Methods for improving bone growth by administration of IL-4R antagonists

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application was filed on November 22, 2023 as a PCT international patent application, claiming priority to and the 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 which are incorporated herein by reference.

[0003] Reference to Sequence Listing XML

[0004] This application contains a sequence listing, which has been submitted electronically in XML format. The sequence listing XML is incorporated herein by reference. The XML file, created on November 17, 2023, is named 40848_0118WOU1_SL.xml and is 267,776 bytes in size. Technical Field

[0005] The present disclosure relates to the use of interleukin-4 receptor (IL-4R) antagonists for improving bone growth. Background Art

[0006] Children with atopic dermatitis (AD) are at risk for low bone mineral density (BMD), which is associated with an 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). Compared with healthy children, factors such as limited nutrition, vitamin D deficiency, poor sleep, and the use of corticosteroids lead to lower bone alkaline phosphatase (BALP) levels (a marker of bone mineralization) in moderate to severe AD children (Silverberg, Pediatr Allergy Immunol, 2015, 26:54-61).

[0007] The major determinant of lifetime risk for fractures and osteoporosis is peak bone mass reached during prepubertal age (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 lead to a higher prevalence of osteopenia and osteoporosis. Summary of the Invention

[0008] In one aspect, a method for improving bone growth is provided. In some embodiments, the method comprises:

[0009] selecting a subject having a bone growth defect, wherein the subject is a pediatric or adolescent subject less than 18 years of age; and

[0010] One or more doses of an interleukin-4 receptor (IL-4R) antagonist are administered to the subject.

[0011] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof, e.g., comprising one or more of the 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 of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0012] In some embodiments, the subject has atopic dermatitis (AD).In some embodiments, the subject has moderate to severe or severe AD.

[0013] In some embodiments, the subject is a pediatric subject less than 12 years of age. In some embodiments, the subject is between 6 and 11 years of age. In some embodiments, the subject is between 6 months and 5 years of age.

[0014] In some embodiments, the subject is an adolescent between the ages of 12 and 17.

[0015] In some embodiments, the subject has comorbid asthma.

[0016] In some embodiments, the step of selecting comprises selecting a subject who exhibits a level of a bone turnover marker below a threshold, wherein the bone turnover marker is bone-specific alkaline phosphatase, carboxyl-terminal cross-linking 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 average level of the bone turnover marker in a population of healthy subjects of the same age as the selected pediatric or adolescent subject.

[0017] In some embodiments, the bone turnover marker is bone-specific alkaline phosphatase.

[0018] 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 once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, the IL-4R antagonist is administered at an initial dose of 100-600 mg, followed by one or more subsequent doses of 50-300 mg, wherein each subsequent dose is administered one to four weeks after the immediately preceding dose.

[0019] In some embodiments, the IL-4R antagonist is administered in an initial dose of 200 mg, followed by one or more subsequent doses of 200 mg.

[0020] In some embodiments, the IL-4R antagonist is administered in an initial dose of 300 mg, followed by one or more subsequent doses of 300 mg.

[0021] In some embodiments, the IL-4R antagonist is administered in an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg.

[0022] In some embodiments, the IL-4R antagonist is administered in an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg.

[0023] In some embodiments, the subject is a pediatric subject between 6 and 11 years of age or an adolescent between 12 and 17 years of age, and wherein the subject has a baseline weight of ≥ 60 kg, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W.

[0024] In some embodiments, the subject is an adolescent with a baseline weight <60 kg, and the IL-4R antagonist is administered subcutaneously at an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

[0025] 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, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

[0026] 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, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q4W.

[0027] In some embodiments, the subject is a pediatric subject aged 6 to 11 years and weighing ≥15 kg to <60 kg at baseline, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 300 mg on day 1, followed by 300 mg on day 15, followed by one or more subsequent doses of 300 mg Q4W starting four weeks after the day 15 dose.

[0028] In some embodiments, the subject is a pediatric subject aged 6 months to 5 years and having a baseline weight of ≥15 kg to <30 kg, wherein the IL-4R antagonist is administered subcutaneously at a dose of 300 mg Q4W.

[0029] In some embodiments, the subject is a pediatric subject aged 6 months to 5 years and having a baseline weight ≥5 kg to <15 kg, wherein the IL-4R antagonist is administered subcutaneously at a dose of 200 mg Q4W.

[0030] In some embodiments, the IL-4R antagonist is administered for at least 16 weeks.

[0031] In some embodiments, the IL-4R antagonist is administered in combination with a topical AD drug. In some embodiments, the topical AD drug is TCS.

[0032] In some embodiments, treatment with the IL-4R antagonist 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.

[0033] 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.

[0034] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a prefilled syringe, a pen delivery device, and an autoinjector. In some embodiments, the IL-4R antagonist is contained in a prefilled syringe. In some embodiments, the prefilled syringe is a single-dose prefilled syringe. In some embodiments, the IL-4R antagonist is contained in a pen delivery device. In some embodiments, the IL-4R antagonist is contained in an autoinjector.

[0035] 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, e.g., comprising 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 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 used to improve bone growth in a child or adolescent subject (e.g., a child or adolescent subject with atopic dermatitis).

[0036] In another aspect, provided herein are interleukin-4 receptor (IL-4R) antagonists for use in 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, e.g., comprising one or more of the 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 of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the medicament is used to improve bone growth in a child or adolescent subject (e.g., a child or adolescent subject with atopic dermatitis).

[0037] Other embodiments will become apparent upon reading the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1Shown are geometric mean bone alkaline phosphatase (BALP) (mcg / L) relative to baseline at visit for patients treated with placebo + topical corticosteroids (TCS), dupilumab 300 mg Q4W + TCS, or dupilumab 100 mg or 200 mg Q2W + TCS in the 16-week parent study (R668-AD-1652; "LIBERTY AD PEDS") or the subsequent open-label extension study (R668-AD-1434; "LIBERTY AD PED-OLE"). Visits at Weeks 8, 12, and 16 were from the parent study, and the visit at Week 52 was from the open-label extension study. Patients treated with placebo + TCS during the parent study were switched to dupilumab 100 mg or 200 mg Q2W or 300 mg Q4W for the open-label extension study. ns, not significant; SE, standard error.

[0039] Figure 2 Shown are osteocalcin levels (ng / mL) in patients treated with placebo plus TCS or dupilumab (100 / 200 mg Q2W or 300 mg Q4W) plus TCS at treatment weeks 8, 12, 16, or 52. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper limits of the box), which correspond to the values ​​at the top of the graph.

[0040] Figure 3 Shown are levels of type I procollagen N-terminal propeptide (PINP) (ng / mL) in patients treated with placebo plus TCS or dupilumab (100 / 200 mg Q2W or 300 mg Q4W) plus TCS at treatment weeks 8, 12, 16, or 52. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper limits of the box), which correspond to the values ​​at the top of the graph.

[0041] Figure 4 Shown are insulin-like growth factor 1 (IGF-1) levels (ng / mL) in patients treated with placebo plus TCS or dupilumab (100 / 200 mg every 2 weeks or 300 mg every 4 weeks) plus TCS at treatment weeks 8, 12, 16, or 52. Connecting lines represent data from the same subject. Box plots show the median (middle horizontal line) and interquartile range (lower and upper limits of the box), which correspond to the values ​​at the top of the graph.

[0042] Figure 5Shown are levels of carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX) (pg / mL) at treatment weeks 8, 12, 16, or 52 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 limits of the box), which correspond to the values ​​at the top of the graph.

[0043] Figure 6A and Figure 6B Shown are the geometric mean BALP values ​​over time for female patients (6A) and male patients (6B) in the 6-11 year old treatment group. a The slashes represent the BALP reference intervals for females or males. b After 16 weeks, these patients received active dupilumab treatment at the time of enrollment in the LIBERTY AD PED-OLE trial. Weeks 8, 12, and 16 were from the LIBERTY AD PEDS trial, and Week 52 was from the LIBERTY AD PED-OLE trial. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 for all comparisons to corresponding placebo plus TCS. ns, not significant; SE, standard error.

