Methods for treating digitally-identified il-4 / il-13 related disorders

Abstract

To provide a composition for use in a method of treating an IL-4 / IL-13 related disorder.SOLUTION: Provided is a composition for use in a method of treating an eye-related disorder in a subject in need thereof with an anti-interleukin-4 receptor α (anti-IL-4Rα) antibody, wherein the eye-related disorder is selected from dry eye, blepharitis, cicatricial pemphigoid, Mooren's corneal ulcer, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, phacoanaphylaxis endophthalmitis, or a combination thereof, and wherein the method comprises administering a therapeutically effective amount of the anti-IL-4Rα antibody to the subject.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit from U.S. Provisional Patent Application No. 62 / 945,807, filed December 9, 2019, U.S. Provisional Patent Application No. 63 / 028,919, filed May 22, 2020, European Patent Application No. 20315280.6, filed May 29, 2020, European Patent Application No. 20315281.4, filed May 29, 2020, and European Patent Application No. 20315450.5, filed November 13, 2020, the contents and disclosures of which are incorporated herein by reference in their entireties.

[0002] Reference to sequence listing This application contains a Sequence Listing, which is incorporated herein by reference in its entirety. The file, created on December 1, 2020, is contained in a text file named 37488-0781_Sequence_Listing.txt and is 15.589 kilobytes in size.

[0003] Technical Field The present disclosure relates to the treatment of various disorders with anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab). [Background technology]

[0004] Interleukin-4 (IL-4, also known as B cell stimulating factor or BSF-1) stimulates B cell proliferation in response to low concentrations of antibodies directed against surface immunoglobulins. IL-4 has a wide range of biological activities, including stimulating the proliferation of T cells, mast cells, granulocytes, megakaryocytes, and erythrocytes. IL-4 induces the expression of class II major histocompatibility complex molecules in resting B cells and enhances the secretion of IgE and IgG1 isotypes by stimulated B cells. The biological activity of IL-4 is mediated by a specific cell surface receptor for IL-4, namely, the human IL-4 receptor alpha (hIL-4R).

[0005] Interleukin-13 (IL-13), a multifunctional cytokine, acts via the IL-13Ra1 / IL-4Rα complex to induce activation responses that contribute to inflammatory diseases. IL-13 is involved in several stages of B cell maturation and differentiation; IL-13 upregulates CD23 and MHC class II expression and promotes B cell switching to IgE isotype. IL-13 also downregulates macrophage activation, thereby inhibiting the production of pro-inflammatory cytokines and chemokines.

[0006] Dupilumab is an anti-IL-4Rα monoclonal antibody that inhibits IL-4 and interleukin-13 (IL-13) signal transduction. Dupilumab is currently used to treat patients aged 12 years or older with moderate to severe atopic dermatitis whose disease is not adequately controlled by topical drug therapy or for whom such therapy is ineffective. It is also used as an add-on maintenance therapy in patients with moderate to severe asthma and in patients with chronic rhinosinusitis with nasal polyps. There remains a need for the use of anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) to treat other disorders. Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure is based, at least in part, on the discovery of new disorders treatable with anti-IL-4Rα antibodies, such as dupilumab. The treatable disorders described herein were identified, at least initially, using novel computational methods that are capable of analyzing data from large patient populations and predicting therapeutic outcomes of treatment with anti-IL-4Rα antibodies. [Means for solving the problem]

[0008] Thus, disclosed herein are methods for treating a subject with an anti-interleukin-4 receptor antibody that exhibits at least one symptom of, or has been determined to be susceptible to, an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder. In some cases, the method includes administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject with an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder that exhibits at least one symptom of, or has been determined to be susceptible to, the disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA), a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT), a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV), a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY), a variable light chain CDR2 of SEQ ID NO: 5 (LGS), and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0009] In some cases, the method includes (a) identifying a subject for treatment with an anti-IL-4Rα antibody; and (b) administering a therapeutically effective amount of an anti-IL-4Rα antibody to the subject, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, identifying a subject for treatment includes: (a) selecting a characteristic or characteristics in a set of patients; (b) clustering, by a computer system, a subset of patients having the characteristic or characteristics according to the characteristic or characteristics, wherein the characteristic or characteristics are determined to be associated with at least one symptom of an IL-4Rα-associated disorder or a predisposition to the disorder; (c) identifying, in the subset of patients clustered in step (b), an IL-4Rα-associated disorder based on the characteristic or characteristics associated with the IL-4 / IL-13 pathway; and (d) selecting a subject exhibiting at least one symptom of an IL-4Rα-associated disorder or a predisposition to the disorder identified in step (c).

[0010] In some cases, the method includes identifying a subject as a candidate for treatment for an anti-interleukin-4 receptor alpha (IL-4Rα) associated disorder with an anti-IL-4Rα antibody, comprising: (a) selecting, in a data set representing medical records of a plurality of subjects, a trait or traits associated with the IL4 / IL13 pathway; (b) clustering, by a computer system, a subset of subjects from the plurality of subjects according to the trait or traits associated with the IL-4 / IL-13 pathway, wherein the subset includes the trait or traits; and (c) identifying a subject clustered in step (b). (d) identifying, among the identified subset, an IL-4Rα-associated disorder based on symptoms associated with a characteristic or characteristics associated with the IL-4 / IL-13 pathway; and (d) identifying a patient with at least one symptom of or suffering from an IL-4Rα-associated disorder identified in step (c), provided that the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA). and selecting the subject determined to be susceptible to the disease.

[0011] In some cases, the method includes steps of identifying a subject as a candidate for treatment for an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder with an anti-IL-4Rα antibody, the steps including: (a) selecting, in a data set representing the medical records of a plurality of subjects, a trait or traits associated with the IL4 / IL13 pathway; (b) clustering, by a computer system, a subset of subjects from the plurality of subjects according to the trait or traits associated with the IL-4 / IL-13 pathway, wherein the subset comprises the trait or traits; (c) identifying, in the subset clustered in step (b), an IL-4Rα-associated disorder based on a symptom associated with the trait or traits associated with the IL-4 / IL-13 pathway; and (d) selecting a subject having at least one symptom of or determined to be susceptible to the IL-4Rα-associated disorder identified in step (c). In some cases, the method further includes administering a therapeutically effective amount of an anti-IL-4Rα antibody to the subject, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0012] In some cases, the method includes identifying a subject as a candidate for treatment for an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder with an anti-IL-4Rα antibody, comprising: (a) selecting, in a data set representing medical records of a plurality of subjects, a trait or traits associated with the IL4 / IL13 pathway; (b) clustering, by a computer system, a subset of subjects from the plurality of subjects according to the trait or traits associated with the IL-4 / IL-13 pathway, wherein the subset comprises the trait or traits; and (c) identifying, in the subset clustered in step (b), (d) identifying an IL-4Rα-associated disorder based on symptoms associated with a characteristic or characteristics associated with the IL-4 / IL-13 pathway; and (d) selecting a subject having at least one symptom of or susceptible to an IL-4Rα-associated disorder identified in step (c), provided that the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA). In some cases, the method further includes administering a therapeutically effective amount of an anti-IL-4Rα antibody to the subject, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0013] In some cases, a method of treating a subject with an anti-interleukin-4 receptor antibody comprises the steps of: (a) selecting a characteristic or plurality of characteristics in a set of patients; (b) clustering, by a computer system, a subset of patients having the characteristic or plurality of characteristics according to the characteristic or plurality of characteristics, wherein the characteristic or plurality of characteristics is determined to be associated with at least one symptom of an IL-4R-associated disorder or a predisposition to the disorder; and (c) administering a therapeutically effective amount of an anti-IL-4R antibody to a subject exhibiting at least one symptom of an IL-4R-associated disorder or a predisposition to the disorder, wherein the anti-IL-4R antibody is an antibody having an IL-4R receptor sequence identified as SEQ ID NO: 1 (GFTFRD and a variable light chain CDR3 of SEQ ID NO:6 (MQALQTPYT). In some cases, the anti-IL-4R antibody is an anti-IL-4R-α antibody. In some cases, the anti-IL-4R antibody is dupilumab. In some cases, the IL-4R-associated disorder is an IL-4R-α-associated disorder. In some cases, the IL-4Rα-associated disorder is a condition listed in Table 9 or Table 10. A method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising the steps of: (a) selecting a characteristic or plurality of characteristics in a set of patients; (b) clustering, by a computer system, a subset of patients having the characteristic or plurality of characteristics according to the characteristic or plurality of characteristics, wherein the characteristic or plurality of characteristics is determined to be associated with at least one symptom of an IL-4Rα-associated disorder or to be predisposed to the disorder; and (c) administering a therapeutically effective amount of the anti-IL-4Rα antibody to an IL-4Rα-associated patient. and administering to a subject who exhibits at least one symptom of or has been determined to be susceptible to an IL-4Rα disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0014] Also disclosed herein are methods of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, wherein the IL-4Rα-associated disorder is susceptible to selection by machine learning methods. In some cases, the method includes the steps of: (a) selecting a trait or traits associated with the IL-4 / IL-13 pathway in a data set representing the medical records of a plurality of patients; (b) clustering, by a computer system, a subset of patients having the trait or traits associated with the IL-4 / IL-13 pathway according to the trait or traits; and (c) selecting, in the subset of patients clustered in step (b), a trait or traits associated with the IL-4 / IL-13 pathway. (d) identifying an IL-4Rα-associated disorder based on gender-related symptoms; and (d) selecting an IL-4Rα-associated disorder identified in step (c), provided that the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA). In some cases, the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0015] In some cases, the anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody is used for the prevention of an IL-4Rα-associated disorder. In some cases, the anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody is used for the prevention of an IL-4Rα-associated disorder using the methods disclosed herein. In some cases, the anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody is used for the treatment of an IL-4Rα-associated disorder. In some cases, the anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody is used for the treatment of an IL-4Rα-associated disorder using the methods disclosed herein. In some cases, the IL-4Rα-associated disorder is atopic dermatitis, asthma, or the like. , chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), allergic bronchopulmonary aspergillosis (ABPA) or any combination thereof.

[0016] In some cases, the IL-4Rα-related disorder is not atopic dermatitis. In some cases, the IL-4Rα-related disorder is not asthma. In some cases, the IL-4Rα-related disorder is not chronic rhinosinusitis with nasal polyps. In some cases, the IL-4Rα-related disorder is not eosinophilic esophagitis. In some cases, the IL-4Rα-related disorder is not peanut allergy. In some cases, the IL-4Rα-related disorder is not grass allergy. In some cases, the IL-4Rα-related disorder is not chronic obstructive pulmonary disease (COPD). In some cases, the IL-4Rα-related disorder is not prurigo nodularis. In some cases, the IL-4Rα-related disorder is not bullous pemphigoid. In some cases, the IL-4Rα-related disorder is not chronic idiopathic urticaria (CSU). In some cases, the IL-4Rα-associated disorder is not allergic bronchopulmonary aspergillosis (ABPA).

