IL-4Rα antibody comprises a pair of amino acid sequences selected from the group consisting of: SEQ ID NOs: 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NOs: 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 NOs: 79 / 80 (MEDI-8-VH / MEDI-8-VL); 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: 85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NOs: 87 / 88 (MEDI-11-VH / MEDI-11-VL); SEQ ID NOs: 89 / 90 (MEDI-12-VH / MEDI-12-VL); SEQ ID NOs: 91 / 92 (MEDI-13-VH / MEDI-13-VL); SEQ ID NOs: 93 / 94 (MEDI-14-VH / MEDI-14-VL) SEQ ID NOs: 95 / 96 (MEDI-15-VH / MEDI-15-VL); SEQ ID NOs: 97 / 98 (MEDI-16-VH / MEDI-16-VL); SEQ ID NOs: 99 / 100 (MEDI-17-VH / MEDI-17-VL); SEQ ID NOs: 101 / 102 (MEDI-18-VH / MEDI-18-VL); SEQ ID NOs: 103 / 104 (MEDI-19-VH / MEDI-19-VL); SEQ ID NOs: 105 / 106 (MEDI-20-VH / MEDI-20-VL); SEQ ID NOs: 107 / 108 (MEDI-21-VH / MEDI-21-VL); Sequence numbers 109 / 110 (MEDI-22-VH / MEDI-22-VL); Sequence numbers 111 / 112 (MEDI-23-VH / MEDI-23-VL); Sequence numbers 113 / 114 (MEDI-24-VH / MEDI-24-VL); Sequence numbers 115 / 116 (MEDI-25-VH / MEDI-25-VL); Sequence numbers 117 / 118 (MEDI-26-VH / MEDI-26-VL); Sequence numbers 119 / 120 (MEDI-27-VH / MEDI-27-VL); Sequence numbers 121 / 122 (MEDI-28-VH / MEDI-28-VL);SEQ ID NOs: 123 / 124 (MEDI-29-VH / MEDI-29-VL); SEQ ID NOs: 125 / 126 (MEDI-30-VH / MEDI-30-VL); SEQ ID NOs: 127 / 128 (MEDI-31-VH / MEDI-31-VL); SEQ ID NOs: 129 / 130 (MEDI-32-VH / MEDI-32-VL); SEQ ID NOs: 131 / 132 (MEDI-33-VH / MEDI-33-VL); SEQ ID NOs: 133 / 134 (MEDI-34-VH / MEDI-34-VL); SEQ ID NOs: 135 / 136 (MEDI-35-VH / MEDI-35-VL); SEQ ID NOs: 137 / 138 (MEDI-36-VH / MEDI-36-VL) SEQ ID NOs: 139 / 140 (MEDI-37-VH / MEDI-37-VL); SEQ ID NOs: 141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NOs: 143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NOs: 145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NOs: 147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NOs: 149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NOs: 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).

[0084] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of (i) 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 (ii) an HCVR comprising the amino acid sequence of SEQ ID NO: 168 (AJOU-33-VL), SEQ ID NO: 169 (AJOU-34-VL), SEQ ID NO: 161 (AJOU-35-VL), SEQ ID NO: 162 (AJOU-10-VH), SEQ ID NO: 163 (AJOU-69-VH), SEQ ID NO: 164 (AJOU-70-VH), SEQ ID NO: 165 (AJOU-71-VH), SEQ ID NO: 166 (AJOU-72-VH), or SEQ ID NO: 167 (AJOU-83-VH); (iii) an HCVR comprising the amino acid sequence of SEQ ID NO: 168 (AJOU-33-VL), SEQ ID NO: 169 (AJOU-34-VL), SEQ ID NO: 170 (AJOU-35-VL), SEQ ID NO: 171 (AJOU-35-VL), SEQ ID NO: 172 (AJOU-35-VH), SEQ ID NO: 173 (AJOU-35-VL), SEQ ID NO: 174 (AJOU-35-VH), SEQ ID NO: 175 (AJOU-35-VL), SEQ ID NO: 176 (AJOU-35-VH), SEQ ID NO: 177 (AJOU-35-VH), SEQ ID NO: 178 (AJOU-35-VL), SEQ ID NO: 179 (AJOU-36-VL), SEQ ID NO: 180 (AJOU-36-VL), SEQ ID NO: 181 (AJOU-36-VL), SEQ ID NO: 182 (AJOU-36-VL), SEQ ID NO SEQ ID NO: 170 (AJOU-35-VL), SEQ ID NO: 171 (AJOU-36-VL), SEQ ID NO: 172 (AJOU-37-VL), SEQ ID NO: 173 (AJOU-38-VL), SEQ ID NO: 174 (AJOU-39-VL), SEQ ID NO: 175 (AJOU-40-VL), SEQ ID NO: 176 (AJOU-41-VL), SEQ ID NO: 177 (AJOU-42-VL), SEQ ID NO: 178 (AJOU-77-VL), SEQ ID NO: 179 (AJOU-40-VL), SEQ ID NO: 179 (AJOU-41-VL), SEQ ID NO: 180 (AJOU-42-VL), SEQ ID NO: 181 (AJOU-42-VL), SEQ ID NO: 182 (AJOU-42-VL), SEQ ID NO: 183 (AJOU-42-VL), SEQ ID NO: 184 (AJOU-42-VL), SEQ ID NO: 185 (AJOU-42-VL), SEQ ID NO: 186 (AJOU-42-VL), SEQ ID NO: 187 (AJOU-42-VL), SEQ ID NO: 188 (AJOU-42-VL), SEQ ID NO: 189 (AJOU-42-VL), SEQ ID NO: 190 (AJOU-42-VL), SEQ ID NO: 191 (AJOU-42-VL), SEQ ID NO: 192 (AJOU-42-VL), SEQ ID NO: 193 (AJOU-42-VL), SEQ ID NO: 194 (A and an LCVR comprising the amino acid sequence of SEQ ID NO: 180 (AJOU-78-VL), SEQ ID NO: 180 (AJOU-79-VL), SEQ ID NO: 181 (AJOU-80-VL), SEQ ID NO: 182 (AJOU-86-VL), SEQ ID NO: 183 (AJOU-87-VL), SEQ ID NO: 184 (AJOU-88-VL), SEQ ID NO: 185 (AJOU-89-VL), SEQ ID NO: 186 (AJOU-90-VL), or SEQ ID NO: 187 (AJOU-91-VL).