[0044] Figure 7 Shown are the geometric mean BALP values ​​at visit for female (upper panel) and male (lower panel) 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. The numbers under the sex and treatment regimen labels represent the group median and the range from the lower quartile to the upper quartile. a After 16 weeks, these patients received active dupilumab treatment when they were enrolled in the LIBERTY AD PED-OLE trial. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 for all patients compared with their respective baselines. DETAILED DESCRIPTION

[0045] definition

[0046] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0047] Unless defined otherwise, 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.

[0048] As used herein, the term "about" when used in reference to a specific recited 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.).

[0049] As used herein, the terms "treat," "treating," and the like mean to temporarily or permanently alleviate symptoms, eliminate the cause of symptoms, or prevent or slow the onset of symptoms of the disorder or condition.

[0050] As used herein, the term "subject in need thereof" refers to a human or non-human animal having a bone growth defect. In some embodiments, a "bone growth defect" refers to a reduced level of bone mineral density and / or a reduced level of a biomarker of bone formation or bone mineralization, for example, compared to a healthy subject or subject population. In some embodiments, the term "subject in need thereof" refers to a pediatric patient less than 12 years of age, such as a patient between 6 months and 5 years of age or a patient between 6 years of age and 11 years of age. 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.

[0051] As used herein, "atopic dermatitis" or "AD" means an inflammatory skin disease characterized by intense itching (e.g., severe itching) and scaly and 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., to certain foods, pollens, molds, dust mites, animals, etc.), radiation exposure, and / or asthma. The present disclosure includes methods for treating patients with moderate to severe or severe AD. As used herein, "moderate to severe AD" is characterized by intense itching, widespread skin lesions, which are 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 skin, lichenification, and fibrous papules. Generally, patients affected by moderate to severe AD also have more than 20% of their body skin affected, or 10% of their skin area affected in addition to the eyes, hands, and body folds. Moderate to severe AD is also believed to be present in patients who require frequent use of topical corticosteroids for treatment. When a patient is resistant or refractory to treatment with topical corticosteroids or calcineurin inhibitors, the patient may also be referred to as having moderate to severe AD. As used herein, "severe AD" is characterized by the presence of widespread skin lesions, persistent itching, or physically or emotionally disabling diseases that significantly impair the patient's quality of life. In some cases, patients with severe AD also exhibit one or more symptoms, such as abrasions, extensive skin thickening, bleeding, exudation, and / or skin cracking, and changes in pigmentation. In some embodiments, severe AD is refractory to treatment with topical therapies (e.g., topical corticosteroids, calcineurin inhibitors, or crisaborole).

[0052] As used herein, term " TCS " comprises Class I, Class II, Class III and Class IV topical corticosteroids.According to the anatomical therapeutic classification system of the World Health Organization, based on the activity compared with hydrocortisone (hydrocortisone), corticosteroids are classified as weak (Group I), moderately effective (Group II) and effective (Group III) and very effective (Group IV).The effectiveness of Group IV TCS (very effective) is 600 times that of hydrocortisone, and comprises clobetasol propionate (clobetasol propionate) and halcinonide (halcinonide). Group III TCS (effective) is 50 to 100 times more potent than hydrocortisone and includes, but is not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately effective; also referred to herein as "moderately effective") is 2 to 25 times more potent than hydrocortisone and includes, but is not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (mild; also referred to herein as "low effectiveness") includes hydrocortisone.

[0053] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, typical methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0054] Treatment

[0055] In one aspect, methods for improving bone growth in a subject are provided. In some embodiments, the subject has a bone growth defect, such as a bone formation or bone metabolism defect. In some embodiments, the method comprises 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 as disclosed herein.

[0056] In some embodiments, the subject is a pediatric subject or an adolescent subject less than 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.

[0057] In some embodiments, the subject is a pediatric or adolescent subject weighing <60 kg at baseline. In some embodiments, the subject is a pediatric or adolescent subject weighing <30 kg at baseline. In some embodiments, the subject weighs ≥5 kg and <30 kg at baseline. In some embodiments, the subject weighs ≥5 kg and <15 kg at baseline. In some embodiments, the subject weighs ≥15 kg and <30 kg at baseline.

[0058] In some embodiments, the subject suffers from atopic disease. In some embodiments, the subject suffers from AD (e.g., moderate to severe AD or severe AD). In some embodiments, the subject is diagnosed with chronic atopic dermatitis at least 6 months (e.g., at least 9 months or at least 1 year) before treatment begins. In some embodiments, the subject suffers from moderate to severe or severe AD that is not adequately responded to topical therapy (e.g., TCS with or without topical calcineurin inhibitors (TCI)), or for which topical therapy is undesirable (e.g., due to adverse side effects or safety risks). In some embodiments, the subject suffers from moderate to severe or severe AD and is a candidate for systemic therapy.

[0059] In some embodiments, the subject has AD (e.g., moderate to severe AD or severe AD) and has one or more concomitant allergic conditions (i.e., excluding AD). In some embodiments, the subject has a concurrent atopic or allergic condition selected from the group consisting of allergic rhinitis, asthma, food allergy, non-food allergy, allergic conjunctivitis, urticaria, chronic sinusitis, nasal polyps, and eosinophilic esophagitis.

[0060] In some embodiments, the subject has a bone growth defect. In some embodiments, the subject has abnormal bone metabolism relative to a healthy control or a healthy control subject colony. In some embodiments, the subject has reduced bone formation relative to a healthy control or a healthy control subject colony. In some embodiments, the subject has reduced bone mineral density relative to a healthy control or a healthy control subject colony. In some embodiments, the subject is under the risk of bone fracture. In some embodiments, the subject has a history of bone fracture. In some embodiments, the subject suffers from osteopenia. In some embodiments, the subject suffers from osteoporosis (for example, idiopathic juvenile osteoporosis or secondary osteoporosis). In some embodiments, the subject with a bone growth defect has a treatment history using local therapy (for example, local corticosteroids, calcineurin inhibitors or crisaborole).

[0061] In some embodiments, subjects with bone growth defects are selected based on the level of bone-specific markers (e.g., bone formation markers or bone turnover markers). In some embodiments, the marker is bone-specific alkaline phosphatase, carboxyl-terminal cross-linked telopeptide of type I collagen (CTX-1), type I procollagen N-terminal propeptide (PINP), insulin-like growth factor 1 (IGF-1), or osteocalcin. In some embodiments, subjects are selected based on the level of markers (e.g., bone turnover markers) that exhibit a lower threshold.

[0062] In some embodiments, subjects are selected as having a bone growth defect based on their 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 bone growth defect if the subject has a BMD Z-score of ≤-2.0, e.g., as measured for the lumbar spine, femur, hip, or another skeletal site.

[0063] In some embodiments, a "threshold value" for a parameter or marker as disclosed herein (e.g., a bone turnover marker or BMD Z score) is determined by reference to a population of healthy subjects that are the same age as the selected pediatric or adolescent subject or whose age range covers the selected pediatric or adolescent subject. For a given parameter or marker, one skilled in the art can determine the threshold value for a specific age or age range based on knowledge of the level of the parameter or marker in the general population in the art. For example, methods for calculating mean BMD Z scores for different age ranges in children and adolescent subjects with AD or healthy control subjects are disclosed 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 mean levels of 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 95th percentile reference interval for a bone turnover marker established for pediatric or adolescent patients, e.g., as shown in Table 3 of Diemar et al., Bone, 2021, 146: 115879, or as provided in the Mayo Clinic Laboratories Pediatric Catalog (pediatric.testcatalog.org) (incorporated herein by reference).

[0064] In some embodiments, subjects are selected based on exhibiting a level of bone alkaline phosphatase below a threshold, such as the lower value of a 95% reference interval for bone alkaline phosphatase established for a pediatric or adolescent patient population. In some embodiments, a subject is selected if the subject's serum bone alkaline phosphatase level is <70 μg / L, <65 μg / L, <60 μg / L, or <55 μg / L.