[0017] In some cases, disclosed is an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody for use in preventing or treating a skin-related disorder selected from the group consisting of lichen planus, seborrheic dermatitis, solar urticaria, vitiligo, and dyshidrotic eczema, the anti-IL-4Rα antibody comprising a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, preventing or treating the skin-related disorder comprises administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject exhibiting at least one symptom of or determined to be susceptible to a skin-related disorder.

[0018] In some cases, the anti-IL-4Rα antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:14.

[0019] In some cases, the skin-related indication is lichen planus. In some cases, the skin-related indication is seborrheic dermatitis. In some cases, the skin-related indication is solar urticaria. In some cases, the skin-related indication is vitiligo. In some cases, the skin-related indication is dyshidrotic eczema. In some cases, the subject is a human. In some cases, the administering step is intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, or epidural administration. In some cases, the administering step is subcutaneous administration and is performed by a prefilled syringe, prefilled pen, or autoinjector. In some cases, the anti-IL-4Rα antibody is administered in multiple doses. In some cases, the anti-IL-4Rα antibody is administered in two doses. In some cases, the anti-IL-4Rα antibody is administered at a dose of about 0.0001 to about 10 mg / kg of patient body weight. In some cases, the method further comprises administering a second therapeutic agent. In some cases, the second therapeutic agent is a second antibody or antigen-binding fragment thereof, a soluble cytokine receptor, an IgE antagonist, an anti-asthma medication, or a checkpoint inhibitor. In some cases, the anti-asthma medication is a corticosteroid, a non-steroidal drug, a beta agonist, a leukotriene antagonist, a xanthine, fluticasone, salmeterol, or albuterol. In some cases, the checkpoint inhibitor is a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some cases, the anti-IL-4Rα antibody is administered before, simultaneously with, or after the administration of the second therapeutic agent. It is given.

[0020] In some cases, the present invention provides an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody for use in the prevention or treatment of an IL-4Rα-associated disorder, the IL-4Rα-associated disorder being selected from the following steps: (a) selecting, in a data set representing medical records of a plurality of patients, a characteristic or characteristics associated with the IL4 / IL-13 pathway; (b) clustering, by a computer system, a subset of patients having the characteristic or characteristics associated with the IL-4 / IL-13 pathway according to the characteristic or characteristics; (c) identifying, in the subset of patients clustered in step (b), an IL-4Rα-associated disorder based on symptoms associated with the characteristic or characteristics associated with the IL-4 / IL-13 pathway; and (d) identifying, in the subset of patients clustered in step (b), an IL-4Rα-associated disorder based on symptoms associated with the characteristic or characteristics associated with the IL-4 / IL-13 pathway. and selecting the IL-4Rα-associated disorder identified in step (c) from the group consisting of: nut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA), with the proviso that the IL-4Rα-associated disorder is not selected from the group consisting of: nut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA), wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0021] In some cases, preventing or treating an IL-4Rα-associated disorder comprises administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject exhibiting at least one symptom of or determined to be susceptible to an IL-4Rα-associated disorder. In some cases, the anti-IL-4Rα antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 14. In some cases, the IL-4Rα-associated disorder is a skin-related disorder, an allergic reaction, arthritis, a nasal-related disorder, a lung-related disorder, a blood-related disorder, an eye-related disorder, an esophageal-related disorder, a gastrointestinal-related disorder, a kidney-related disorder, a prostate-related disorder, Kawasaki disease, a thyroid-related disorder, a vascular-related disorder, a pregnancy-related disorder, or cancer.

[0022] In some cases, the skin-related disorder is selected from the group consisting of dyshidrotic eczema, lichen planus, seborrheic dermatitis, solar urticaria, vitiligo, acne, erythema multiforme, pityriasis rosea, epidermolysis bullosa, dermatitis herpetiformis, allergic contact dermatitis, chronic hand eczema, nummular dermatitis, scleroderma, generalized scleroderma, hypertrophic scarring, skin infections, focal alopecia, and Netherton syndrome.

[0023] In some cases, the allergic reaction is selected from the group consisting of hypersensitivity to dairy products, eggs, wheat, soy, corn, fish, shellfish, tree nuts, beef, chicken, oats, barley, pork, green beans, apples, or pineapple; and hypersensitivity to insect venom, plant-derived substances, chemicals, medications, or animal dander.

[0024] In some cases, the lung-related disorder is selected from the group consisting of pulmonary fibrosis, cirrhosis, chronic fibrotic lung disease, cystic fibrosis, allergic bronchopulmonary mycosis, bleomycin-induced pulmonary disease and fibrosis, pulmonary alveolar proteinosis, adult respiratory distress syndrome, sarcoidosis, tuberculosis, or aspirin asthma.

[0025] In some cases, the blood-related disorder is selected from the group consisting of sickle cell anemia, Churg-Strauss syndrome, a combination thereof, autoimmune lymphoproliferative syndrome, lupus (systemic lupus erythematosus), antiphospholipid syndrome (APS), and autoimmune hemolytic anemia.

[0026] In some cases, the ocular-related disorder is selected from the group consisting of Sjogren's syndrome, autoimmune uveitis, autoimmune lymphoproliferative syndrome, atrophic keratoconjunctivitis (AKC), dry eye, blepharitis, blepharoconjunctivitis, cicatricial pemphigoid, Mooren corneal ulcer, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, anaphylactic lenticular endophthalmitis, and keratoconjunctivitis sicca (KCS).

[0027] In some cases, the esophageal or gastrointestinal disorder is selected from the group consisting of Barrett's esophagus, eosinophilic gastritis, achalasia, gastroesophageal reflux disease (GERD), ulcerative colitis, Whipple's disease, Behcet's disease, or Wegener's granulomatosis. In some cases, the kidney-related disorder is selected from the group consisting of nephrosis, glomerulonephritis, and Goodpasture's syndrome. In some cases, the prostate-related disorder is benign prostatic hyperplasia (BPH) or chronic prostatitis syndrome.

[0028] In some cases, the cancer is cutaneous T-cell lymphoma.

[0029] In some cases, the thyroid-related disorder is Hashimoto's disease or Graves' disease.

[0030] In some cases, the vascular-related disorder is vasculitis, panarteritis nodosa, lupus, or antiphospholipid syndrome (APS).

[0031] In some cases, the pregnancy-related disorder is selected from the group consisting of antiphospholipid syndrome, immune thrombocytopenia, and pre-eclampsia.

[0032] In some cases, the subject is a human. In some cases, the administering step is intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, or epidural administration. In some cases, the administering step is subcutaneous administration and is performed using a prefilled syringe, prefilled pen, or autoinjector. In some cases, the anti-IL-4Rα antibody is administered in multiple doses. In some cases, the anti-IL-4Rα antibody is administered in two doses. In some cases, the anti-IL-4Rα antibody is administered at a dose of about 0.0001 to about 10 mg / kg of patient body weight. In some cases, the method further includes administering a second therapeutic agent. In some cases, the second therapeutic agent is a second antibody or antigen-binding fragment thereof, a soluble cytokine receptor, an IgE antagonist, an anti-asthma medication, or a checkpoint inhibitor. In some cases, the anti-asthma medication is a corticosteroid, a nonsteroidal drug, a beta agonist, a leukotriene antagonist, a xanthine, fluticasone, salmeterol, or albuterol. In some cases, the checkpoint inhibitor is a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some cases, the anti-IL-4Rα antibody is administered before, simultaneously with, or after administration of a second therapeutic agent.

[0033] In some cases, the anti-IL-4Rα antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:14.

[0034] In some cases, the IL-4Rα-related disorder is an allergic reaction. In some cases, the allergic reaction is hypersensitivity to foods selected from dairy products, eggs, wheat, soybeans, corn, fish, shellfish, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, apples, and pineapple. In some cases, the allergic reaction is hypersensitivity to insect venom, plant-derived substances, chemicals, medicines, or animal dander.

[0035] In some cases, the IL-4Rα-associated disorder is arthritis.

[0036] In some cases, the IL-4Rα-associated disorder is asthma.

[0037] In some cases, the IL-4Rα-related disorder is a nasal-related disorder. In some cases, the nasal-related disorder is nasal polyps. In some cases, the nasal-related disorder is sinusitis. In some cases, the nasal-related disorder is rhinitis.

[0038] In some cases, the IL-4Rα-associated disorder is a pulmonary disorder. In some cases, the pulmonary disorder is pulmonary fibrosis or cirrhosis. In some cases, the pulmonary disorder is selected from chronic fibrotic lung disease, cystic fibrosis, allergic bronchopulmonary mycosis, chronic obstructive pulmonary disease, bleomycin-induced pulmonary disease and fibrosis, pulmonary alveolar proteinosis, adult respiratory distress syndrome, sarcoidosis, tuberculosis, aspirin-induced asthma, or a combination thereof.

[0039] In some cases, the IL-4Rα-associated disorder is a blood-related disorder, hi some cases, the blood-related disorder is sickle cell anemia, Churg-Strauss syndrome, or a combination thereof.

[0040] In some cases, the IL-4Rα-associated disorder is an ocular-related disorder, hi some cases, the ocular-related disorder is selected from Sjogren's syndrome, autoimmune uveitis, autoimmune lymphoproliferative syndrome, atrophic keratoconjunctivitis, or a combination thereof.

[0041] In some cases, the IL-4Rα-associated disorder is an esophageal-related disorder. In some cases, the esophageal-related indication is selected from Barrett's esophagus, eosinophilic esophagitis, eosinophilic gastritis, or a combination thereof.

[0042] In some cases, the IL-4Rα-associated disorder is a skin-related indication, selected from atopic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, dyshidrotic eczema, chronic hand eczema, nummular dermatitis, scleroderma, generalized scleroderma, hypertrophic scarring, urticaria, skin infections, focal alopecia, prurigo nodularis, bullous pemphigoid, Netherton syndrome, or a combination thereof.

[0043] In some cases, the IL-4Rα-associated disorder is a gastrointestinal-related disorder. In some cases, the gastrointestinal-related disorder is ulcerative colitis or Whipple's disease.

[0044] In some cases, the IL-4Rα-associated disorder is a kidney-related disorder. In some cases, the kidney-related disorder is nephrosis.