[0085] In some embodiments, the anti-IL-4Rα antibody (i) comprises 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 HCVR comprising the amino acid sequence of SEQ ID NO: 198 (REGN-VL-11), SEQ ID NO: 199 (REGN-VL-27), SEQ ID NO: 200 (REGN-VL-43), SEQ ID NO: 201 (REGN-VL-59), SEQ ID NO: 202 (REGN-VL-75), SEQ ID NO: 203 (REGN-VL-91), SEQ ID NO: 204 (REGN-VL-107), SEQ ID NO: 205 (REGN-VL-123), SEQ ID NO: 206 (REGN-VL-155), or SEQ ID NO: 207 (REGN-VL-171).

[0086] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) SEQ ID NO: 208 (STSA-C27-VH), SEQ ID NO: 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), a HCVR comprising the amino acid sequence of SEQ ID NO: 217 (STSA-C27-54-54-VH), SEQ ID NO: 218 (STSA-C27-36-36-VH), SEQ ID NO: 219 (STSA-C27-53-53-VH), SEQ ID NO: 220 (STSA-C27-67-67-VH), SEQ ID NO: 221 (STSA-C27-55-55-VH), SEQ ID NO: 222 (STSA-C27-59-59-VH), SEQ ID NO: 223 (STSA-C27-58-58-VH), SEQ ID NO: 224 (STSA-C27-52-52-VH), or SEQ ID NO: 225 (STSA-C27-Y2-Y2-VH);and (ii) SEQ ID NO: 226 (STSA-C27-VL), SEQ ID NO: 227 (STSA-C27-6-33-VL), SEQ ID NO: 228 (STSA-C27-7-33-VL), SEQ ID NO: 229 (STSA-C27-24-56-VL), SEQ ID NO: 230 (STSA-C27-47-56-VL), SEQ ID NO: 231 (STSA-C27-33-33-VL), SEQ ID NO: 232 (STSA-C27-56-56-VL), SEQ ID NO: 233 (STSA-C27-78-78-VL), SEQ ID NO: 234 (STSA-C27-82-58-VL), SEQ ID NO: 235 (ST and a LCVR comprising the amino acid sequence of SEQ ID NO: 236 (STSA-C27-36-36-VL), SEQ ID NO: 237 (STSA-C27-53-53-VL), SEQ ID NO: 238 (STSA-C27-67-67-VL), SEQ ID NO: 239 (STSA-C27-55-55-VL), SEQ ID NO: 240 (STSA-C27-59-59-VL), SEQ ID NO: 241 (STSA-C27-58-58-VL), SEQ ID NO: 242 (STSA-C27-52-52-VL), or SEQ ID NO: 243 (STSA-C27-Y2-Y2-VL);