[0065] In some embodiments, if the subject:

[0066] Aged 8-9 years and with a serum bone alkaline phosphatase level <53.4 μg / L (for female subjects) or <46.2 μg / L (for male subjects); or

[0067] Aged 10-11 years and with a serum bone alkaline phosphatase level <50.6 μg / L (for female subjects) or <52.7 μg / L (for male subjects); or

[0068] Aged 12-13 years and with a serum bone alkaline phosphatase level <54.6 μg / L (for female subjects) or <49.5 μg / L (for male subjects); or

[0069] Aged 14-15 years and with a serum bone alkaline phosphatase level <14.2 μg / L (for female subjects) or <30.1 μg / L (for male subjects); or

[0070] Subjects were selected if they were 16-17 years of age and had a serum bone alkaline phosphatase level <12.3 μg / L (for female subjects) or <25.7 μg / L (for male subjects).

[0071] In some embodiments, a subject is selected based on exhibiting an osteocalcin level below a threshold value, such as the lower value of a 95% reference interval for osteocalcin established for a pediatric or adolescent patient population. In some embodiments, if a subject:

[0072] Aged 8-9 years and with a serum osteocalcin level <68.5 μg / L (for female subjects) or <54.1 μg / L (for male subjects); or

[0073] Aged 10-11 years, with a serum osteocalcin level <72.2 μg / L (for female subjects) or <55.8 μg / L (for male subjects); or

[0074] Aged 12-13 years and with a serum osteocalcin level <82.9 μg / L (for female subjects) or <58.7 μg / L (for male subjects); or

[0075] Aged 14-15 years, with a serum osteocalcin level <22.2 μg / L (for female subjects) or <54.1 μg / L (for male subjects); or

[0076] Subjects were selected if they were 16-17 years old and had a serum osteocalcin level <18.8 μg / L (for female subjects) or <61.5 μg / L (for male subjects).

[0077] In some embodiments, a subject is selected based on exhibiting a level of PINP below a threshold value, such as the lower value of a 95% reference interval for PINP established for a pediatric or adolescent patient population. In some embodiments, if a subject:

[0078] Aged 8-9 years, with serum PINP level <415 μg / L (for female subjects) or <381 μg / L (for male subjects); or

[0079] Aged 10-11 years, with serum PINP levels <352 μg / L (for female subjects) or <298 μg / L (for male subjects); or

[0080] Aged 12-13 years, with serum PINP levels <387 μg / L (for female subjects) or <168 μg / L (for male subjects); or

[0081] Aged 14-15 years, with serum PINP levels <65 μg / L (for female subjects) or <219 μg / L (for male subjects); or

[0082] Subjects were selected if they were 16-17 years old and had serum PINP levels <55 μg / L (for female subjects) or <166 μg / L (for male subjects).

[0083] In some embodiments, a subject is selected based on exhibiting a level of β-CTX below a threshold, such as the lower value of a 95% reference interval for β-CTX established for a pediatric or adolescent patient population. In some embodiments, if a subject:

[0084] Aged 8-9 years and serum β-CTX level <1030 ng / L (for female subjects) or <1080 ng / L (for male subjects); or

[0085] Aged 10-11 years, and serum β-CTX level <1103 ng / L (for female subjects) or <1140 ng / L (for male subjects); or

[0086] Aged 12-13 years, with serum β-CTX levels <960 ng / L (for female subjects) or <1100 ng / L (for male subjects); or

[0087] Aged 14-15 years, with serum β-CTX levels <330 ng / L (for female subjects) or <1000 ng / L (for male subjects); or

[0088] Subjects were selected if they were 16-17 years old and had serum β-CTX levels <290 ng / L (for female subjects) or <1060 ng / L (for male subjects).

[0089] In some embodiments, a subject is selected based on exhibiting an IGF-1 level below a threshold value, such as the lower value of the 95th percentile reference interval for IGF-1 established for a pediatric or adolescent patient population. In some embodiments, if a subject:

[0090] Age is <1 year, and serum IGF-1 level is <14 ng / mL (for female subjects) or <18 ng / mL (for male subjects); or

[0091] Age 1 year and serum IGF-1 level <23 ng / mL (for female subjects) or <14 ng / mL (for male subjects); or

[0092] Age 2 years and serum IGF-1 level <28 ng / mL (for female subjects) or <16 ng / mL (for male subjects); or

[0093] Age 3 years and serum IGF-1 level <31 ng / mL (for female subjects) or <22 ng / mL (for male subjects); or

[0094] Age 4 years and serum IGF-1 level <33 ng / mL (for female subjects) or <30 ng / mL (for male subjects); or

[0095] Age 5 years and serum IGF-1 level <36 ng / mL (for female subjects) or <39 ng / mL (for male subjects); or

[0096] Age 6 years and serum IGF-1 level <39 ng / mL (for female subjects) or <47 ng / mL (for male subjects); or

[0097] Age 7 years and serum IGF-1 level <44 ng / mL (for female subjects) or <54 ng / mL (for male subjects); or

[0098] Age 8 years and serum IGF-1 level <51 ng / mL (for female subjects) or <61 ng / mL (for male subjects); or

[0099] Age 9 years and serum IGF-1 level <61 ng / mL (for female subjects) or <67 ng / mL (for male subjects); or

[0100] Age 10 years and serum IGF-1 level <73 ng / mL for female subjects or <73 ng / mL for male subjects; or

[0101] Age 11 years and serum IGF-1 level <88 ng / mL (for female subjects) or <79 ng / mL (for male subjects); or

[0102] Age 12 years and serum IGF-1 level <104 ng / mL (for female subjects) or <84 ng / mL (for male subjects); or

[0103] Age 13 years and serum IGF-1 level <120 ng / mL (for female subjects) or <90 ng / mL (for male subjects); or

[0104] Age 14 years and serum IGF-1 level <136 ng / mL (for female subjects) or <95 ng / mL (for male subjects); or

[0105] Age 15 years and serum IGF-1 level <147 ng / mL (for female subjects) or <99 ng / mL (for male subjects); or

[0106] Age 16 years and serum IGF-1 level <153 ng / mL (for female subjects) or <104 ng / mL (for male subjects); or

[0107] Age 17 years and serum IGF-1 level <149 ng / mL (for female subjects) or <107 ng / mL (for male subjects); or

[0108] Subjects were selected if they were 16-17 years of age and had serum IGF-1 levels <55 μg / L (for female subjects) or <166 μg / L (for male subjects).

[0109] 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 occurrence or severity of skeletal fractures, or reduces the severity of osteopenia or osteoporosis).

[0110] 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 density, for example, as measured by dual-energy X-ray absorptiometry (DEXA). "Improvement in a bone-related parameter" refers to an improvement (e.g., an increase or normalization) in one or more parameters relative to a baseline. The term "baseline" as used with respect to a bone-related parameter means the value of a subject's bone-related parameter before or at the start of administration of a pharmaceutical composition as disclosed herein.

[0111] To determine whether a bone-related parameter has "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 can be measured on 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 the pharmaceutical compositions of the present disclosure. The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline is used to determine whether there is an "improvement" (eg, a decrease) in the bone-related parameter.

[0112] 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 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. In some embodiments, treatment with the IL-4R antagonist results in an increase in the level of the marker relative to baseline at week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with the IL-4R antagonist results in an increase in the level of a marker by 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% relative to baseline at week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 following administration of the first dose of the IL-4R antagonist.

[0113] 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 of the subject's BMD Z-score relative to baseline at week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 following administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in an increase in BMD Z-score relative to baseline 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% at week 4, week 8, week 12, week 16, week 24, week 30, week 36, week 48, or week 52 following administration of the first dose of the IL-4R antagonist.