[0045] In some cases, the IL-4Rα-related disorder is benign prostatic hyperplasia. In some cases, the IL-4Rα-related disorder is Graves' disease. In some cases, the IL-4Rα-related disorder is Kawasaki disease. In some cases, the IL-4Rα-related disorder is pre-eclampsia.

[0046] In some cases, the IL-4Rα-associated disorder is cancer. In some cases, the cancer is cutaneous T-cell lymphoma.

[0047] A method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject suffering from one of the following conditions: pulmonary fibrosis, such as chronic fibrotic lung disease, cystic fibrosis, interstitial lung disease, nonspecific interstitial pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, idiopathic organizing pneumonia (COP), acute interstitial pneumonia, desquamative interstitial pneumonia, chronic obstructive pulmonary disease ... Also disclosed herein is a method, comprising administering an anti-IL-4Rα antibody to a subject exhibiting at least one symptom of or determined to be susceptible to a disorder selected from the group consisting of pulmonary alveolar proteinosis, adult respiratory distress syndrome (ARDS), asbestosis, sarcoidosis, tuberculosis, and aspirin-induced asthma, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0048] Also disclosed herein, in some cases, is a method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject determined to exhibit at least one symptom of or be susceptible to a blood-related disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the blood-related disorder is sickle cell anemia, Churg-Strauss syndrome, autoimmune lymphoproliferative syndrome, lupus (systemic lupus erythematosus), antiphospholipid syndrome (APS), or autoimmune hemolytic anemia.

[0049] Also disclosed herein, in some cases, is a method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject determined to exhibit at least one symptom of or be susceptible to an ocular-related disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the eye-related disorder is dry eye, blepharitis, blepharoconjunctivitis, cicatricial pemphigoid, Mooren corneal ulcer, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, anaphylactic lenticular endophthalmitis, conjunctivitis sicca (KCS), or atrophic keratoconjunctivitis (AKC).

[0050] Also disclosed herein is a method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of an esophageal-related disorder or has been determined to be susceptible to such a disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the esophageal-related disorder is achalasia or gastroesophageal reflux disease (GERD).

[0051] A method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising the step of administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of or has been determined to be susceptible to a skin-related disorder selected from allergic contact dermatitis, dermatitis herpetiformis, dyshidrotic eczema, chronic hand eczema, nummular dermatitis, scleroderma, generalized sclerosis, dermatomyositis, epidermolysis bullosa, hypertrophic scarring, urticaria, skin infection, localized alopecia, prurigo nodularis, bullous pemphigoid, or Netherton syndrome, wherein the anti-IL-4Rα antibody has the variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); Also disclosed herein are methods comprising a variable heavy chain CDR2 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable heavy chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0052] Also disclosed herein is a method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of a gastrointestinal-related disorder or has been determined to be susceptible to the disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA), a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT), a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV), a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY), a variable light chain CDR2 of SEQ ID NO: 5 (LGS), and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the gastrointestinal-related disorder is ulcerative colitis, Behçet's disease, Wegener's granulomatosis, or GERD.

[0053] Also disclosed herein is a method for treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of a kidney-related disorder or has been determined to be susceptible to such a disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA), a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT), a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV), a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY), a variable light chain CDR2 of SEQ ID NO: 5 (LGS), and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the kidney-related disorder is nephrosis, glomerulonephritis, or Goodpasture's syndrome.

[0054] Also disclosed herein is a method for treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject who exhibits at least one symptom of a prostate-related disorder or is determined to be susceptible to the disorder, wherein the anti-IL-4Rα antibody comprises the variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); the variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); the variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); the variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); the variable light chain CDR2 of SEQ ID NO: 5 (LGS); and the variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).In some cases, the prostate-related disorder is benign prostatic hyperplasia (BPH) or chronic prostatitis syndrome.

[0055] Also disclosed herein is a method for treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of a thyroid-related disorder or has been determined to be susceptible to the disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA), a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT), a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV), a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY), a variable light chain CDR2 of SEQ ID NO: 5 (LGS), and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the thyroid-related disorder is Hashimoto's disease.

[0056] A method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject who exhibits at least one symptom of a vascular-related disorder or has been determined to be susceptible to such a disorder, wherein the anti-IL-4Rα antibody comprises the variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); Also disclosed herein are methods comprising a variable heavy chain CDR2 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the vascular-related disorder is vasculitis, panarteritis nodosa, lupus, or antiphospholipid syndrome (APS).

[0057] Also disclosed herein is a method for treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of a pregnancy-related disorder or has been determined to be susceptible to the disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA), a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT), a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV), a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY), a variable light chain CDR2 of SEQ ID NO: 5 (LGS), and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the pregnancy-related disorder is antiphospholipid syndrome or immune thrombocytopenia.

[0058] Also disclosed herein is a method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of the anti-IL-4Rα antibody to a subject who exhibits at least one symptom of cancer or has been determined to be susceptible to the disorder, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the cancer is cutaneous T-cell lymphoma.

[0059] In some cases, the subject is a human.

[0060] In some cases, the administering step is intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, or epidural administration. In some cases, the administering step is subcutaneous. In some cases, the administering step is performed by a prefilled syringe. In some cases, the administering step is performed by a prefilled pen. In some cases, the administering step is performed by an autoinjector. In some cases, the anti-IL-4Rα antibody is administered in multiple doses. In some cases, the anti-IL-4Rα antibody is administered in two doses. In some cases, the anti-IL-4Rα antibody is administered at a dose of about 0.0001 to about 10 mg / kg of patient body weight.

[0061] In some cases, the methods disclosed herein further include administering a second therapeutic agent. In some cases, the second therapeutic agent is a second antibody or antigen-binding fragment thereof, a soluble cytokine receptor, an IgE antagonist, an anti-asthma medication, or a checkpoint inhibitor. In some cases, the anti-asthma medication is a corticosteroid, a non-steroidal drug, a beta agonist, a leukotriene antagonist, a xanthine, fluticasone, salmeterol, or albuterol. In some cases, the checkpoint inhibitor is a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some cases, the anti-IL-4Rα antibody is administered before administering the second therapeutic agent. In some cases, the anti-IL-4Rα antibody is administered simultaneously with the administration of the second therapeutic agent. In some cases, the anti-IL-4Rα antibody is administered after the administration of the second therapeutic agent.

[0062] Disclosed herein are compositions comprising anti-IL-4Rα antibodies, in some cases, for use in treating a disease. Disclosed herein are compositions comprising anti-IL-4Rα antibodies, in some cases, for use in treating one or more of the diseases or disorders disclosed herein.

[0063] In some cases, compositions comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) are disclosed for use in treating a pulmonary-related indication, such as pulmonary fibrosis, e.g., chronic fibrotic lung disease, cystic fibrosis, interstitial lung disease, nonspecific interstitial pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, cryptopathic organizing pneumonia (COP), acute interstitial pneumonia, desquamative interstitial pneumonia, chronic obstructive pulmonary disease, pulmonary alveolar proteinosis, adult respiratory distress syndrome (ARDS), asbestosis, sarcoidosis, tuberculosis, and aspirin-induced asthma.

[0064] In some cases, disclosed are compositions comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) for use in treating a blood-related indication, in some cases the blood-related indication is sickle cell anemia, Churg-Strauss syndrome, autoimmune lymphoproliferative syndrome, lupus (systemic lupus erythematosus), antiphospholipid syndrome (APS), or autoimmune hemolytic anemia.

[0065] In some cases, compositions are disclosed that include an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) for use in treating an ocular-related indication. In some cases, the ocular indication is Sjogren's syndrome, autoimmune uveitis, or atrophic keratoconjunctivitis (AKC).

[0066] In some cases, disclosed is a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) for use in treating an esophageal-related indication. In some cases, the esophageal-related indication is Barrett's esophagus, eosinophilic esophagitis, or eosinophilic gastritis.

[0067] In some cases, compositions comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) are disclosed for use in treating a skin-related indication. In some cases, the skin-related indication is atopic dermatitis (AD), allergic contact dermatitis, dermatitis herpetiformis, dyshidrotic eczema, chronic hand eczema, nummular dermatitis, scleroderma, hypertrophic scarring, urticaria, skin infection, focal alopecia, prurigo nodularis, bullous pemphigoid, Netherton syndrome, or another skin condition.

[0068] In some cases, compositions are disclosed that include an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) for use in treating a gastrointestinal-related indication. In some cases, the gastrointestinal-related indication is ulcerative colitis or Whipple's disease.

[0069] In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating a kidney-related indication. In some cases, the kidney-related indication is nephrosis.

[0070] In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating benign prostatic hyperplasia (BPH). In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating Graves' disease. In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating pre-eclampsia.

[0071] In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating cancer. In some cases, the cancer is cutaneous T-cell lymphoma (CTCL).

[0072] In some cases, compositions comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) are disclosed for use in enhancing vaccine efficacy.

[0073] In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating allergy. In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating asthma. In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating arthritis.

[0074] In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating a nasal-related indication. In some cases, the nasal-related indication is nasal polyps, sinusitis, or rhinitis.

[0075] In some cases, disclosed herein is the use of a composition comprising anti-IL-4Rα in the manufacture of a medicament for the treatment of one or more diseases or disorders disclosed herein.

[0076] In some cases, the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for the treatment of a pulmonary-related indication is disclosed. In some cases, the pulmonary-related indication includes pulmonary fibrosis, such as chronic fibrotic lung disease, cystic fibrosis, interstitial lung disease, nonspecific interstitial pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, cryptopathic organizing pneumonia (COP), acute interstitial pneumonia, desquamative interstitial pneumonia, chronic obstructive pulmonary disease, pulmonary alveolar proteinosis, adult respiratory distress syndrome (ARDS), asbestosis, sarcoidosis, tuberculosis, and aspirin-induced asthma.

[0077] In some cases, disclosed is the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating a blood-related indication, in some cases the blood-related indication is sickle cell anemia, Churg-Strauss syndrome, autoimmune lymphoproliferative syndrome, lupus (systemic lupus erythematosus), antiphospholipid syndrome (APS), or autoimmune hemolytic anemia.

[0078] In some cases, disclosed is the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating an ocular-related indication, in some cases the ocular-related indication is Sjogren's syndrome, autoimmune uveitis, or atrophic keratoconjunctivitis (AKC).

[0079] In some cases, disclosed is the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating an esophageal-related indication, in some cases the esophageal-related indication is Barrett's esophagus, eosinophilic esophagitis, or eosinophilic gastritis.