[0087] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) 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 NO: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 (HV3-73*2-14 VH), SEQ ID NO:258 (HV3-72-14 VH), SEQ ID NO:259 (HV3-73*2-14 VH), SEQ ID NO:260 (HV3-73*2-14 VH), SEQ ID NO:261 (HV3-73*2-14 VH), SEQ ID NO:262 (HV3-73*2-14 VH), SEQ ID NO:263 (HV3-73*2-14 VH), SEQ ID NO:264 (HV3-73*2-14 VH), SEQ ID NO:265 (HV3-73*2-14 VH), SEQ ID NO:266 (HV3-73*2-14 VH), and (ii) an HCVR comprising the amino acid sequence of SEQ ID NO:260 (Y0188-1 VL), SEQ ID NO:261 (Y0188-2 VL), SEQ ID NO:262 (Y0188-3 VL), SEQ ID NO:263 (Y0188-4 VL), SEQ ID NO:264 (Y0188-6 VL), SEQ ID NO:265 (Y0188-8 VL), SEQ ID NO:266 (Y0188-9 VL), SEQ ID NO:267 (Y0188-10 VL), SEQ ID NO:268 (Y0188-14 VL), SEQ ID NO:269 (Y01-14 VL), SEQ ID NO:270 (164-14 and an LCVR comprising the amino acid sequence of SEQ ID NO: 271 (KV4-14 VL), SEQ ID NO: 272 (KV1-27-14 VL), SEQ ID NO: 273 (KV1-9-14 VL), SEQ ID NO: 274 (KV1-NL1-14 VL), or SEQ ID NO: 275 (KV1D-43-14 VL).

[0088] In some embodiments, the anti-IL-4Rα antibodies used in the methods of the present disclosure may have pH-dependent binding properties. For example, an anti-IL-4Rα antibody for use disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use disclosed herein may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​below 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 lower. As used herein, the expression "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "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.

[0089] In certain instances, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K D values ​​and the K of antibodies binding to IL-4Rα at neutral pH D For example, an antibody or antigen-binding fragment thereof is defined for purposes of this disclosure as having an acidic / neutral K of about 3.0 or greater. D When a ratio is presented, it can be taken as indicating "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K for an antibody or antigen-binding fragment of the present disclosure D The ratio 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 more.

[0090] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for decreased (enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level can produce antibodies with pH-dependent properties. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, an antibody with decreased antigen binding at acidic pH compared to neutral pH can be obtained.

[0091] Preparation of human antibodies Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used in the context of the present disclosure to generate human antibodies that specifically bind to human IL-4R.

[0092] Using VELOCIMMUNE™ technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high-affinity chimeric antibody against IL-4R is first isolated and has a human variable region and a mouse constant region. VELOCIMMUNE® technology involves the generation of transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic challenge. DNA encoding the antibody heavy and light chain variable regions is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0093] Generally, VELOCIMMUNE® mice are challenged with an antigen of interest, and lymphocytes (e.g., B cells) are collected from the mice that express the antibody. The lymphocytes may be fused with a myeloma cell line to prepare an immortalized hybridoma cell line, which is then screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions may be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins may be produced in cells, such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibody or the light and heavy chain variable domains may be isolated directly from antigen-specific lymphocytes.

[0094] First, a high-affinity chimeric antibody is isolated, having a human variable region and a mouse constant region. The antibody is characterized and selected for desirable properties, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with a desired human constant region to generate a fully human antibody of the present disclosure, e.g., wild-type or modified IgG1 or IgG4. While the constant region selected can vary according to the specific use, the high-affinity antigen-binding properties and target specificity properties reside in the variable region.

[0095] Generally, antibodies that can be used in the methods of the present disclosure have high affinity, as described above, as measured by binding to antigen immobilized on either a solid phase or in solution. The mouse constant region is replaced with a desired human constant region to generate a fully human antibody of the present disclosure. While the constant region selected can vary according to the specific use, the high affinity antigen binding and target specificity properties reside in the variable region.

[0096] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the methods disclosed herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1, and three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and 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 antibodies.

[0097] Pharmaceutical Composition In one aspect, the present disclosure provides a method comprising administering to a subject an IL-4R antagonist, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained within a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. A variety of pharmaceutically acceptable carriers and excipients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0098] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions 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. In some embodiments, the pharmaceutical compositions disclosed herein are administered intravenously. In some embodiments, the pharmaceutical compositions disclosed herein are administered subcutaneously.

[0099] In some embodiments, the pharmaceutical composition comprises an injectable preparation, such as a dosage form for intravenous, subcutaneous, intradermal, and intramuscular injection, infusion, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparation can be prepared by dissolving, suspending, or emulsifying the antibody or salt thereof described above in a sterile aqueous or oily medium conventionally used for injections. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose, and other auxiliary agents, which may be used in combination with suitable solubilizing agents such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), etc. Oily media include, for example, sesame oil and soybean oil, which may be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol, etc. The injection solution thus prepared can be filled into suitable ampoules.

[0100] The dose of an antibody administered to a subject according to the methods of the present disclosure may vary depending on the subject's age and size, symptoms, condition, route of administration, and the like. Doses are typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies may be determined empirically; for example, the subject's progress can be monitored by periodic evaluation, and the dose adjusted accordingly. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti, et al., 1991, Pharmaceut. Res., 8:1351). Specific exemplary doses of anti-IL4R antibodies that can be used in the context of the present disclosure, and dosing regimens including the same, are disclosed elsewhere herein.