[0114] Interleukin-4 receptor antagonists

[0115] 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 with a bone growth defect). As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor," "IL-4R blocker," or "L-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or 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. The type 1 IL-4 receptor interacts with and is stimulated by IL-4, while the type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, the IL-4R antagonists useful in the methods of the present disclosure may act by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4 and IL-13-mediated signaling. Thus, the IL-4R antagonists of the present disclosure may prevent the interaction of IL-4 and / or IL-13 with either the type 1 or type 2 receptors.

[0116] Non-limiting examples of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptobodies" (e.g., engineered molecules comprising the ligand binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind 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.

[0117] Anti-IL-4Rα antibodies and antigen-binding fragments thereof

[0118] In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains (two heavy (H) chains and two light (L) chains) interconnected by disulfide bonds, and multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and the heavy chain constant region. The heavy chain constant region contains three domains: C H 1. C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L) and the light chain constant region. The light chain constant region contains a domain (C L 1). V H Area and V L The V domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L It is composed of three CDRs and four FRs arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.

[0119] As used herein, the term "antibody" also includes the antigen-binding fragment of a complete antibody molecule. As used herein, the term "antigen-binding portion thereof," "antibody antigen-binding fragment" etc. include any naturally occurring, enzymatically available, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can be derived from a full antibody molecule using any suitable standard technique (such as proteolytic digestion or the recombinant genetic engineering technology of the operation and expression of the DNA encoding antibody variable domains and optionally antibody constant domains). Such DNA is known, and / or can be easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA sequencing can be performed, and chemically or by using molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains into a suitable configuration, or to import codons, produce cysteine ​​residues, modify, add or delete amino acid, etc.

[0120] 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 that mimic the hypervariable region of an antibody (e.g., isolated complementary determining regions (CDRs) such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. As used herein, other engineered molecules (such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tribodies, tetrabodies, microbodies, 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."

[0121] The antigen-binding fragment of an antibody generally includes at least one variable domain. The variable domain can have any size or amino acid composition and will generally include at least one CDR adjacent to or in frame with one or more framework sequences. H Domain and V L In the antigen-binding fragments associated with the structural domains, V H and V L The domains may be positioned relative to each other in any suitable arrangement. For example, the variable region may be a dimer and contain V H -V H 、V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomer V H or V L domain.

[0122] In certain embodiments, the antigen-binding fragment of an antibody may contain 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 the antigen-binding fragment of an antibody of the present disclosure include: (i) 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 H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H3;(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 connected to each other or may be connected by a full-length or partial hinge or linker region. The hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragment of the antibody of the present disclosure may comprise any of the variable and constant domain configurations listed above, coupled to each other and / or to one or more monomeric V domains. H or V L The domains are non-covalently associated (eg, through disulfide bonds) as homodimers or heterodimers (or other multimers).

[0123] The constant region of an antibody is important for the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, in some embodiments, the isotype of an antibody can be selected based on whether the antibody is required for cytotoxicity.

[0124] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies generally include at least two different variable domains, each of which is capable of specifically binding to a separate antigen or a different epitope on the same antigen. Using conventional techniques available in the art, any multispecific antibody format can be applied to the context of the antibodies or antigen-binding fragments of antibodies disclosed herein. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies, wherein 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 portion. Exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knob-in-hole, common light chain (e.g., common light chain with knob-in-hole, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual-action Fab (DAF)-IgG, and Mab 2Bispecific formats (for a review of the aforementioned formats, see, e.g., Klein et al., 2012, mAbs, 4:6, 1-11, and references cited therein). Peptide / nucleic acid conjugation can also be used to construct bispecific antibodies, e.g., where unnatural amino acids with orthogonal chemical reactivities are used to generate site-specific antibody-oligonucleotide conjugates that are then self-assembled into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub 2012 Dec 4]).

[0125] In some embodiments, the antibody used in the method of the present disclosure is a human antibody. As used herein, the term "human antibody" is intended to include antibodies with variable regions and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies of the present disclosure may 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 mutations in vivo), such as in CDR, and specifically, in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species (such as a mouse) are implanted into human framework sequences.

[0126] The antibody used in the disclosed method can be a recombinant human antibody. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, established or separated by a recombinant manner, such as antibodies expressed using a recombinant expression vector (described further below) transfected into a host cell, antibodies separated from a recombinant combination human antibody library (described further below), antibodies separated from an animal (e.g., mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al., (1992) Nucl. Acids Res., 20: 6287-6295), or antibodies prepared, expressed, established or separated by any other means involving splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or, when using an animal that is transgenic for human Ig sequences, undergo in vivo somatic mutagenesis) and therefore the V H and V L The amino acid sequence of the region is derived from human germline V H and V L Sequences that are related to, but may not naturally occur within the human antibody germline repertoire in vivo.

[0127] An "isolated antibody" refers to an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally occurs or naturally produces, 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 undergone at least one purification or separation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular material and / or chemicals.

[0128] According to certain embodiments, the antibodies used in the disclosed methods specifically bind to IL-4Rα. As used herein, the term "specifically binds" means that the antibody or antigen-binding fragment thereof forms a relatively stable complex with the antigen 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. D ) binds to IL-4Rα or a portion thereof, as determined by surface plasmon resonance (e.g., BIAcore TM , 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) may also specifically bind to another antigen, such as 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.

[0129] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-4R antibodies described 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 antigen-binding fragment thereof comprising a heavy chain complementarity determining region (HCDR) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of a 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 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 GFTFRDYA (SEQ ID NO:3), HCDR2 comprises the amino acid sequence ISGGNT (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).

[0130] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCDR1 comprising the amino acid sequence of GFTFRDYA (SEQ ID NO:3), a HCDR2 comprising the amino acid sequence of ISGSGGNT (SEQ ID NO:4), a HCDR3 comprising the amino acid sequence of AKDRLSITIRPRYYGLDV (SEQ ID NO:5), a LCDR1 comprising the amino acid sequence of QSLLYSIGYNY (SEQ ID NO:6), a LCDR2 comprising the amino acid sequence of LGS, and a LCDR3 comprising the amino acid sequence of 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 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. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a LCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO: 2.

[0131] 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.

[0132] 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 a 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, "duplimab" also includes bioequivalents of dupilumab. The term "bioequivalent," as used herein with respect to dupilumab, refers to an anti-IL-4R antibody or IL-4R binding protein or fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute and that exhibits no significant difference in rate and / or extent of absorption from dupilumab when administered at the same molar dose (whether single or multiple doses) under similar experimental conditions. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and does not have clinically meaningful differences in safety, purity, and / or potency from dupilumab.

[0133] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present disclosure include, for example, the antibody known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI 9314, or U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, U.S. Patent No. 8,877,189, U.S. Patent No. 10,774,141, or International Patent Publication Nos. WO 2020 / 096381, WO 2020 / 182197, WO 2020 / 239134, WO 2020 / 239206, WO 2020 / 239304, WO 2020 / 239408, WO 2020 / 239509, WO 2020 / 239609, WO 2020 / 239708, WO 2020 / 239709 ... Any of the anti-IL-4Rα antibodies described in WO2021 / 213329, WO2022 / 052974, WO2022 / 136669, or WO2022 / 136675, the contents of each of which are incorporated herein by reference.

[0134] In some embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof for use in the methods of the present disclosure comprises one or more CDR, HCVR, and / or LCVR sequences listed in Table 1 below.

[0135] In some embodiments, the anti-IL-4Rα antibody comprises (i) a HCVR comprising the amino acid sequence of SEQ ID NO:32 (SCB-VH-59), SEQ ID NO:33 (SCB-VH-60), SEQ ID NO:34 (SCB-VH-61), SEQ ID NO:35 (SCB-VH-62), SEQ ID NO:36 (SCB-VH-63), SEQ ID NO:37 (SCB-VH-64), SEQ ID NO:38 (SCB-VH-65), SEQ ID NO:39 (SCB-VH-66), SEQ ID 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 (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-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) LCVR comprising 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 a HCVR comprising the amino acid sequence of SEQ ID NO: 64 (SCB-VH-91) and a 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).