[0080] In some cases, the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for the treatment of a skin-related indication is disclosed. In some cases, the skin-related indication is atopic dermatitis (AD), allergic contact dermatitis, dermatitis herpetiformis, dyshidrotic eczema, chronic hand eczema, nummular dermatitis, scleroderma, generalized scleroderma, hypertrophic scarring, urticaria, skin infections, focal alopecia, prurigo nodularis, bullous pemphigoid, or Netherton syndrome. be.

[0081] In some cases, the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for the treatment of a gastrointestinal-related indication is disclosed. In some cases, the gastrointestinal-related indication is ulcerative colitis or Whipple's disease.

[0082] In some cases, the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating a kidney-related indication is disclosed. In some cases, the kidney-related indication is nephrosis.

[0083] In some cases, use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating benign prostatic hyperplasia (BPH) is disclosed. In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating Graves' disease. In some cases, a composition comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is disclosed for use in treating pre-eclampsia.

[0084] In some cases, the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating cancer is disclosed. In some cases, the cancer is cutaneous T-cell lymphoma (CTCL).

[0085] In some cases, the use of a composition comprising anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for enhancing vaccine efficacy is disclosed.

[0086] In some cases, the use of a composition comprising anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating allergy is disclosed. In some cases, the use of a composition comprising anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating asthma is disclosed. In some cases, the use of a composition comprising anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating arthritis is disclosed.

[0087] In some cases, the use of a composition comprising an anti-IL-4Rα (e.g., dupilumab) in the manufacture of a medicament for treating a nasal-related indication is disclosed. In some cases, the nasal-related indication is nasal polyps, sinusitis, or rhinitis.

[0088] All publications, patents, patent applications, and internet-available information mentioned herein are incorporated by reference to the same extent as if each individual publication, patent, patent application, or item of information was specifically and individually indicated to be incorporated by reference. In the event that the publications, patents, patent applications, and items of information incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or supersede any such conflicting material.

[0089] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials are described herein for use in this disclosure; other suitable methods and materials known in the art can also be used.Materials, methods, and examples are only illustrative and are not intended to be limiting.

[0090] When values ​​are described in terms of ranges, the description is to be understood to encompass all possible subranges within such ranges, and specific numerical values ​​contained within such ranges, whether or not a specific numerical value or specific subrange is explicitly stated.

[0091] When the term "each" is used in reference to a collection of items, unless otherwise specified or the context of usage clearly indicates otherwise, the term is intended to identify an individual item in the collection, but does not necessarily refer to every item in the collection.

[0092] Various aspects of the features of the present disclosure are described herein. However, it should be understood that such aspects are provided by way of example only, and that numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the scope of the present disclosure. It should also be understood that various alternatives to the specific aspects described herein are within the scope of the present disclosure. [Brief explanation of the drawings]

[0093] [Figure 1] FIG. 1 illustrates an example of a data processing system for repurposing drugs. [Figure 2] 1 is a flowchart illustrating an exemplary method for repurposing medication. [Figure 3] FIG. 1 illustrates an experiment using the systems and methods described herein. [Figure 4] 1 shows an ordered list of features for the input data that created the feature vector used for clustering. The feature vector was created using multiple correspondence analysis (MCA). [Figure 5] FIG. 1 is a block diagram of an exemplary computer system that may be used to provide computer-implemented functionality associated with the described algorithms, methods, functions, processes, flows, and procedures described in this disclosure. [Figure 6A] The top 30 indications are presented based on co-occurrence with at least one of the four reference "immunologic conditions": asthma, atopic dermatitis, hyperimmunoglobulin E (IgE) syndrome, and a broader composite immunologic score. [Figure 6B] The top 30 indications are presented based on co-occurrence with at least one of the four reference "immunologic conditions": asthma, atopic dermatitis, hyperimmunoglobulin E (IgE) syndrome, and a broader composite immunologic score. [Figure 6C]The top 30 indications are presented based on co-occurrence with at least one of the four reference "immunologic conditions": asthma, atopic dermatitis, hyperimmunoglobulin E (IgE) syndrome, and a broader composite immunologic score. [Figure 6D] The top 30 indications are presented based on co-occurrence with at least one of the four reference "immunologic conditions": asthma, atopic dermatitis, hyperimmunoglobulin E (IgE) syndrome, and a broader composite immunologic score. [Figure 7A] Re-ranking of the top 30 novel indications in each reference group after removal of indications already known in clinical trials, including investigator-initiated trials (IITs), is shown. Indications in italics appear in more than one reference group. [Figure 7B] Re-ranking of the top 30 novel indications in each reference group after removal of indications already known in clinical trials, including investigator-initiated trials (IITs), is shown. Indications in italics appear in more than one reference group. [Figure 7C] Re-ranking of the top 30 novel indications in each reference group after removal of indications already known in clinical trials, including investigator-initiated trials (IITs), is shown. Indications in italics appear in more than one reference group. [Figure 7D] Re-ranking of the top 30 novel indications in each reference group after removal of indications already known in clinical trials, including investigator-initiated trials (IITs), is shown. Indications in italics appear in more than one reference group. [Figure 8] 1 is a description of a machine-based learning method for creating dupi-like flag cohorts. DETAILED DESCRIPTION OF THE INVENTION

[0094] The present disclosure is based, at least in part, on the discovery that dupilumab (i.e., DUPIXENT®) can be used to treat a variety of disorders in addition to those currently approved by the FDA. FDA-approved uses for dupilumab include, for example, (1) the treatment of adult patients with moderate to severe atopic dermatitis whose disease is not adequately controlled by topical medications or for which such medications are inadvisable; (2) use with other asthma medications for the maintenance treatment of moderate to severe eosinophilic or oral steroid-dependent asthma in people 12 years of age or older whose asthma is uncontrolled with current asthma medications; and (3) use with other medications to treat chronic rhinosinusitis with nasal polyps in adults whose disease is uncontrolled.

[0095] The new indications that are the subject of this specification were identified, at least in part, using computational methods that analyze data from millions of patients to predict the therapeutic outcomes of particular drugs. Starting with these predictions, the inventors have developed treatments for the various diseases and disorders described herein that use anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab).

[0096] As used herein, "IL-4" is a multifunctional cytokine produced by activated T cells that is a ligand for the interleukin-4 receptor (IL-4R). The interleukin-4 receptor (IL-4R) also binds IL-13, which may contribute to the many overlapping functions of IL-4 and IL-13 cytokines. STAT6, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immunoregulatory signals of IL-4. Together with IL-13, IL-4 plays an important role in regulating the responses of lymphoid, myeloid, and non-hematopoietic cells. In T cells, IL-4 induces the differentiation of naive CD4 T cells into Th2 cells. In B cells, IL-4 drives immunoglobulin (Ig) class switching to IgG1 and IgE. In macrophages, IL-4 induces alternative macrophage activation.

[0097] The term "human IL-4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4). The term "human interleukin-13" (hIL-13) refers to a human cytokine that specifically binds to the IL-13 receptor, and "hIL-13 / hIL-13R1 complex" refers to a complex formed by hIL-13 binding to the hIL-13R1 complex, where the complex initiates biological activity by binding to the hIL-4 receptor.

[0098] The term "anti-interleukin-4 receptor alpha antibody" (or IL-4R antibody, IL-4Rα antibody, hIL-4R antibody, or hIL-4Rα antibody), as used herein, is intended to mean an antibody that binds to IL-4 (or IL-4Rα) and inhibits its function.

[0099] "Dupilumab" (or "DUPIXENT®") is an interleukin-4 (IL-4) receptor alpha antagonist. Dupilumab is a human monoclonal antibody of the immunoglobulin G4 subclass that inhibits IL-4 and interleukin-13 (IL-13) signaling by specifically binding to the IL-4 receptor alpha subunit, which is shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling through type 1 receptors and both IL-4 and IL-13 signaling through type 2 receptors. By blocking the IL-4R alpha subunit, dupilumab inhibits the inhibition of pro-inflammatory cytokines, chemokines, and inflammatory cytokines. It inhibits responses induced by IL-4 and IL-13 cytokines, such as the release of IL-1, IL-2, and immunoglobulin E.

[0100] The term "antibody," as used herein, refers to an immunoglobulin molecule comprising four polypeptide chains: two heavy chains (H) and two light chains (L), interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability called "complementarity-determining regions" (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0101] The term "antigen-binding fragment" (also referred to as "antigen-binding portion" or "antibody fragment") of an antibody refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (e.g., hIL-4R). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Exemplary antigen-binding fragments include: (i) a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL1, and CH1 domains; (ii) a F(ab')2 fragment, i.e., a bivalent fragment comprising two F(ab)' fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain (Ward et al. (1989) Nature 241:544-546); and (vi) a CDR. Furthermore, the two domains of an Fv fragment, VL and VH, are encoded by separate genes and can be linked using recombinant DNA techniques with a synthetic linker that allows the VL and VH regions to be paired together to form a single continuous chain that forms a monovalent molecule (known as a single-chain Fv (scFv)); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883. Such single-chain antibodies are also encompassed by the term "antigen-binding fragment" of an antibody. Other forms of single-chain antibodies, such as diabodies, are also encompassed (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448). A more detailed description of antigen-binding fragments useful in the present disclosure is provided below.

[0102] A "neutralizing" or "blocking" antibody refers to an antibody that binds to hIL-4Rα, resulting in inhibition of the biological activity of hIL-4 and / or hIL-13. Inhibition of the biological activity of hIL-4 and / or IL-13 can be assessed by measuring one or more indicators of the biological activity of hIL-4 and / or IL-13 known in the art, such as hIL-4- and / or IL-13-induced cell activation and hIL-4 binding to hIL-4Rα (see Examples below).

[0103] "CDRs" or "complementarity-determining regions" are regions of hypervariability interspersed with more conserved regions called "framework regions" (FRs). In different embodiments of the anti-hIL-4Rα antibodies or antigen-binding fragments of the present disclosure, the FRs are identical to human germline sequences or are naturally or artificially modified.

[0104] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as a paratope. A single antigen may contain more than one epitope. Epitopes can be either conformational or linear. Conformational epitopes are created by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are created by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes can include carbohydrate, phosphoryl, or sulfonyl moieties on an antigen.

[0105] The terms "substantially identical," "substantially the same," "substantially similar," "substantially similar," derivatives, and variations, when referring to nucleic acids or proteins, refer to sequences that are at least about 75% identical to SEQ ID NOS: 1-16 described herein and can be used in the methods and compositions described herein. In some cases, the nucleotide sequences are about 80%, 85%, 90%, 95%, 99%, or 100% identical.