[0101] In some embodiments, the IL-4R antagonist or pharmaceutical composition of the present disclosure is contained within a container. Thus, in another aspect, a container is provided comprising an IL-4R antagonist or pharmaceutical composition disclosed herein. For example, in some embodiments, the pharmaceutical composition is contained within a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an auto-injector.

[0102] In some embodiments, the pharmaceutical compositions of the present disclosure are delivered using a standard needle and syringe, e.g., subcutaneously or intravenously. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, a pen delivery device or auto-injector is used to deliver the pharmaceutical compositions of the present disclosure (e.g., for subcutaneous delivery). The pen delivery device can be reusable or disposable. Typically, reusable pen delivery devices utilize a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition in the cartridge is administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, the disposable pen delivery device comes pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0103] Examples of suitable pen and autoinjector delivery devices include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Burgdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTIPEN™, the OPTIPEN PRO™, the OPTIPEN Examples of disposable pen delivery devices having application in the subcutaneous delivery of pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ Pen (Abbott Labs, Abbott Park, IL).

[0104] In some embodiments, pharmaceutical compositions are delivered using a controlled-release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material may be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, Florida. In yet another embodiment, a controlled-release system may be placed in the vicinity of the target of the composition, 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). Other controlled-release systems are discussed in the review by Langer, 1990, Science, 249:1527-1533. Other delivery systems are known and can be used to administer pharmaceutical compositions, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu, et al., 1987, J. Biol. Chem., 262:4429-4432).

[0105] In some embodiments, 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). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly distinguished between multi-dose container systems and single-dose (with partial or complete emptiness) container systems. The container may be an exchangeable container or a one-piece, non-exchangeable container.

[0106] As further described in ISO 11608-1:2014(E), a multi-dose container system may include a needle-based injection device with an exchangeable 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 include a needle-based injection device with a unitary, non-exchangeable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).

[0107] As further described in ISO11608-1:2014(E), a single-dose container system may include a needle-based injection device with an exchangeable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (full discharge). In a further example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial discharge). Also, as described in ISO11608-1:2014(E), a single-dose container system may include a needle-based injection device with a unitary, non-exchangeable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (full discharge). In a further example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial discharge).

[0108] An exemplary sleeve-trigger autoinjector with manual needle insertion is described in International Publication No. WO 2015 / 004052. Exemplary audible end-of-dose feedback mechanisms are described in International Publication Nos. WO 2016 / 193346 and WO 2016 / 193348. An exemplary needle safety mechanism after use of the autoinjector is described in International Publication No. WO 2016 / 193352. An exemplary needle sheath removal mechanism for a syringe autoinjector is described in International Publication No. WO 2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication No. WO 2016 / 193355.

[0109] In some embodiments, the pharmaceutical compositions for use as described herein are prepared in dosage forms suitable for dosage of the active ingredient in a unit dose. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0110] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in US Pat. No. 8,945,559.

[0111] Dosage and Administration In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered in a therapeutically effective amount to a subject (e.g., a subject having a defect in bone growth) according to the methods of the present disclosure. As used herein with reference to an IL-4R antagonist, the phrase "therapeutically effective amount" means an amount of an IL-4R antagonist that results in one or more of the following: (a) an improvement in bone formation; (b) an improvement in bone mineralization and / or bone density; (c) a reduction in bone loss; (d) an improvement or normalization (e.g., compared to healthy control levels) of 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, type I N-terminal propeptide of procollagen, insulin-like growth factor 1, or osteocalcin); and / or (e) a reduction in the incidence of osteopenia, osteoporosis, or fractures (e.g., compared to healthy control levels).

[0112] In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 600 mg, for example, 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, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg The amount of the anti-IL-4R antibody can be 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, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In some embodiments, the therapeutically effective amount is about 50 mg to about 600 mg, or about 100 mg to about 600 mg, or about 200 mg to about 600 mg. In specific embodiments, 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.

[0113] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained within an individual dose may be expressed in terms of milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of the subject's 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. In some embodiments, 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.

[0114] In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject at a dosing frequency of about 4 times per week, twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently, so long as a therapeutic response is achieved. In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject once per week, once per 2 weeks, once per 3 weeks, or once per 4 weeks. In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject monthly or twice per month.

[0115] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a defined time course. In some embodiments, the methods of the present disclosure include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequentially administering" means that each dose of an IL-4R antagonist is administered to a subject at different time points, e.g., on different days separated by a predetermined interval (e.g., hour, day, week, or month). In some embodiments, the methods of the present disclosure include sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of the IL-4R antagonist, and, optionally, one or more tertiary doses of the IL-4R antagonist.