[0136] In some embodiments, the anti-IL-4Rα antibody comprises an amino acid sequence pair selected from the group consisting of: SEQ ID NO: 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NO: 69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NO: 71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NO: 73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NO: 75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NO: 77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NO: 79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NO: 81 / 82 (MEDI-8-VH / MEDI-8-VL); SEQ ID NO: 83 / 84 (MEDI-9-VH / MEDI-9-VL); NO: 83 / 84 (MEDI-9-VH / MEDI-9-VL); SEQ ID NO: 85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NO: 87 / 88 (MEDI-11-VH / MEDI-11 / VL); SEQ ID NO: 89 / 90 (MEDI-12-VH / MEDI-12-VL); SEQ ID NO: ID NO:91 / 92(MEDI-13-VH / MEDI-13-VL); SEQ ID NO:93 / 94(MEDI-14-VH / MEDI-14-VL); SEQ ID NO:95 / 96(MEDI-15-VH / MEDI-15-VL); SEQ ID NO:97 / 98(MEDI-16-VH / MEDI-16 / VL); SEQ ID NO:99 / 100(MEDI-17-VH / MEDI-17-VL); SEQ ID NO:101 / 102(MEDI-18-VH / MEDI-18-VL); SEQ ID NO:103 / 104(MEDI-19-VH / MEDI-19-VL); SEQ ID NO:105 / 106(MEDI-20-VH / MEDI-20-VL); SEQ ID NO:107 / 108(MEDI-21-VH / MEDI-21-VL); SEQ ID NO:109 / 110(MEDI-22-VH / MEDI-22-VL); SEQ ID NO:111 / 112(MEDI-23-VH / MEDI-23-VL); SEQ ID NO:113 / 114(MEDI-24-VH / MEDI-24-VL);SEQ ID NO: 115 / 116 (MEDI-25-VH / MEDI-25-VL); SEQ ID NO: 117 / 118 (MEDI-26-VH / MEDI-26-VL); SEQ ID NO: 119 / 120 (MEDI-27-VH / MEDI-27-VL); SEQ ID NO: 121 / 122 (MEDI-28-VH / MEDI-28-VL); SEQ ID NO: 123 / 124 (MEDI-29-VH / MEDI-29-VL); SEQ ID NO: 125 / 126 (MEDI-30-VH / MEDI-30-VL); SEQ ID NO: 127 / 128 (MEDI-31-VH / MEDI-31-VL); SEQ ID NO: 129 / 130 (MEDI-32-VH / MEDI-32-VL); SEQ ID NO: 131 / 132 (MEDI-33-VH / MEDI-33-VL); SEQ ID NO: 133 / 134 (MEDI-34-VH / MEDI-34-VL); SEQ ID NO: 135 / 136 (MEDI-35-VH / MEDI-35-VL); SEQ ID NO: 137 / 138 (MEDI-36-VH / MEDI-36-VL); SEQ ID NO: 139 / 140 (MEDI-37-VH / MEDI-37-VL); SEQ ID NO: 141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NO: 143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NO: 145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NO: 147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NO: 149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NO: 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).;

[0137] In some embodiments, the anti-IL-4Rα antibody comprises (i) a HCVR comprising the amino acid sequence of SEQ ID NO:153 (AJOU-1-VH), SEQ ID NO:154 (AJOU-2-VH), SEQ ID NO:155 (AJOU-3-VH), SEQ ID NO:156 (AJOU-4-VH), SEQ ID NO:157 (AJOU-5-VH), SEQ ID NO:158 (AJOU-6-VH), SEQ ID NO:159 (AJOU-7-VH), SEQ ID NO:160 (AJOU-8-VH), SEQ ID NO:161 (AJOU-9-VH), SEQ ID NO:162 (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); and (ii) a LCVR 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-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-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).

[0138] In some embodiments, the anti-IL-4Rα antibody comprises (i) a HCVR comprising the amino acid sequence of SEQ ID NO: 188 (REGN-VH-3), SEQ ID NO: 189 (REGN-VH-19), SEQ ID NO: 190 (REGN-VH-35), SEQ ID NO: 191 (REGN-VH-51), SEQ ID NO: 192 (REGN-VH-67), SEQ ID NO: 193 (REGN-VH-83), SEQ ID NO: 194 (REGN-VH-99), SEQ ID NO: 195 (REGN-VH-115), SEQ ID NO: 196 (REGN-VH-147), or SEQ ID NO: 197 (REGN-VH-163); and (ii) a LCVR 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-VH-35), SEQ ID NO: 201 (REGN-VH-51), SEQ ID NO: 202 (REGN-VH-67), SEQ ID NO: 203 (REGN-VH-83), SEQ ID NO: 204 (REGN-VH-99), SEQ ID NO: 205 (REGN-VH-115), SEQ ID NO: 206 (REGN-VH-147), or SEQ ID NO: 207 (REGN-VH-163). 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).

[0139] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising 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), SEQ ID NO: 217 (STSA-C27-92-92-VH), SEQ ID NO: 218 (STSA-C27-100-100-VH), SEQ ID NO: 219 (STSA-C27-110-110-VH), SEQ ID NO: 220 (STSA-C27-111-110-VH), SEQ ID NO: NO: 224 (STSA-C27-52-52-VH), or SEQ ID NO: 225 (STSA-C27-Y2-Y2-VH);and (ii) an LCVR comprising the amino acid sequence of 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 (STSA-C27-54-54-VL), 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);

[0140] In some embodiments, the anti-IL-4Rα antibody comprises (i) a HCVR comprising 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 (HV3-58-15 VH), SEQ ID NO: 256 (HV3-64-15 VH), SEQ ID NO: 257 (HV3-72-15 VH), SEQ ID NO: 258 (HV3-73-15 VH), SEQ ID NO: 259 (HV3-74-15 VH), SEQ ID NO: 260 (HV3-75-15 VH), SEQ ID NO: 261 (HV3-76-15 VH), SEQ ID NO: NO: 255 (HV3-73*2-14 VH), SEQ ID NO: 256 (HV3-72-14 VH), SEQ ID NO: 257 (Y01-14 VH), SEQ ID NO: 258 (I62-14 VH) or SEQ ID NO: 259 (VH73-14 Vh); and (ii) LCVRs comprising 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: 270 (Y0188-1 VL), SEQ ID NO: 271 (Y0188-2 VL), SEQ ID NO: 272 (Y0188-3 VL), SEQ ID NO: 273 (Y0188-4 VL), SEQ ID NO: 274 (Y0188-6 VL), SEQ ID NO: 275 (Y0188-8 VL), SEQ ID NO: 276 (Y0188-9 VL), SEQ ID NO: The amino acid sequence of 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 VL), 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).

[0141] In some embodiments, the anti-IL-4Rα antibodies used in the methods of the present disclosure may have pH-dependent binding characteristics. For example, the anti-IL-4Rα antibodies used as disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibodies used as disclosed herein may exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​of less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. 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.

[0142] In certain instances, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K of the antibody binding to IL-4Rα at acidic pH. D The K values ​​of the antibodies binding to IL-4Rα at neutral pH were compared with the K values ​​of the antibodies binding to IL-4Rα at neutral pH. D For example, for the purposes of this disclosure, if an antibody or antigen-binding fragment thereof exhibits an acidic / neutral K of about 3.0 or greater, D In certain exemplary embodiments, the acidic / neutral K of an antibody or antigen-binding fragment of the present disclosure is 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.

[0143] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening an antibody population for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. Additionally, antibodies with pH-dependent binding characteristics can be generated by modifying the antigen-binding domain at the amino acid level. For example, by replacing one or more amino acids of the antigen-binding domain (e.g., within the CDRs) with histidine residues, antibodies can be obtained whose antigen binding is reduced at acidic pH relative to neutral pH.

[0144] Preparation of human antibodies

[0145] Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present disclosure to prepare human antibodies that specifically bind to human IL-4R.