[0106] To determine the percent identity of two sequences, the sequences are aligned for optimal comparison purposes (gaps are introduced into one or both of the first and second amino acid or nucleic acid sequences, if necessary for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). The length of the reference sequence aligned for comparison purposes is at least 80% (in some embodiments, about 85%, 90%, 95%, or 100% of the length of the reference sequence). Nucleotides or residues at corresponding positions are then compared. If a position in the first sequence is occupied by the same nucleotide or residue as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that needed to be introduced for optimal alignment of the two sequences and the length of each gap.

[0107] Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, percent identity between two amino acid sequences can be determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm, which is incorporated into the GAP program in the GCG software.

[0108] As used herein, the terms "subject" and "patient" are used interchangeably. A subject can be an animal. In some cases, a subject is a mammal, such as a non-primate (e.g., a cow, a pig, a horse, a cat, a dog, a rat, etc.) or a primate (e.g., a monkey or a human). In some cases, a subject is a human. In certain cases, such terms refer to a non-human animal (e.g., a non-human animal such as a pig, a horse, a cow, a cat, or a dog).

[0109] As used herein, the terms "about" or "approximately," when used to modify a numerical value or numerical range, indicate that deviations of 5% to 10% above and below that value or range are still within the intended meaning of the recited value or range.

[0110] Where an embodiment is described herein by the language "comprising," it should be understood that other similar embodiments described in the terms "consisting of" and / or "consisting essentially of" are also provided.

[0111] The term "and / or" is used herein to refer to phrases such as "A and / or B." When used in phrases such as "A, B, and / or C," the term "and / or" is intended to include "A and B," "A or B," "A," and "B." Similarly, the term "and / or," when used in phrases such as "A, B, and / or C," is intended to include each of the following embodiments: A, B, and C; A, B, or C; A, or C; A or B; B or C; A and C; A and B; B and C; A (only); B (only); and C (a only).

[0112] Anti-IL-4Rα antibodies, antigen-binding fragments, and compositions The present disclosure describes, among other things, the use of anti-IL-4Rα antibodies to treat various disorders. Various disorders have been identified as treatable with anti-IL-4Rα antibodies using the digital process of analyzing patient data described herein. Prior to the present disclosure, these disorders were not known to be treatable with anti-IL-4Rα antibodies, such as dupilumab. Accordingly, a brief description of anti-IL-4Rα antibodies and fragments, compositions, and dosages useful in the presently described methods is provided below.

[0113] I. Antibodies and Fragments Of particular use in the present disclosure is an anti-IL-4Rα antibody. A skilled practitioner will understand that a complete antibody comprises four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and in some cases, multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability called "complementarity-determining regions" (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present disclosure, the FRs of an anti-IL-4Rα antibody (or antigen-binding fragment thereof) can be identical to human germline sequences or can be naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0114] Antigen-binding fragments of intact antibodies are also useful in the presently described methods. Antigen-binding fragments (e.g., of anti-IL-4Rα antibodies) can be, for example, any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained, for example, from intact antibody molecules using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques, involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to align one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0115] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 (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 regions of antibodies (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment" as used herein.

[0116] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains are positioned in any suitable orientation relative to each other. For example, the variable region may be dimeric and contain VH-VH, VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0117] In certain cases, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found in an antigen-binding fragment of an antibody include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains are directly linked to each other or are linked by a complete or partial hinge or linker region. Hinge regions can consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids, such that they can provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present disclosure can comprise homodimers or heterodimers (or other multimers) of any of the above-listed variable and constant domain configurations in non-covalent association with each other and / or with one or more monomeric VH or VL domains (e.g., via disulfide bonds).

[0118] In some cases, the anti-IL-4Rα antibody is a multispecific (e.g., bispecific) antibody. Multispecific antibodies or antigen-binding fragments of antibodies typically comprise at least two different variable domains, where each variable domain can specifically bind to a separate antigen or a different epitope on the same antigen. Using routine techniques available in the art, any multispecific antibody format can be adapted for use in conjunction with the antibodies or antigen-binding fragments of the antibodies of the present disclosure. For example, the present disclosure includes methods involving the use of bispecific antibodies, where one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in conjunction with the present disclosure include, but are not limited to, scFv-based or diabodies. Bispecific formats include bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knobs-into-holes, common light chains (e.g., common light chains with knobs-into-holes), CrossMab, CrossFab, (SEED) bodies, leucine zipper, duobodies, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab2 bispecific formats (for reviews of the foregoing formats, see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, where, for example, unnatural amino acids with orthogonal chemical reactivity are used to create site-specific antigen-oligonucleotide conjugates that then self-assemble into multimers with defined composition, valency, and geometry (see, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012).

[0119] The antibody used in the method of the present disclosure may be a human antibody. The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibody of the present disclosure may include, for example, amino acid residues in CDRs and certain CDR3s that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0120] Antibodies useful in the methods of the present disclosure may be recombinant human antibodies. The term "recombinant human antibody," as used herein, refers to human antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain cases, such recombinant human antibodies have undergone in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutation) such that the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, but may not naturally exist within the human antibody germline repertoire in vivo.

[0121] In some cases, the antibody used in the methods of the present disclosure specifically binds to IL-4Rα. The term "specifically binds" or the like means that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4Rα, as used in the context of the present disclosure, has a binding affinity 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, or less than about 20 nM, as measured in a surface plasmon resonance assay. The term "antibody" includes antibodies that bind to IL-4Rα or a portion thereof with a KD of less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. However, isolated antibodies that specifically bind to human IL-4Rα may have cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0122] Anti-IL-4Rα antibodies useful in the presently described methods are those described in U.S. Pat. No. 7,608,693, or antigen-binding fragments thereof comprising the heavy chain variable region (HCVR), light chain variable region (LCVR), and / or complementarity-determining regions (CDRs), which are incorporated herein by reference in their entirety.

[0123] In some cases, anti-IL-4Rα antibodies or antigen-binding fragments useful in the presently described methods comprise three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO: 1; HCDR2 comprises the amino acid sequence of SEQ ID NO: 2; HCDR3 comprises the amino acid sequence of SEQ ID NO: 3; LCDR1 comprises the amino acid sequence of SEQ ID NO: 4; LCDR2 comprises the amino acid sequence of SEQ ID NO: 5; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 6. SEQ ID NOs: 1-6 are set forth in Table 1.

[0124] In some cases, anti-IL-4Rα antibodies or antigen-binding fragments useful in the presently described methods comprise three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:7; HCDR2 comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:8; HCDR3 comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:9; LCDR1 comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:10; LCDR2 comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:11; and LCDR3 comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO:12. SEQ ID NOs:7-12 are set forth in Table 2.

[0125] In some cases, an anti-IL-4Rα antibody or antigen-binding fragment useful in the presently described methods comprises a heavy chain complementarity determining region (HCDR) of a heavy chain variable region (HCVR) of SEQ ID NO: 13 and a light chain complementarity determining region (LCDR) of a light chain variable region (LCVR) of SEQ ID NO: 14. SEQ ID NOs: 13-14 are shown in Table 3.

[0126] In some cases, an anti-IL-4Rα antibody or antigen-binding fragment useful in the presently described methods comprises a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) encoded by the nucleotide sequence of SEQ ID NO: 15 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) encoded by the nucleotide sequence of SEQ ID NO: 16. SEQ ID NOs: 15-16 are shown in Table 4.

[0127] In some cases, an anti-IL-4Rα antibody or antigen-binding fragment useful in the presently described methods comprises the heavy chain sequence of SEQ ID NO: 17 and the light chain sequence of SEQ ID NO: 18. SEQ ID NOs: 17-18 are shown in Table 5.

[0128] One useful anti-IL-4Rα antibody or antigen-binding fragment thereof is, for example, one that specifically binds to human interleukin-4 receptor (hIL-4R) comprising the amino acid sequence of SEQ ID NO: 19. SEQ ID NO: 19 is shown in Table 6. The anti-IL-4Rα antibody or antigen-binding fragment thereof may, in some cases, specifically bind to hIL-4Rα with a KD of about 300 pM or less as measured by surface plasmon resonance in a monomer or dimer assay. The antibody or antigen-binding fragment thereof may, in some cases, exhibit a KD of about 200 pM or less, about 150 pM or less, about 100 pM or less, or about 50 pM or less. In some cases, the antibody or antigen-binding fragment blocks hIL-4 activity with an IC50 of about 100 pM or less, as measured by luciferase bioassay. In some cases, the antibody or antigen-binding fragment exhibits an IC50 of about 50 pM or less, about 30 pM or less, or about 25 pM or less, as measured by STAT6 luciferase bioassay. The antibody or antigen-binding fragment may, in some cases, block hIL-13 activity with an IC50 of about 100 pM or less, about 90 pM or less, about 50 pM or less, or about 20 pM or less, as measured by STAT6 luciferase bioassay.

[0129] Specifically used in the presently described methods is an anti-IL-4Rα antibody known in the art, called dupilumab, or a biological equivalent thereof.

[0130] [Table 1]

[0131] [Table 2]

[0132] [Table 3]

[0133] [Table 4]

[0134] [Table 5]

[0135] [Table 6]

[0136] Other anti-IL-4Rα antibodies that can be used in connection with the methods of the present disclosure include, for example, an antibody known in the art called AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or any of the anti-IL-4Rα antibodies described in U.S. Patent Nos. 7,186,809, 7,605,237, 7,608,693, or 8,092,804. Additional anti-IL-4Rα antibodies that can be used herein include 4R34.1.19, disclosed in Kim et al. (Sci Rep. 2019 May 23;9(1):7772); CBP-201 (Connect Biopharma); and Medi9314, disclosed, for example, in NCT02669667.

[0137] Anti-IL-4Rα antibodies useful in the presently described methods may have pH-dependent binding properties. For example, an anti-IL-4Rα antibody may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" refers to a pH value below about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or lower. As used herein, the expression "neutral pH" means a pH of about 7.0 to about 7.4. The expression "neutral pH" encompasses pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0138] In certain instances, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" is expressed in terms of the ratio of the KD value of the antibody that binds to IL-4Rα at acidic pH to the KD value of the antibody that binds to IL-4Rα at neutral pH (or vice versa). For example, if an antibody or antigen-binding fragment thereof exhibits an acidic / neutral KD ratio of about 3.0 or greater, the antibody or antigen-binding fragment thereof can be considered to exhibit "reduced binding to IL-4Rα at acidic pH compared to neutral pH" for purposes of the present disclosure. In certain cases, the acidic / neutral KD ratio for an antibody or antigen-binding fragment of the disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0139] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. Furthermore, modification of the antigen-binding domain at the amino acid level can result in antibodies with pH-dependent properties. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues, antibodies can be obtained that have reduced antigen-binding properties at acidic pH compared to neutral pH. As used herein, the expression "acidic pH" refers to a pH of 6.0 or less.