[0116] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order of administration of an IL-4R antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "loading dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist but may generally differ from one another with respect to 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 during the course of treatment (e.g., adjusted up or down as appropriate). In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of a treatment regimen as a "loading dose," followed by subsequent doses (e.g., "maintenance doses") administered on a less frequent basis. In some embodiments, the initial dose or loading dose and the one or more secondary doses or maintenance doses each comprise the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of IL-4R antagonist, and the one or more secondary doses each comprise a second amount of IL-4R antagonist. For example, the first amount of IL-4R antagonist can be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more of the second amount of IL-4R antagonist. In some embodiments, the one or more maintenance doses of IL-4R antagonist are administered without a loading dose.

[0117] In some embodiments, the loading dose is a "split dose," administered as two or more doses (e.g., 2, 3, 4, or 5 doses) administered on separate days. In some embodiments, the loading dose is administered as a split dose, where the two or more doses are administered at least about one week apart. In some embodiments, the loading dose is administered as a split dose, where the two or more doses are administered about one week, two weeks, three weeks, or four weeks apart. In some embodiments, the loading dose is evenly divided across two or more doses (e.g., half of the loading dose is administered as a first portion and half of the loading dose is administered as a second portion). In some embodiments, the loading dose is unequally divided across two or more doses (e.g., more than half of the loading dose is administered as a first portion and less than half of the loading dose is administered as a second portion).

[0118] In some embodiments, each secondary and / or tertiary dose is administered 1 to 14 weeks (e.g., 1, 1 + 1 / 2, 2, 2 + 1 / 2, 3, 3 + 1 / 2, 4, 4 + 1 / 2, 5, 5 + 1 / 2, 6, 6 + 1 / 2, 7, 7 + 1 / 2, 8, 8 + 1 / 2, 9, 9 + 1 / 2, 10, 10 + 1 / 2, 11, 11 + 1 / 2, 12, 12 + 1 / 2, 13, 13 + 1 / 2, 14, 14 + 1 / 2, or more) after the immediately preceding dose. The phrase "immediately preceding dose," as used herein, refers to the dose of an IL-4R antagonist administered to a patient in a multiple administration sequence, without any intervening doses, prior to administration of the immediately next dose in the sequence.

[0119] The methods of the present disclosure can include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in certain embodiments, only a single secondary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to a patient. Similarly, in certain embodiments, only a single tertiary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to a patient.

[0120] In embodiments comprising multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to the patient one week, two weeks, three weeks, or four weeks after the immediately preceding dose. Similarly, in some embodiments comprising multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose can be administered to the patient one week, two weeks, three weeks, or four weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient can vary over the course of the treatment regimen. The frequency of administration can also be adjusted by the physician during the course of treatment, depending on the needs of each individual patient after clinical examination.

[0121] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) 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.

[0122] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) 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.

[0123] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an 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). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) 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 dose on day 15. In some embodiments, no loading dose is administered.

[0124] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every four weeks (Q4W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) 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.

[0125] In some embodiments, for subjects ≥ 12 to < 18 years of age (e.g., subjects ≥ 12 to < 18 years of age with moderate to severe or severe AD), for subjects ≥ 6 to < 18 years of age (e.g., subjects ≥ 6 to < 18 years of age with moderate to severe or severe AD), or for subjects ≥ 6 to < 12 years of age (e.g., subjects ≥ 6 to < 12 years of age with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W) if the subject weighs ≥ 60 kg. In some embodiments, a 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 weighs ≥ 60 kg. In some embodiments, a loading dose is not administered.

[0126] In some embodiments, for subjects ≥ 12 to < 18 years of age (e.g., subjects ≥ 12 to < 18 years of age with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered once every two weeks (Q2W) if the subject weighs < 60 kg. In some embodiments, 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 weighs < 60 kg. In some embodiments, no loading dose is administered.

[0127] In some embodiments, for subjects ≥ 12 to < 18 years of age (e.g., subjects ≥ 12 to < 18 years of age with moderate to severe or severe AD), for subjects ≥ 6 to < 18 years of age (e.g., subjects ≥ 6 to < 18 years of age with moderate to severe or severe AD), or for subjects ≥ 6 to < 12 years of age (e.g., subjects ≥ 6 to < 12 years of age with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W) if the subject weighs ≥ 30 kg to < 60 kg. In some embodiments, a 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 weighs ≥ 30 kg to < 60 kg. In some embodiments, no loading dose is administered.

[0128] In some embodiments, for subjects ≥ 6 months to < 6 years old (e.g., subjects ≥ 6 months to < 6 years old with moderate to severe or severe AD), for subjects ≥ 6 years to < 12 years old (e.g., subjects ≥ 6 years to < 12 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 18 years old (e.g., subjects ≥ 6 years to < 18 years old with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W) if the subject weighs ≥ 15 kg to < 60 kg. In some embodiments, a 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 weighs ≥ 15 kg to < 60 kg. In some embodiments, no loading dose is administered.