[0146] Using VELOCIMMUNE TM High-affinity chimeric antibodies to IL-4R having human variable regions and mouse constant regions are initially isolated using the ELISA technique (see, e.g., US 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies. The technology involves generating transgenic mice having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies comprising human variable regions and mouse constant regions in response to antigenic stimulation. DNA encoding the heavy and light chain variable regions of the antibodies is isolated and operably linked to DNA encoding human heavy and light chain constant regions. Subsequently, the DNA is expressed in cells capable of expressing fully human antibodies.

[0147] Typically, challenge with the antigen of interest In some embodiments, the present invention relates to a method for producing an antibody that is expressed in a mouse. The method comprises the steps of: using a mouse to express an antibody, and reclaiming lymphocytes (such as B cells) from the mouse expressing the antibody. Lymphocytes can be fused with a myeloma cell line to prepare an infinite hybridoma cell line, and this type of hybridoma cell line is screened and selected to identify the hybridoma cell line that produces an antibody that is specific to the antigen being paid attention to. The DNA encoding heavy chain and light chain variable region can be separated and connected to the isotype constant region of the desired heavy chain and light chain. This type of antibody protein can be produced in cells such as Chinese hamster ovary celI. Alternatively, the DNA encoding antigen-specific chimeric antibodies or light chain and heavy chain variable domains can be directly isolated from antigen-specific lymphocytes.

[0148] First, high-affinity chimeric antibodies with human variable regions and mouse constant regions are isolated. Standard procedures known to those skilled in the art are used to characterize and select the antibodies to obtain desired characteristics, including affinity, selectivity, epitopes, etc. The mouse constant region is replaced with the desired human constant region to generate fully human antibodies disclosed herein, such as wild-type or modified IgG1 or IgG4. Although the selected constant region can vary depending on the specific application, high-affinity antigen binding and target specificity characteristics are present in the variable region.

[0149] Typically, antibodies useful in the methods of the present disclosure have high affinity as described above when measured by binding to an antigen immobilized on a solid phase or in solution. Mouse constant regions are substituted with desired human constant regions to generate fully human antibodies disclosed herein. Although the selected constant region can vary depending on the specific application, high affinity antigen binding and target specificity characteristics are present in the variable region.

[0150] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to an 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 conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence differences, 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 can also be used to identify CDR sequences within antibodies.

[0151] Pharmaceutical composition

[0152] In one aspect, the present disclosure provides methods comprising administering an IL-4R antagonist to a subject, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained in a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. Various pharmaceutically acceptable carriers and excipients are well known in the art. See, for example, 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.

[0153] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. Compositions can be administered by any convenient route, such as by infusion or bolus injection, by absorption through the epithelium or mucocutaneous lining (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents. In some embodiments, pharmaceutical compositions as disclosed herein are administered intravenously. In some embodiments, pharmaceutical compositions as disclosed herein are administered subcutaneously.

[0154] 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 can be prepared by known methods. For example, the injectable preparation can be prepared by dissolving, suspending or emulsifying the antibody described above or its salt in a sterile aqueous medium or an oily medium conventionally used for injection. As an aqueous medium for injection, there are, for example, normal saline, isotonic solutions containing glucose and other adjuvants, etc., which can be used in combination with suitable solubilizers (such as alcohol (for example, ethanol), polyols (for example, propylene glycol, polyethylene glycol), nonionic surfactants [for example, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As an oily medium, sesame oil, soybean oil, etc. are used, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be loaded into a suitable ampoule.

[0155] The dosage of the antibody administered to a subject according to the methods of the present disclosure can vary depending on the age and size of the subject, symptoms, condition, route of administration, and the like. Dosages are typically calculated based on body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. The effective dosage and schedule for administering a pharmaceutical composition comprising an anti-IL-4R antibody can be determined empirically; for example, the patient's progress can be monitored by regular assessments, and the dosage adjusted accordingly. In addition, 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 dosages of anti-IL4R antibodies useful in the context of the present disclosure, as well as administration regimens involving such dosages, are disclosed elsewhere herein.

[0156] In some embodiments, an IL-4R antagonist or pharmaceutical composition of the present disclosure is contained in a container. Thus, in another aspect, a container comprising an IL-4R antagonist or pharmaceutical composition as disclosed herein is provided. For example, in some embodiments, the pharmaceutical composition is contained in a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an autoinjector.

[0157] In some embodiments, the pharmaceutical composition of the present disclosure is delivered, for example, subcutaneously or intravenously, with a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, a pen-type delivery device or an automatic injector is used to deliver the pharmaceutical composition of the present disclosure (e.g., for subcutaneous delivery). The pen-type delivery device can be reusable or disposable. Typically, a reusable pen-type delivery device utilizes a replaceable barrel containing the pharmaceutical composition. Once the pharmaceutical composition in the barrel has been applied and the barrel becomes empty, the empty barrel can be easily discarded and replaced with a new barrel containing the pharmaceutical composition. The pen-type delivery device can then be reused. In a disposable pen-type delivery device, there is no replaceable barrel. In fact, the disposable pen-type delivery device is pre-filled with the pharmaceutical composition in the reservoir in the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded.

[0158] Examples of suitable pen and autoinjector delivery devices include, but are not limited to, AUTOPEN TM (Owen Mumford, Inc., Woodstock, UK), DISSETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TMPen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM 、OPTIPEN PRO TM 、OPTIPEN STARLET TM and OPTICLIK TM (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen delivery devices that can be used for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, SOLOSTAR TM Pen (sanofi-aventis), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA TM Pen (Abbott Labs, Abbott Park IL).

[0159] In some embodiments, a controlled release system is used to deliver the pharmaceutical composition. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed near the target of the composition, thus requiring only a small portion 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 the pharmaceutical composition, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant virus, receptor-mediated endosomes (see, e.g., Wu et al., 1987, J. Biol. Chem., 262:4429-4432).

[0160] 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, such as those 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 categorized as multi-dose container systems and single-dose (partially or fully evacuated) container systems. The container can be a refillable container or a single-piece, non-refillable container.

[0161] As further described in ISO 11608-1:2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, and the size of the multiple doses may be fixed or variable (preset by the user). Another multi-dose container system may involve a needle-based injection device with an integral, non-replaceable container. In such a system, each container holds multiple doses, and the size of the multiple doses may be fixed or variable (preset by the user).

[0162] As further described in ISO 11608-1:2014 (E), a single-dose container system can relate to a needle-based injection device with a replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (completely evacuated). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partially evacuated). Additionally, as described in ISO 11608-1:2014 (E), a single-dose container system can relate to a needle-based injection device with an integrated non-replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (completely evacuated). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partially evacuated).

[0163] An exemplary sleeve-activated autoinjector with a manual needle inserter is described in International Publication WO 2015 / 004052. An exemplary audible end-of-dose feedback mechanism is described in International Publications WO 2016 / 193346 and WO 2016 / 193348. An exemplary needle safety mechanism after use of the autoinjector is described in International Publication WO 2016 / 193352. An exemplary needle guard remover mechanism for a syringe autoinjector is described in International Publication WO 2016 / 193353. An exemplary support mechanism for supporting the axial position of the syringe is described in International Publication WO 2016 / 193355.

[0164] In some embodiments, the pharmaceutical composition for use as described herein is prepared in a dosage form in a unit dose suitable for the dosage of the active ingredient. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0165] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[0166] Dosage and administration

[0167] In some embodiments, according to the methods of the present disclosure, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject (e.g., a subject with a bone growth defect). As used herein with respect to an IL-4R antagonist, the phrase "therapeutically effective amount" refers to an amount of an IL-4R antagonist that results in one or more of the following: (a) improvement in bone formation; (b) improvement in bone mineralization and / or bone mineral density; (c) reduction in bone loss; (d) improvement or normalization (e.g., relative to healthy control values) 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, N-terminal propeptide of type I procollagen, insulin-like growth factor 1, or osteocalcin); and / or (e) a reduction in the incidence of bone loss, osteoporosis, or fractures (e.g., relative to healthy control values).