[0140] II. Pharmaceutical Compositions The present disclosure provides methods comprising administering to a subject an anti-IL-4Rα antibody, such as dupilumab, wherein the antibody is an ingredient of a pharmaceutical composition. Useful pharmaceutical compositions can be formulated using suitable carriers, excipients, and other agents that provide suitable transport, delivery, tolerance, etc. Many suitable formulations are described in the formulary Remington's Pharmaceutical Sciences, Mack Publishing, 1999. Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vehicles (e.g., Lipofectin™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311. Various delivery systems, such as encapsulation in liposomes, microparticles, and microcapsules, are known and can be used to administer pharmaceutical compositions (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432).

[0141] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. In some cases, administration is subcutaneous. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents. It can be given.

[0142] The pharmaceutical composition can be delivered subcutaneously or intravenously using a standard needle and syringe. For subcutaneous delivery, a pen delivery device is easily adapted to deliver the pharmaceutical composition in the presently described manner. Such a pen delivery device can be reusable or disposable. Reusable pen delivery devices generally use a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. Disposable pen delivery devices do not have a replaceable cartridge. Rather, the disposable pen delivery device is prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0143] In certain circumstances, the pharmaceutical composition can be delivered in a controlled release system. In some cases, a pump can be used. In some cases, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In some cases, controlled-release systems can be located near the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, (See, e.g., Langer, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138.) Other controlled-release systems are described in the review by Langer, 1990, Science 249:1527-1533.

[0144] Injectable preparations are particularly used in the currently described method. Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, infusions, etc. These injectable preparations can be prepared using known methods. For example, injectable preparations can be prepared by dissolving, suspending, or emulsifying the antibody or its salt described above in a sterile aqueous or oily medium commonly used for injections. Aqueous vehicles for injections include, for example, saline, isotonic solutions containing glucose and other auxiliary agents, and these can be used in combination with appropriate solubilizing agents, such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), and the like. Useful oily vehicles include, for example, sesame oil and / or soybean oil, which can be used in combination with solubilizing agents, such as benzyl benzoate and / or benzyl alcohol. In some cases, the pharmaceutical composition is placed in a suitable ampoule.

[0145] The above-described pharmaceutical compositions for oral or parenteral use can be prepared into dosage forms with unit doses suitable for the dosage of active ingredients.Such dosage forms with unit doses include, for example, tablets, pills, capsules, injection solutions (ampoules), suppositories, etc.

[0146] Exemplary pharmaceutical compositions comprising anti-IL-4Rα antibodies that can be used in connection with the present disclosure are disclosed, for example, in U.S. Pat. No. 8,945,559, the disclosure of which is incorporated herein by reference in its entirety.

[0147] III. Methods of Producing Anti-IL-4Rα Antibodies and Fragments Generally, methods for producing human antibodies include those described in, for example, U.S. Patent No. 6,596,541, Green et al. (1994) Nature Genetics 7:13-21, U.S. Patent No. 5,545,807, and U.S. Patent No. 6,787,637, each of which is incorporated herein by reference in its entirety. Methods for producing anti-IL-4Rα antibodies that are particularly useful in the presently described methods (e.g., methods for producing dupilumab) are disclosed in U.S. Patent No. 7,608,693, which is incorporated herein by reference in its entirety.

[0148] Methods for identifying disorders treatable with anti-IL-4Rα antibodies As described above, the presently described new indications treatable by anti-IL-4Rα antibodies were identified, at least in part, using computational drug repurposing methods. In some cases, the methods disclosed herein include identifying a disorder treatable by an anti-IL-4Rα antibody. In some cases, the method for identifying a disorder includes: (a) selecting a trait or traits related to the IL4 / IL13 pathway in a set of data representing medical records of a plurality of subjects; (b) clustering a subset of subjects from the plurality of subjects by a computer system according to the trait or traits related to the IL-4 / IL-13 pathway, wherein the subset includes the trait or traits; (c) identifying the IL-4Rα-associated disorder in the clustered subset in step (b) based on a symptom associated with the trait or traits related to the IL-4 / IL-13 pathway; and (d) selecting subjects who have at least one symptom of or are susceptible to the anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder identified in step (c). In some cases, the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA). In some cases, the method further includes administering a therapeutically effective amount of an anti-IL-4Rα antibody to the subject, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0149] A review of drug repurposing methods used for the indications described herein is provided below.

[0150] I. Background Drug repurposing can be used to find new clinical indications (e.g., reasons for using a drug) for clinically approved drugs. When guided by relevant clinical questions, powerful advanced analytical techniques can unearth clinically relevant information hidden in large amounts of data, supporting clinical decision-making.

[0151] Computational drug repurposing methods can use similarity measures (chemical similarity, molecular activity similarity, gene expression similarity, or side effect similarity), molecular docking, or shared molecular pathology to detect novel drug-disease relationships. Drug repurposing approaches can be categorized as network-based text mining (literature research) and semantic approaches.

[0152] The data processing systems and methods generally described herein can be used to identify potential indications that were not previously identified using conventional techniques.

[0153] In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. However, it will be apparent that the present disclosure may be practiced without these specific details. In other instances, well-known structures and devices are shown in block diagram form in order to avoid unnecessarily obscuring the present disclosure.

[0154] In the drawings, a particular arrangement or order of diagrammatic elements, such as representing devices, modules, instruction blocks, and data elements, is shown for ease of explanation. However, those skilled in the art should understand that the particular order or arrangement of diagrammatic elements in the drawings is not intended to imply that a particular order or sequence of processing, or separation of processing, is required. Furthermore, the inclusion of a diagrammatic element in a drawing is not intended to imply that such element is required in all implementations, or that features represented by such element are not included in some implementations or are combined with other elements in some implementations.

[0155] Furthermore, when connecting elements, such as solid or dashed lines or arrows, are used in the drawings to indicate a connection, relationship, or association between two or more other diagrammatic elements, the absence of such connecting elements is not intended to imply the absence of the connection, relationship, or association. In other words, some connections, relationships, or associations between elements may not be shown in the drawings so as not to obscure the disclosure. Additionally, for ease of illustration, a single connecting element may be used to represent multiple connections, relationships, or associations between elements. For example, when a connecting element represents communication of signals, data, or instructions, those skilled in the art should understand that such element represents one or more signal paths (e.g., buses) to affect that communication, if necessary.

[0156] Reference will now be made in detail to the implementations, examples of which are illustrated in the accompanying drawings. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the various implementations being described. However, it will be apparent to those skilled in the art that the various implementations described may be practiced without these specific details. In other instances, well-known methods, procedures, components, circuits, and networks have not been described in detail so as not to unnecessarily obscure aspects of the implementations.

[0157] Several features are described below, each of which can be used independently of one another or in any combination with other features. However, some individual features may not address any of the problems described above, or may address only one of the problems described above. Some of the problems described above may not be fully addressed by any of the features described herein. Headings are provided, but data related to a particular heading but not found in the section having that heading may also be found elsewhere in this description.

[0158] II. EXEMPLARY DATA PROCESSING SYSTEM AND METHOD FIG. 1 illustrates an example of a data processing system 100. In some implementations, the data processing system 100 is configured to process data that may represent medical records of multiple patients to identify new indications for a drug (drug for repurposing). The system 100 includes a computer processor 110. The computer processor 110 includes computer-readable memory 111 and computer-readable instructions 112. The system 100 also includes a machine learning system 150. The machine learning system 15 ... The machine learning model 120 may be separate from the computer processor 110 or may be integrated with the computer processor 110.

[0159] The computer-readable medium 111 (or computer-readable memory) can include any type of data storage technology suitable for the local technology environment, including, but not limited to, semiconductor-based memory devices, magnetic memory devices and systems, optical memory devices and systems, fixed memory, removable memory, disk memory, flash memory, dynamic random access memory (DRAM), static random access memory (SRAM), electronically erasable programmable read-only memory (EEPROM), etc. In some implementations, the computer-readable medium 111 includes code segments having executable instructions.

[0160] In some implementations, the computer processor 110 includes a general-purpose processor. In some implementations, the computer processor 110 includes a central processing unit (CPU). In some implementations, the computer processor 110 includes at least one application-specific integrated circuit (ASIC). The computer processor 110 may also include a general-purpose programmable microprocessor, a graphics processing unit, a special-purpose programmable microprocessor, a digital signal processor (DSP), a programmable logic array (PLA), a field-programmable gate array (FPGA), special-purpose electronic circuitry, or the like, or a combination thereof. The computer processor 110 is configured to execute program code, such as computer-executable instructions 112, as well as executable logic, including the machine learning model 120.

[0161] The computer processor 110 is configured to receive data representing medical records of multiple patients. For example, the computer processor 110 can receive data from a database containing electronic medical record (EMR) data for approximately 94 million (or more) patients identifiable by key identifiers (IDs) that enable matching of patients across different data tables. In some implementations, the data indicates diagnoses, clinical trials, procedures, medications, patient events, insurance, biomarkers, measurements, clinical conditions, lifestyle parameters, microbiology, prescriptions, etc. In some implementations, the data includes data driven by natural language processing. The data can be received via any of a variety of technologies, such as wireless communication, fiber optic communication, USB, CD-ROM, etc.

[0162] Machine learning system 150 can apply machine learning techniques to train machine learning model 120. As part of training machine learning model 120, machine learning system 150 can form a training set of input data by identifying a positive training set of input data items that have been determined to have the characteristics in the question, and in some implementations can form a negative training set of input data items that lack the characteristics in the question.

[0163] The machine learning system 150 extracts feature values ​​from the input data of a training set, where the features are variables that are considered potentially relevant to whether an input data item has the relevant characteristic. The ordered list of features for the input data is referred to herein as a feature vector for the input data. In some implementations, the machine learning system 150 applies dimensionality reduction to reduce the amount of data in the feature vector for the input data into a smaller, more representative data set. For example, the machine learning system 150 can apply multiple correspondence analysis (MCA), linear discriminant analysis (LDA), principal component analysis (PCA), etc.