[0129] In some embodiments, for subjects ≥ 6 months to < 6 years old (e.g., subjects ≥ 6 months to < 6 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 12 years old (e.g., subjects ≥ 6 years to < 12 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 18 years old (e.g., subjects ≥ 6 years to < 18 years old with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W) if the subject weighs ≥ 15 kg to < 60 kg. In some embodiments, a subject is administered a 600 mg loading dose, followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W) if the subject weighs ≥ 15 kg to < 60 kg. In some embodiments, subjects are 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 4 weeks after the dose on day 15. In some embodiments, no loading dose is administered.

[0130] In some embodiments, for subjects ≥ 6 months to < 6 years old (e.g., subjects ≥ 6 months to < 6 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 12 years old (e.g., subjects ≥ 6 years to < 12 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 18 years old (e.g., subjects ≥ 6 years to < 18 years old with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W) if the subject weighs ≥ 15 kg to < 30 kg. In some embodiments, a subject is administered a 600 mg loading dose, followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W) if the subject weighs ≥ 15 kg to < 30 kg. In some embodiments, subjects are 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 4 weeks after the dose on day 15. In some embodiments, no loading dose is administered.

[0131] In some embodiments, for subjects ≥ 6 months to < 6 years old (e.g., subjects ≥ 6 months to < 6 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 12 years old (e.g., subjects ≥ 6 years to < 12 years old with moderate to severe or severe AD), or for subjects ≥ 6 years to < 18 years old (e.g., subjects ≥ 6 years to < 18 years old with moderate to severe or severe AD), a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every four weeks (Q4W) if the subject weighs ≥ 5 kg to < 15 kg. In some embodiments, a subject is administered a 400 mg loading dose, followed by one or more subsequent doses of 200 mg administered every four weeks (Q4W) if the subject weighs ≥ 5 kg to < 15 kg. In some embodiments, subjects are 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 4 weeks after the dose on day 15. In some embodiments, no loading dose is administered.

[0132] Combination therapy In some embodiments, the methods of the present disclosure comprise administering to a subject (e.g., a pediatric or adolescent subject with a defect in bone growth) an IL-4R antagonist (e.g., an anti-IL-4R antibody) according to the present disclosure in combination with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a local therapeutic agent, such as TCS or a topical nonsteroidal medication, such as TCI or crisaborole. In some embodiments, the additional therapeutic agent is a systemic agent, such as cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, a systemic or oral corticosteroid, a Janus kinase (JAK) inhibitor, or interferon gamma. In some embodiments, the additional therapeutic agent is an immunobiological, such as a tumor necrosis factor alpha (TNFα) inhibitor (e.g., an anti-TNFα 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). As used herein, the phrase "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with the IL-4R inhibitor. The term "in combination with" also includes sequential or simultaneous administration of the IL-4R inhibitor and the additional therapeutic agent.

[0133] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, an additional therapeutic agent 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 before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, an 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 administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently with" or in conjunction with a pharmaceutical composition comprising an 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 of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[0134] In some embodiments, the additional therapeutic agent is TCS. In some embodiments, the TCS is a medium-potency TCS. In some embodiments, the TCS is a low-potency TCS. In some embodiments, the additional therapeutic agent is a TCI. In some embodiments, the additional therapeutic agent is crisaborole. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18

Example

[0135] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the disclosed methods and compositions, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0136] Example 1: Dupilumab treatment of children with moderate to severe atopic dermatitis increases bone alkaline phosphatase, a marker of bone mineralization The aim of this analysis is to report the effect of dupilumab treatment on markers of bone formation in children aged ≥6 to <12 years with moderate to severe AD.

[0137] method Retrospective analyses were performed on serum from participants in LIBERTY AD PEDS (NCT03345914) and LIBERTY AD PED-OLE (NCT02612454). In LIBERTY AD PEDS, a double-blind, 16-week, phase 3 trial, children aged 6 to <12 years were randomized 1:1:1 to receive 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w for patients with a baseline weight <30 kg, and 200 mg q2w for patients with a baseline weight ≥30 kg), or placebo; with concurrent medium-potency topical corticosteroids (TCS). After the initial 16-week trial, children aged 6 to <12 years were enrolled in the open-label extension study, LIBERTY AD PED-OLE. Patients received dupilumab 300 mg q4w, which could be titrated in case of inadequate clinical response at week 16 (200 mg q2w for patients with baseline weight <60 kg and 300 mg q2w for patients with baseline weight ≥60 kg); with concurrent medium-potency TCS. Bone biomarkers, including BALP, procollagen type 1 N-terminal propeptide, C-terminal cross-linked telopeptide of type 1 collagen, osteocalcin, and insulin-like growth factor 1, were analyzed at baseline, 8 weeks, 12 weeks, and 16 weeks, with BALP only at week 52.

[0138] result Dupilumab treatment led to a rapid and significant increase in the geometric mean (standard error) levels of BALP in children with moderate to severe AD at 16 weeks compared with patients in the placebo group (77.7 (1.02) μg / L vs. 65.0 (1.04) μg / L; P < 0.0001). In addition, a rapid and significant increase in BALP levels was observed in children from the placebo group once they entered the OLE trial. BALP levels increased over 52 weeks in all treated children, reaching levels of 78–84 μg / L, which constitutes a significant improvement compared with baseline and is comparable to the healthy reference range. See Figure 1.