[0168] In the case of an anti-IL-4R antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg. or about 600 mg of an anti-IL-4R antibody. In some embodiments, the therapeutically effective amount is from about 50 mg to about 600 mg, or from about 100 mg to about 600 mg, or from about 200 mg to about 600 mg. In certain 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.

[0169] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in an individual dose can be expressed as milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of subject body weight, such as about 1 mg / kg to about 10 mg / kg, about 2 mg / kg to about 9 mg / kg, or about 3 mg / kg to about 8 mg / kg. In some embodiments, the IL-4R antagonist can 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.

[0170] In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently, as long as a therapeutic response is achieved. In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject once a month or twice a month.

[0171] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a specified time period. In some embodiments, the methods of the present disclosure comprise administering multiple doses of an IL-4R antagonist sequentially to a subject. As used herein, "sequential administration" means that each dose of an IL-4R antagonist is administered to a subject at a different time point, such as on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the present disclosure comprise administering a single initial dose of an IL-4R antagonist to a patient sequentially, followed by administration of one or more secondary doses of the IL-4R antagonist, and optionally followed by administration of one or more tertiary doses of the IL-4R antagonist.

[0172] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order in which the IL-4R antagonist is administered. Thus, the "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "loading dose"); the "secondary dose" is the dose administered after the initial dose; and the "tertiary dose" is the dose administered after the second dose. The initial dose, the second dose, and the third dose can all contain the same amount of IL-4R antagonist, but generally can differ from one another in terms of the frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial dose, the second dose, and / or the third dose varies from one another during the course of treatment (e.g., adjusted upward or downward 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 "loading doses," followed by subsequent doses (e.g., "maintenance doses") administered at a less frequent rate. In some embodiments, the initial dose or loading dose and the one or more secondary doses or maintenance doses each contain the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the IL-4R antagonist, and the one or more second doses each comprise a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist can be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more of the second amount of the IL-4R antagonist. In some embodiments, one or more maintenance doses of the IL-4R antagonist are administered without a loading dose.

[0173] In some embodiments, the loading dose is a "split dose" of two or more doses (e.g., 2, 3, 4, or 5 doses) administered on different days. In some embodiments, the loading dose is administered as a split dose, wherein the two or more doses are administered at least one week apart. In some embodiments, the loading dose is administered as a split dose, wherein the two or more doses are administered about 1 week, 2 weeks, 3 weeks, or 4 weeks apart. In some embodiments, the loading dose is divided equally into 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 divided unequally into 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).

[0174] In some embodiments, each second and / or third dose is administered 1 week 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, 61 / 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 As used herein, the phrase "immediately preceding" means that, in a sequence of multiple administrations, the dose of the IL-4R antagonist is administered to the patient prior to the administration of the immediately next dose in the sequence, without an intervening dose.

[0175] The methods of the present disclosure can include administering to the patient any number of second and / or third doses of an IL-4R antagonist. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to the patient.

[0176] In some embodiments involving multiple second doses, each second dose is administered at the same frequency as the other second doses. For example, each second dose can be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the previous dose. Similarly, in some embodiments involving 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 1 week, 2 weeks, 3 weeks, or 4 weeks after the previous dose. Alternatively, the frequency of the second and / or third doses administered to the patient can vary during the course of the treatment regimen. The physician can also adjust the frequency of administration during treatment, depending on the needs of each patient after clinical examination.

[0177] 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.

[0178] 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.

[0179] 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 divided loading dose of 600 mg (e.g., wherein 300 mg is administered on day 1 and 300 mg is administered on day 15), followed by one or more subsequent doses of 300 mg administered Q4W starting four weeks after the day 15 dose. In some embodiments, no loading dose is administered.

[0180] 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.

[0181] In some embodiments, for subjects aged ≥12 to <18 years (e.g., subjects aged ≥12 to <18 years with moderate to severe or severe AD), or for subjects aged ≥6 to <18 years (e.g., subjects aged ≥6 to <18 years with moderate to severe or severe AD), or for subjects aged ≥6 to <12 years (e.g., subjects aged ≥6 to <12 years with moderate to severe or severe AD), if the subject weighs ≥60 kg, the therapeutically effective amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, if the subject weighs ≥60 kg, a loading dose of 600 mg is administered to the subject, followed by one or more subsequent doses of 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0182] In some embodiments, for subjects aged ≥12 to <18 years (e.g., subjects aged ≥12 to <18 years with moderate to severe or severe AD), if the subject weighs <60 kg, 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, if the subject weighs <60 kg, a loading dose of 400 mg is administered to the subject, followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0183] In some embodiments, for subjects aged ≥12 to <18 years (e.g., subjects aged ≥12 to <18 years with moderate to severe or severe AD), or for subjects aged ≥6 to <18 years (e.g., subjects aged ≥6 to <18 years with moderate to severe or severe AD), or for subjects aged ≥6 to <12 years (e.g., subjects aged ≥6 to <12 years with moderate to severe or severe AD), if the subject weighs ≥30 kg to <60 kg, the therapeutically effective amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, if the subject weighs ≥30 kg to <60 kg, a loading dose of 400 mg is administered to the subject, followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0184] In some embodiments, for subjects aged ≥6 months to <6 years (e.g., subjects aged ≥6 months to <6 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <12 years (e.g., subjects aged ≥6 years to <12 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <18 years (e.g., subjects aged ≥6 years to <18 years with moderate to severe or severe AD), if the subject weighs ≥15 kg to <60 kg, the therapeutically effective amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, if the subject weighs ≥15 kg to <60 kg, a loading dose of 400 mg is administered to the subject, followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0185] In some embodiments, for subjects aged ≥6 months to <6 years (e.g., subjects aged ≥6 months to <6 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <12 years (e.g., subjects aged ≥6 years to <12 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <18 years (e.g., subjects aged ≥6 years to <18 years with moderate to severe or severe AD), if the subject weighs ≥15 kg to <60 kg, the therapeutically effective amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W). In some embodiments, if the subject weighs ≥15 kg to <60 kg, the subject is administered a loading dose of 600 mg, followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W). In some embodiments, subjects are administered a divided loading dose of 600 mg (e.g., where 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.

[0186] In some embodiments, for subjects aged ≥6 months to <6 years (e.g., subjects aged ≥6 months to <6 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <12 years (e.g., subjects aged ≥6 years to <12 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <18 years (e.g., subjects aged ≥6 years to <18 years with moderate to severe or severe AD), if the subject weighs ≥15 kg to <30 kg, the therapeutically effective amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W). In some embodiments, if the subject weighs ≥15 kg to <30 kg, the subject is administered a loading dose of 600 mg, followed by one or more subsequent doses of 300 mg administered every four weeks (Q4W). In some embodiments, subjects are administered a divided loading dose of 600 mg (e.g., where 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.

[0187] In some embodiments, for subjects aged ≥6 months to <6 years (e.g., subjects aged ≥6 months to <6 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <12 years (e.g., subjects aged ≥6 years to <12 years with moderate to severe or severe AD), or for subjects aged ≥6 years to <18 years (e.g., subjects aged ≥6 years to <18 years with moderate to severe or severe AD), if the subject weighs ≥5 kg to <15 kg, the therapeutically effective amount of the IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 200 mg administered every four weeks (Q4W). In some embodiments, if the subject weighs ≥5 kg to <15 kg, the subject is administered a loading dose of 400 mg, followed by one or more subsequent doses of 200 mg administered every four weeks (Q4W). In some embodiments, subjects are administered a divided loading dose of 400 mg (e.g., where 200 mg is administered on day 1 and 200 mg is administered on day 15), followed by one or more subsequent doses of 200 mg administered Q4W starting four weeks after the dose on day 15. In some embodiments, no loading dose is administered.