[0164] In some implementations, the machine learning system 150 uses unsupervised machine learning to train the machine learning model 120. Typically, unsupervised machine learning techniques use input vectors to make inferences from a dataset without reference to known or labeled outcomes. In some implementations, the machine learning system 150 can perform clustering, which separates data points into groups such that data points in the same group are more similar to other data points in the same group and more different from data points in other groups. In some implementations, the clustering process includes performing K-means clustering, in which a one-level unnested partitioning of data points is created by iteratively partitioning the dataset. That is, in each iteration, the dataset is partitioned into K disjoint clusters, where K is the desired number of clusters. The process continues until a specified cluster link criterion function value is optimized. In some implementations, the machine learning system 150 is configured to perform bisecting K-means clustering. Bisection of K-means clustering typically involves splitting one cluster into two sub-clusters at each bisection step (e.g., by using k-means) until k clusters are obtained. Bisection of K-means clustering can be more beneficial when compared to K-means clustering because it can reduce computation time for relatively large values ​​of K, can generate clusters of similar size, and can generate clusters with lower entropy.

[0165] The computer processor 110 is configured to execute computer-executable instructions 112 to perform one or more operations. In some implementations, the one or more operations include receiving data representing medical records of multiple patients. For example, the computer processor 110 can receive data from a database containing electronic medical records (EMRs) for approximately 94 million (or more) patients identifiable by key identifiers (IDs) that enable matching of patients across different data tables. In some implementations, the data indicates diagnoses, clinical trials, procedures, medications, patient events, insurance, biomarkers, measurements, clinical conditions, lifestyle parameters, microbiology, prescriptions, etc. In some implementations, the data includes data driven by natural language processing. The data can be received via any of a variety of technologies, such as wireless communication, fiber optic communication, USB, CD-ROM, etc.

[0166] In some implementations, the one or more operations include selecting a set of patients based on medical records. Selecting the set of patients includes determining at least one target signaling pathway associated with the drug for repurposing. For example, if the drug is dupilumab, the computer processor 110 can determine that the drug modulates the interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling pathways based on the drug's known function. Selecting the set of patients also includes determining one or more indicators based on one or more factors corresponding to a diagnosis linked to the target signaling pathway. For example, factors such as pathway mechanism, associated clinical symptoms, therapeutic analogs, data and epidemiology, and drug lifecycle management alignment can be used to search through sources including medical databases and medical evidence software to identify diseases linked to the determined signaling pathway. These diseases can be categorized based on the strength of their link to the determined signaling pathway. The categories can include a focused group, a medium group, and a broad group. For example, referring again to the IL-4 / IL-13 example, a group of diseases of interest include diseases that have a direct relationship to the IL-4 / IL-13 mechanism of action on the Th2 pathway. The interesting group can include diseases with an indirect relationship to the IL-4 / IL-13 mechanism of action on the Th2 pathway, and the broad group can include diseases associated with a broader inflammatory response. Moving from the interesting group to the broad group can increase the number of indications considered when selecting a patient set and reduce the likelihood of molecular conflicts. Thus, in some practices, only the interesting group, or the interesting group and the intermediate group, are used to select a patient set. In some practices, only patients with at least one diagnosis, medication, clinical trial, and / or procedure associated with the determined signaling pathway are selected for inclusion in the patient set. Detailed examples of factors and indications are provided below with reference to Table 7.

[0167] In some implementations, the one or more operations include determining a plurality of patient characteristics (sometimes referred to herein as features) for a set of patients, where each patient in the set of patients exhibits at least one of the plurality of patient characteristics. Determining the plurality of patient characteristics may include analyzing initially received data to identify broad patient characteristics, capturing all or a substantial portion of the received data. For example, the broad patient characteristics may correspond to diagnoses (e.g., immune status, diabetes), prescriptions (e.g., immune medications, other drug classes), procedures (e.g., human leukocyte antigen typing), and test results (e.g., abnormally high / low IgE levels). In some implementations, determining the plurality of patient characteristics includes receiving user input (e.g., via a user interface in communication with the computer processor 110). For example, a user can enter patient characteristics based on clinical input, demographics, medications, comorbidities, procedures, and immune-specific clinical trial data. Pre-canned feature classes may also be added to increase data completeness and representativeness and to gather more detailed information about diseases and drug responses. In some implementations, determining the plurality of patient characteristics includes validating the plurality of patient characteristics. The validating step may include determining whether the patient characteristics in the initially received data are correctly mapped to the set of selected patients by calculating a percentage of selected patients having at least one of each characteristic family (e.g., the percentage of patients with prescription records) and comparing this percentage to the percentage of patients in the initially received data having at least one of each characteristic family. The closer the two numbers are, the more correctly the mapping is performed. The validating step may include determining whether the patient characteristics are mapped to the correct patients by identifying the number of patients included in both the initially received data and the set of selected patients to verify identical mapping of patient characteristics between the patients in the initially received data and the set of selected patients.

[0168] In some implementations, the one or more operations include grouping the set of patients according to a plurality of patient characteristics (e.g., as defined by features associated with the determined signaling pathway) to create a plurality of distinct groups, each group including at least one patient from the set of patients. For example, the one or more computer processors 110 can execute the machine learning model 120 to perform a clustering technique, such as the K-means clustering bisection technique described above. The clustering process can result in multiple clusters (e.g., distinct groups) of patients, such that patients in one cluster are more similar to each other with respect to their corresponding patient characteristics than patients in other clusters. In some implementations, the created clusters can exhibit correlations between patient characteristics, even if they are not present in the same patient. Clinical input can be received and used at various stages of the clustering process to ensure the clinical relevance of the resulting clusters. For example, clinical input from a disease expert can be used in the inclusion and grouping of clinically relevant features, as well as in the validation and evaluation of the clusters. This can facilitate the creation of clinically relevant cohorts. Patient characteristics can be identified as unique in a cluster if they occur more frequently than in the general population (e.g., across a selected set of patients).

[0169] In some practices, multiple correspondence analysis (MCA) is used to reduce the dimensionality of patient characteristics. K-means bisection can facilitate adequate and effective separation of patients into sufficiently "tight" yet stable clusters, allowing for many clusters that exhibit immune associations, which are used for scoring patient characteristics, as described in more detail below. The resulting clusters can be presented (e.g., via a user interface) to a user (e.g., a clinical expert) for validation and evaluation. This can reduce the risk of cluster non-interpretability and ensure the absence of overlapping features between different clusters.

[0170] In some implementations, the one or more operations include selecting a set of distinct groups from the plurality of distinct groups based on one or more group selection criteria. In some implementations, selecting the set of distinct groups includes ranking the groups and selecting the highest ranked groups (e.g., the top 60 ranked groups). The groups can be ranked based on immune enrichment, stability, purity, and size. In some implementations, one or more measures (sometimes referred to herein as characteristic scores) are calculated for each patient characteristic to rank the clusters. The one or more measures may include, for example, distinctiveness (sometimes referred to herein as "lift score"), the number of patients in the cluster that exhibit the patient characteristic, and an immune score. The distinctiveness score measures how distinctive a patient characteristic is within the range of the cluster versus the rest of the population (e.g., if men make up 50% of the population and 75% of the cluster, the "lift score" is equal to 1.5). In some implementations, only patient characteristics that have a lift score above a threshold lift score (e.g., 1) and appear in more than a threshold percentage of patients (e.g., 10%) are considered to define a cluster and correspond to the theme of that cluster. Patient characteristics considered to define a cluster are sometimes referred to herein as potentially relevant patient characteristics. The patient characteristics (e.g., either the patient characteristics considered to define a cluster or all of the patient characteristics) can be assigned an immune score, which scores the patient characteristics according to their type (e.g., disease, drug, clinical trial, procedure, etc.) and immune relevance. The patient characteristic scores within each cluster can then be aggregated (e.g., summed) and normalized. Clusters that meet a threshold cluster score (e.g., 50%) can then be considered immune-specific.

[0171] Selecting the set of different groups can include evaluating one or more of the stability, purity, and number of patients within each cluster. Stability can be evaluated using one or more of the following methods: (1) regenerating clusters for data of different sizes; (2) varying the initialization seeds for the clusters; (3) varying the number of clusters created; and (4) applying a training-testing method. For each cluster in the training set, stability can be defined as the maximum percentage of patients grouped together in the test set. Purity can be measured by the intra-cluster variation of MCA components of patients within a cluster, which can result in a homogeneous and dense cluster. In some implementations, a cluster is selected if it exceeds a threshold stability percentage (e.g., 50%) and a threshold purity percentage (e.g., the cluster is the highest 20% purest of all clusters).

[0172] In some implementations, the one or more operations are performed on a set of different groups. The method includes identifying one or more relevant patient characteristics (e.g., indications) by analyzing each distinct group in the core cluster. Identifying one or more relevant patient characteristics can include ranking the patient characteristics represented by each selected cluster (e.g., all of the patient characteristics or the patient characteristics considered to define the cluster). The ranking can be based on the frequency of co-occurrence with each of several established (reference) characteristics of the drug for repurposing (e.g., if the drug is dupilumab, the reference characteristics can include asthma, atopic dermatitis, IgE allergy, and combined immune score). The co-occurrence can be measured by calculating the proportion of patient-weighted clusters that include both the patient characteristic and the reference characteristic. In some practices, one or more patient characteristics determined by a subject matter expert as being relevant to the core cluster themes (e.g., as indicated by user input received by the user interface) can also be considered for evaluation, regardless of the number of patients in which these characteristics appear (which can be <10%).

[0173] Identifying one or more patient characteristics can include evaluating the clinical and commercial feasibility of the patient characteristics. For example, patient characteristics indicating different clinical diagnoses can be identified. The commercial evaluation can be based on data indicating predicted sales and available competitor assets, determined links to the targeted signaling pathway (whether found in publications), the global prevalence of the patient characteristics, and the disability-adjusted life years (DALYs) of the patient characteristics (e.g., per 100,000 life years). As a result, in some implementations, the one or more operations generally output new indications for the drug for repurposing.

[0174] Although this specification generally describes a patient as a human patient, the practice is not limited thereto. For example, a patient can also refer to a non-human animal.

[0175] Figure 2 is a flow chart illustrating an exemplary method 200 for repurposing drugs. Method 200 may be implemented by data processing system 100 previously described with reference to Figure 1. Method 200 includes receiving data representing medical records (block 210), selecting a set of patients (block 220), determining a plurality of patient characteristics (block 230), grouping the set of patients to create a plurality of distinct groups (block 240), selecting a set of distinct groups (block 250), and identifying one or more relevant patient characteristics (block 260).

[0176] At block 210, data representing medical records of multiple patients is received. The data may be received, for example, from a database including EMRs for approximately 94 million (or more) patients identifiable by key IDs that allow matching of patients across different data tables. In some practices, the data indicates diagnoses, clinical trials, procedures, medications, patient events, insurance, biomarkers, measurements, clinical conditions, lifestyle parameters, microbiology, prescriptions, etc. In some practices, the data includes data driven by natural language processing. The data may be received via any of a variety of technologies, such as wireless communication, fiber optic communication, USB, CD-ROM, etc.