[0139] Both dupilumab dosing regimens led to significant increases in geometric mean (standard error) levels of BALP compared with placebo at weeks 8, 12, and 16. For the 100 / 200 mg q2w group, at week 8, BALP levels were 72.7 (1.03) μg / L for dupilumab vs 62.0 (1.05) μg / L for placebo, P<0.0001; at week 12: 74.7 (1.03) μg / L vs 64.3 (1.05) μg / L, P=0.0002; and at week 16: 78.0 (1.03) μg / L vs 65.0 (1.04) μg / L, P<0.0001). For the 300 mg q4w group, at week 8, BALP levels were 76.7 (1.03) μg / L for dupilumab vs 62.0 (1.05) μg / L for placebo, P<0.0001; at week 12: 73.3 (1.04) μg / L vs 64.3 (1.05) μg / L, P=0.002; at week 16: 77.3 (1.03) μg / L vs 65.0 (1.04) μg / L, P<0.0001). At week 52, BALP levels increased significantly compared to baseline (placebo vs. placebo with dupilumab: 64.2 [1.04] μg / L vs. 82.9 [1.04] μg / L, P<0.0001; 100 / 200 mg q2w: 62.0 [1.05] μg / L vs. 83.8 [1.03] μg / L, P<0.0001; 300 mg q4w: 64.1 [1.04] μg / L vs. 78.7 [1.04] μg / L, P<0.0001) but remained within the reference range (Diemar, et al., Bone, 2021, 146:115879).

[0140] An increasing trend from baseline to 16 weeks of dupilumab treatment was observed for other biomarkers (osteocalcin, PINP, IGF-1, and β-CTX), although there were limited data points due to insufficient serum volumes available for analysis. See Figures 2-5. Overall, mean biomarker levels measured in children treated with dupilumab improved from below to within the reference range for osteocalcin, PINP, and β-CTX, and from low to near-average reference range levels for BALP and IGF-1 in this age group.

[0141] Subgroup analyses of BALP levels by gender were performed on samples from girls and boys aged 6 to 12 years with moderate to severe AD; the patient population for this analysis was 6 to 11 years old at the start of the study. Reference ranges for BALP vary, with girls showing higher values ​​earlier and plateauing around 12 years of age, while BALP levels in boys continue to increase until around 15 years of age. (See Wu, et al., Ann Transl Med, 2021, 9:40; Lowe, et al., J Allergy Clin Immunol, 2020, 145:563-571; Silverberg, Pediatr Allergy Immunol., 2015, 26:54-61; Diemar, et al., Bone, 2021, 146:115-879). Treatment with dupilumab increased BALP levels to the reference range for both female and male patients, reflecting this gender difference. At 16 weeks, dupilumab treatment led to a rapid and significant increase in the geometric mean (standard error) levels of BALP in girls and boys compared with patients in the placebo group (girls: 80.0 (1.04) μg / L vs. 70.1 (1.06) μg / L, P = 0.0018; boys: 75.7 (1.03) μg / L vs. 60.4 (1.07) μg / L, P < 0.0001). Dupilumab treatment led to an increase in BALP levels in all treated children, reaching levels of 90.5 μg / L in girls and 86.6 μg / L in boys. See Figures 6-7.

[0142] Subgroup analyses were also performed to evaluate the effect of dupilumab treatment on BALP levels in children aged 6 to 12 years with moderate to severe AD, with and without comorbid asthma. Regardless of asthma comorbidity, dupilumab treatment led to a rapid and significant increase in geometric mean (standard error) BALP levels at 16 weeks in children with moderate to severe AD compared with patients in the placebo group (with asthma: 76.8 [1.04] μg / L vs. 59.1 [1.07] μg / L, P < 0.0001; without asthma: 78.5 [1.03] μg / L vs. 70.7 [1.05] μg / L, P = 0.0024). At 52 weeks, geometric mean (standard error) BALP levels increased significantly relative to baseline and were comparable to the reference range for patients with and without asthma (with asthma: placebo vs placebo crossed over to dupilumab: 62.3 [1.06] μg / L vs 78.3 [1.07] μg / L; dupilumab: 62.1 [1.04] μg / L vs 82.7 [1.04] μg / L; without asthma: placebo vs placebo crossed over to dupilumab: 66.0 [1.06] μg / L vs 87.5 [1.06] μg / L; dupilumab: 64.0 [1.04] μg / L vs 79.9 [1.03] μg / L).

[0143] conclusion These placebo-controlled results demonstrate, for the first time, a rapid and significant increase in BALP, and possible trends in other biomarkers, in children with AD during treatment with dupilumab. These results suggest increased bone mineralization during the treatment period.