[0188] Combination therapy

[0189] In some embodiments, the methods of the present disclosure comprise administering to a subject (e.g., a pediatric or adolescent subject with a bone growth defect) an IL-4R antagonist according to the present disclosure (e.g., an anti-IL-4R antibody) and one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a topical therapeutic agent, e.g., TCS or a topical nonsteroidal drug, such as TCI or crisaborole. In some embodiments, the additional therapeutic agent is a systemic agent, e.g., cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, systemic or oral corticosteroids, Janus kinase (JAK) inhibitors, or interferon-γ. In some embodiments, the additional therapeutic agent is an immunobiological agent, 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 expression "in combination with" refers to administration of the additional therapeutic agent before, after, or simultaneously with administration of the IL-4R inhibitor. The term "in combination with" also includes sequential or concomitant administration of the IL-4R inhibitor and the additional therapeutic agent.

[0190] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can 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, the additional therapeutic agent can 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 co-administered 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 in a single combined dosage formulation comprising the additional therapeutic agent and the IL-4R antagonist.

[0191] 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 TCI. In some embodiments, the additional therapeutic agent is crisaborole.

[0192] Table 1: Informal Sequence Listing

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208] Example

[0209] The following examples are presented to provide a complete disclosure and description of how to prepare and use the disclosed methods and compositions to those of ordinary skill in the art and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure the accuracy of the figures used (e.g., amounts, temperatures, etc.), but certain experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is degrees Celsius, and pressure is or near atmospheric pressure.

[0210] Example 1: Dupilumab treatment increases bone alkaline phosphatase (a marker of bone mineralization) in children with moderate to severe atopic dermatitis

[0211] The aim of this analysis was to report the effects of dupilumab treatment on markers of bone formation in children aged ≥6 years to <12 years with moderate-to-severe AD.

[0212] method

[0213] A retrospective analysis of serum from participants in LIBERTY AD PEDS (NCT03345914) and LIBERTY AD PED-OLE (NCT02612454) was performed. In LIBERTY AD PEDS, a double-blind, 16-week, Phase 3 trial, children aged 6 to <12 years were randomized 1:1:1 to 300 mg of dupilumab every 4 weeks (300 mg every 4 weeks), a weight-based regimen of dupilumab every 2 weeks (100 mg every 2 weeks for patients with a baseline weight <30 kg and 200 mg every 2 weeks for patients with a baseline weight ≥30 kg), or placebo, accompanied by a moderate-potency topical corticosteroid (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 every 4 weeks, with titration to 200 mg every 2 weeks for patients with a baseline weight <60 kg and 300 mg every 2 weeks for patients with a baseline weight ≥60 kg, accompanied by a moderately potent TCS. Bone biomarkers (including BALP, N-terminal propeptide of type 1 procollagen, 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, and only BALP was analyzed at 52 weeks.

[0214] result

[0215] Dupilumab treatment resulted in a rapid and significant increase in BALP geometric mean (SE) levels 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 enrolled in the OLE trial. BALP levels increased in all treated children over 52 weeks, reaching 78-84 μg / L, which constituted a significant improvement from baseline and was comparable to the healthy reference interval. Figure 1 .

[0216] Both dupilumab dosing regimens resulted in significant increases in geometric mean (standard error) BALP levels compared with placebo at weeks 8, 12, and 16. For the 100 / 200 mg q2w group, BALP levels were 72.7 (1.03) μg / L for dupilumab and 62.0 (1.05) μg / L for placebo at week 8 (P < 0.0001); 74.7 (1.03) μg / L vs. 64.3 (1.05) μg / L at week 12 (P = 0.0002); and 78.0 (1.03) μg / L vs. 65.0 (1.04) μg / L at week 16 (P < 0.0001). For the 300 mg q4w group, at week 8, BALP levels were 76.7 (1.03) μg / L for dupilumab and 62.0 (1.05) μg / L for placebo, P < 0.0001; at week 12, BALP levels were 73.3 (1.04) μg / L vs. 64.3 (1.05) μg / L, P = 0.002; and at week 16, BALP levels were 77.3 (1.03) μg / L vs. 65.0 (1.04) μg / L, P < 0.0001. At 52 weeks, BALP levels increased significantly compared with baseline (placebo vs. placebo switched to 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) and were within the reference interval (Diemar et al., Bone, 2021, 146: 115879).

[0217] For other biomarkers (osteocalcin, PINP, IGF-1, and β-CTX), increasing trends from baseline to 16 weeks of pilimumab treatment were observed, although the number of data points was limited due to insufficient serum available for analysis. Figures 2 to 5 Overall, in this age group, mean biomarker levels measured in children treated with dupilumab improved from below the reference interval to within the reference interval for osteocalcin, PINP, and β-CTX and from below the mean reference interval to near the mean reference interval for BALP and IGF-1.

[0218] A subgroup analysis of BALP levels was performed by sex in samples from girls and boys aged 6-12 years with moderate to severe AD; the patient group in this analysis was 6-11 years old at the beginning of the study. Although the reference intervals for BALP vary, girls show higher values ​​earlier and reach a plateau around the age of 12, while boys' BALP levels continue to increase until they are around 15 years old. (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, 146:115879). Treatment with dupilumab increased BALP levels in female and male patients to the reference interval and reflected this gender difference. At week 16, treatment with dupilumab resulted in rapid and significant increases in geometric mean (standard error) BALP levels in girls and boys compared with those 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 resulted in increases in BALP levels in all treated children, reaching 90.5 μg / L in girls and 86.6 μg / L in boys. See Figures 6 to 7. Figure 7 .

[0219] Subgroup analyses were also performed to assess the effect of dupilumab treatment on BALP levels in children aged 6 to 12 years with moderate to severe AD, with or without concomitant asthma. Regardless of concomitant asthma, dupilumab treatment resulted in a rapid and significant increase in the geometric mean (standard error) BALP levels in children with moderate to severe AD at 16 weeks compared with those 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 week 52, geometric mean (standard error) BALP levels increased significantly compared with baseline and were comparable to reference intervals in patients with and without asthma (with asthma: placebo versus placebo switched to dupilumab: 62.3 [1.06] μg / L versus 78.3 [1.07] μg / L; dupilumab: 62.1 [1.04] μg / L versus 82.7 [1.04] μg / L; without asthma: placebo versus placebo switched to dupilumab: 66.0 [1.06] μg / L versus 87.5 [1.06] μg / L; dupilumab: 64.0 [1.04] μg / L versus 79.9 [1.03] μg / L).

[0220] in conclusion :

[0221] These placebo-controlled results show for the first time that BALP, and possibly other biomarkers, increase rapidly and significantly during treatment with dupilumab in children with AD. These results suggest increased bone mineralization during treatment.

[0222] The scope of the present invention is not limited by the specific embodiments described herein. In fact, various modifications of the present invention in addition to those described herein will be 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. A method for improving bone growth, comprising: selecting a subject having a bone growth defect, wherein the subject is a pediatric subject or an adolescent subject less than 18 years of age; and One or more doses of an interleukin-4 receptor (IL-4R) antagonist is administered to the subject, 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 of LGS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

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

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 less than 12 years of age.

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

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

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

8. The method of any one of claims 1 to 7, wherein the subject suffers from comorbid asthma.

9. The method of any one of claims 1 to 8, wherein the selecting step comprises selecting a subject who exhibits a level of a bone turnover marker below a threshold, wherein the bone turnover marker is bone-specific alkaline phosphatase, carboxyl-terminal cross-linking 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. The method of claim 9, wherein the threshold value is the average level of a bone turnover marker in a population of healthy subjects of the same age as the selected pediatric or adolescent subject.

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

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 a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

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

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

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

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

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

18. The method of any one of claims 1 to 5 and 8 to 13, wherein the subject is a pediatric subject 6 to 11 years of age with a baseline weight of ≥15 kg to <60 kg, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 300 mg on day 1, followed by an initial dose of 300 mg on day 15, followed by one or more subsequent doses of 300 mg Q4W starting four weeks after the day 15 dose.

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

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

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

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

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

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

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. 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 autoinjector.

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

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

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

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

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