[0144] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. 1. A method for improving bone growth, said method comprising: Selecting a subject having a defect in bone growth, wherein the subject is a pediatric or adolescent subject under the age of 18; and 1. A method comprising administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (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.

2. 10. The method of claim 1, wherein the subject has atopic dermatitis (AD).

3. 3. The method of claim 1 or 2, wherein the subject has moderate to severe or severe atopic dermatitis (AD).

4. The method of any one of claims 1 to 3, wherein the subject is a pediatric subject under the age of 12.

5. 5. The method of claim 4, wherein the subject is between 6 and 11 years old.

6. 5. The method of claim 4, wherein the subject is between 6 months and 5 years old.

7. The method of any one of claims 1 to 3, wherein the subject is an adolescent subject aged between 12 and 17 years.

8. The method of any one of claims 1 to 7, wherein the subject has co-occurring asthma.

9. 9. The method of claim 1, wherein the selecting step comprises selecting a subject exhibiting a level of a bone turnover marker below a threshold, and the bone turnover marker is bone-specific alkaline phosphatase, carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), N-terminal propeptide of type I procollagen (PINP), insulin-like growth factor 1 (IGF-1), or osteocalcin.

10. 10. The method of claim 9, wherein the threshold value is the mean level of the bone turnover marker for a population of healthy subjects having the same age as the selected pediatric or adolescent subject.

11. 10. The method of claim 9, wherein the bone turnover marker is bone-specific alkaline phosphatase.

12. 12. The method of any one of claims 1 to 11, wherein the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg once per week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

13. 12. The method of any one of claims 1 to 11, wherein the IL-4R antagonist is administered as an initial dose of 100 to 600 mg, followed by one or more subsequent doses of 50 to 300 mg, with each subsequent dose being administered one to four weeks after the immediately preceding dose.

14. 14. The method of any one of claims 1-5 and 7-13, wherein the subject is a pediatric subject aged 6 to 11 years or an adolescent subject aged 12 to 17 years, the subject has a baseline body weight ≥ 60 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W.

15. 14. The method of any one of claims 1-3 and 7-13, wherein the subject is an adolescent subject aged 12 to 17 years with a baseline body weight <60 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

16. 14. The method of any one of claims 1-5 and 8-13, wherein the subject is a pediatric subject aged 6 to 11 years with a baseline body weight of ≥ 30 kg to < 60 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

17. 14. The method of any one of claims 1-5 and 8-13, wherein the subject is a pediatric subject aged 6 to 11 years with a baseline body weight of ≥ 15 kg to < 30 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q4W.

18. 14. The method of any one of claims 1-5 and 8-13, wherein the subject is a pediatric subject aged 6 to 11 years with a baseline body weight of ≥ 15 kg to < 60 kg, and the IL-4R antagonist is administered subcutaneously 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 4 weeks after the day 15 dose.

19. 13. The method of any one of claims 1-4, 6, and 8-12, wherein the subject is a pediatric subject 6 months to 5 years of age with a baseline body weight of ≥ 15 kg to < 30 kg, and the IL-4R antagonist is administered subcutaneously at a dose of 300 mg Q4W.

20. 13. The method of any one of claims 1-4, 6, and 8-12, wherein the subject is a pediatric subject 6 months to 5 years of age with a baseline body weight of ≥ 5 kg to < 15 kg, and the IL-4R antagonist is administered subcutaneously at a dose of 200 mg Q4W.

21. 21. The method of any one of claims 1-13 and 18-20, wherein the IL-4R antagonist is administered subcutaneously as an initial dose of 200 mg, followed by one or more subsequent doses of 200 mg, or as an initial dose of 300 mg, followed by one or more subsequent doses of 300 mg.

22. 22. The method of any one of claims 1 to 21, wherein the IL-4R antagonist is administered in combination with a topical AD medication.

23. 23. The method of claim 22, wherein the topical AD medication is a topical corticosteroid.

24. 24. The method of any one of claims 1 to 23, wherein the IL-4R antagonist is administered for at least 16 weeks.

25. 25. The method of any one of claims 1 to 24, wherein administration of the IL-4R antagonist for at least 16 weeks results in increased 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, β-CTX, PINP, IGF-1, and osteocalcin.

26. The method of any one of claims 1 to 25, wherein 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 a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

27. The method of any one of claims 1 to 26, wherein 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 NO:

10.

28. The method of any one of claims 1 to 27, wherein the IL-4R antagonist is dupilumab.

29. 29. The method of any one of claims 1 to 28, wherein 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 auto-injector.

30. 30. The method of claim 29, wherein the IL-4R antagonist is contained in a pre-filled syringe.

31. 31. The method of claim 30, wherein the pre-filled syringe is a single dose pre-filled syringe.

32. 30. The method of claim 29, wherein the IL-4R antagonist is contained in an autoinjector.

33. 30. The method of claim 29, wherein the IL-4R antagonist is contained in a pen delivery device.

Images