[0177] At block 220, at least one target signaling pathway associated with the drug for repurposing is determined. For example, if the drug is dupilumab, it is determined that the drug modulates the IL-4 and IL-13 signaling pathways based on the known function of the drug. In some implementations, one or more indicators are determined based on one or more factors corresponding to a diagnosis linked to the target signaling pathway. For example, factors such as pathway mechanism, associated clinical symptoms, therapeutic analogs, data and epidemiology, and drug lifecycle management alignment can be used to search through sources, including medical databases and medical evidence software, to identify diseases linked to the determined signaling pathway. These diseases can be categorized based on the strength of their link to the determined signaling pathway. The categories can include a focus group, a moderate group, and a broad group. For example, referring again to the IL-4 / IL-13 example, the focus group of diseases can include diseases with a direct relationship to the IL-4 / IL-13 mechanism of action on the Th2 pathway, the moderate group of diseases can include diseases with an indirect relationship to the IL-4 / IL-13 mechanism of action on the Th2 pathway, and the broad group of diseases can include diseases related to a broader inflammatory response. Moving from the focus group to the broad group can increase the number of indications considered when selecting a patient set and reduce the possibility of molecular conflicts. Therefore, in some practices, only the focus group or the focus group and the moderate group are used to select a patient set. In some practices, only patients who have at least one diagnosis, pharmaceutical, clinical trial, and / or procedure related to the determined signaling pathway are selected for inclusion in the patient set.

[0178] At block 230, a plurality of patient characteristics are determined for the set of patients, where each patient in the set of patients exhibits at least one of the plurality of patient characteristics. Determining the plurality of patient characteristics may include analyzing initially received data to identify broad patient characteristics, capturing all or a substantial portion of the received data. For example, the broad patient characteristics may correspond to diagnoses (e.g., immune status, diabetes), prescriptions (e.g., immunology medications, other drug classes), procedures (e.g., human leukocyte antigen typing), and test results (e.g., abnormally high / low IgE levels). In some implementations, determining the plurality of patient characteristics includes receiving user input (e.g., via a user interface). For example, a user may enter patient characteristics based on clinical input and demographics, medications, comorbidities, procedures, and immunology-specific clinical trial data. Pre-canned characteristic classes may also be added to increase data completeness and representativeness and to gather more detailed information about diseases and drug responses. In some implementations, determining the plurality of patient characteristics includes validating the plurality of patient characteristics. The verifying step may include determining whether the patient characteristics in the initially received data are correctly mapped to the set of selected patients by calculating the percentage of selected patients (e.g., the percentage of patients with prescription records) who have at least one of each characteristic family and comparing this percentage to the percentage of patients in the initially received data who have at least one of each characteristic family. The closer the two numbers are, the more correct the mapping. The verifying step may include determining whether the patient characteristics are mapped to the correct patients by identifying the number of patients included in both the initially received data and the set of selected patients to verify identical mapping of patient characteristics between the patients in the initially received data and the set of selected patients.

[0179] At block 240, the set of patients is grouped according to a plurality of patient characteristics (e.g., as defined by features associated with the determined signaling pathways) to create a plurality of distinct groups, each distinct group including at least one patient from the set of patients. For example, a clustering technique, such as the K-means clustering bisection technique described above, can be performed on the set of patients using the plurality of patient characteristics. The clustering process results in patients in one cluster being more similar to each other than patients in other clusters with respect to their corresponding patient characteristics. This may result in multiple clusters (e.g., different groups) of patients that are more similar. In some implementations, the clusters created may show correlations between patient characteristics even if they are not present in the same patient. Clinical input can be received and used at various stages of the clustering process to ensure the clinical relevance of the resulting clusters. For example, clinical input from disease experts can facilitate the creation of clinically relevant cohorts, including clinically relevant features and grouping, and validation and evaluation of the clusters. Patient characteristics can be identified as unique in a cluster if they occur more frequently than in the general population (e.g., the entire selected set of patients).

[0180] In some practices, multiple correspondence analysis (MCA) is used to reduce the dimensionality of patient characteristics. K-means bisection can facilitate adequate and effective separation of patients into sufficiently "tight" yet stable clusters, allowing for many clusters that exhibit immune associations, which are used for scoring patient characteristics, as described in more detail later. The resulting clusters can be presented (e.g., via a user interface) to a user (e.g., a clinical expert) for validation and evaluation. This can reduce the risk of cluster non-interpretability and ensure the absence of overlapping features between different clusters.

[0181] In block 250, a set of distinct groups from the plurality of distinct groups is selected based on one or more group selection criteria. In some implementations, selecting the set of distinct groups includes ranking the groups and selecting the highest ranked groups (e.g., the top 60 ranked groups). The groups can be ranked based on immune enrichment, stability, purity, and size. In some implementations, one or more measures are calculated for each patient characteristic to rank the clusters. The one or more measures may include, for example, distinctiveness (sometimes referred to herein as a "lift score"), the number of patients in the cluster that exhibit the patient characteristic, and an immune score. The distinctiveness score measures how distinctive a patient characteristic is within the range of the cluster versus the rest of the population (e.g., if men make up 50% of the population and 75% of the cluster, the "lift score" is equal to 1.5). In some implementations, only patient characteristics that have a lift score above a threshold lift score (e.g., 1) and that appear in more than a threshold percentage of patients (e.g., 10%) are considered to define a cluster and correspond to the theme of that cluster. Patient characteristics considered to define a cluster are sometimes referred to herein as potentially relevant patient characteristics. The patient characteristics (e.g., either the patient characteristics considered to define a cluster or all of the patient characteristics) can be assigned an immune score, which scores the patient characteristics according to their type (e.g., disease, drug, clinical trial, procedure, etc.) and immune relevance. Patient characteristic scores within each cluster can be aggregated (e.g., summed) and normalized. Clusters that meet a threshold cluster score (e.g., 50%) can be considered immune-specific.

[0182] Selecting the set of different groups can include assessing one or more of stability, purity, and the number of patients in each cluster. Stability can be assessed using one or more of the following methods: (1) regenerating clusters for data of different sizes; (2) varying the initialization seeds for the clusters; (3) varying the number of clusters created; and (4) applying a training-testing method. For each cluster in the training set, stability can be defined as the maximum percentage of patients grouped together in the test set. Purity can be measured by the intra-cluster variability of MCA components of patients within a cluster, which can result in homogeneous and dense clusters. In some implementations, clusters can be evaluated using one or more of the following methods: (1) regenerating clusters for data of different sizes; (2) varying the initialization seeds for the clusters; (3) varying the number of clusters created; and (4) applying a training-testing method. For each cluster in the training set, stability can be defined as the maximum percentage of patients grouped together in the test set. Purity can be measured by the intra-cluster variability of MCA components of patients within a cluster, which can result in homogeneous and dense clusters. A cluster is selected if it exceeds a threshold stability percentage (e.g., 50%) and a threshold purity percentage (e.g., the cluster is the highest 20% pure of all clusters).

[0183] In block 260, one or more relevant patient characteristics are identified by analyzing each distinct group in the set of distinct groups. Identifying one or more relevant patient characteristics can include ranking the patient characteristics represented by each selected cluster (e.g., all of the patient characteristics or the patient characteristics considered to define the cluster). The ranking can be based on the frequency of co-occurrence with each of several established (reference) characteristics of the drug for repurposing (e.g., if the drug is dupilumab, the reference characteristics can include asthma, atopic dermatitis, IgE allergy, and a combined immune score). The co-occurrence can be measured by calculating the proportion of patient-weighted clusters that include both the patient characteristic and the reference characteristic. In some implementations, one or more patient characteristics determined by a subject matter expert as being relevant to the core cluster themes (e.g., as indicated by user input received by the user interface) can also be considered for evaluation, regardless of the number of patients in which these characteristics appear (which can be <10%).

[0184] Identifying one or more patient characteristics can include evaluating the clinical and commercial feasibility of the patient characteristics. For example, patient characteristics that indicate different clinical diagnoses can be identified. Commercial evaluation can be based on data showing predicted sales and available competitor assets, determined links to targeted signaling pathways (whether found in publications), global prevalence of the patient characteristics, and disability-adjusted life years (DALYs) of the patient characteristics (e.g., per 100,000 life years).

[0185] FIG. 5 is a block diagram of an example computer system 600 that may be used to provide computer functionality related to the described algorithms, methods, functions, processes, flows, and procedures described herein (e.g., method 200 previously described with reference to FIG. 2 ) in accordance with some implementations of the present disclosure. The illustrated computer 602 is intended to include any computing device, including physical instances, virtual instances, or both, such as a server, desktop computer, laptop / notebook computer, wireless data port, smartphone, personal data assistant (PDA), tablet computing device, or one or more processors within these devices. The computer 602 may include input devices, such as a keypad, keyboard, and touchscreen capable of receiving user information. Additionally, the computer 602 may include output devices capable of communicating information related to the operation of the computer 602. The information may include digital data, visual data, auditory information, or a combination of information. The information may be presented in a graphical user interface (UI) (or GUI).

[0186] The computer 602 may serve in the role of a client, a network component, a server, a database, a persistence, or a component of a computer system for implementing the subject matter described in this disclosure. The illustrated computer 602 is communicatively coupled to a network 630. In some implementations, one or more components of the computer 602 may be configured to operate in different environments, including, for example, a cloud computing-based environment, a local environment, a global environment, and combinations of environments.

[0187] At a high level, computer 602 is an electronic computing device operable to receive, transmit, process, store, and manage data and information related to the described subject matter. According to some implementations, computer 602 can also include or be communicatively coupled to an application server, email server, web server, cache server, streaming data server, or combination of servers.

[0188] Computer 602 can receive requests from client applications (e.g., running on another computer 602) over network 630. Computer 602 can fulfill the received requests by processing the received requests using software applications. Requests can also be sent to computer 602 from internal users (e.g., from a command console), external (or third) parties, automated applications, entities, individuals, systems, and computers.

[0189] Each of the components of the computer 602 can communicate using a system bus 603. In some implementations, any or all of the components of the computer 602, including hardware or software components, can interface with each other or with an interface 604 (or a combination of both) via the system bus 603. The interface can use an application programming interface (API) 612, a service layer 613, or a combination of an API 612 and a service layer 613. The API 612 can include specifications for routines, data structures, and object classes. The API 612 can be computer language independent or dependent. The API 612 can refer to a complete interface, a single function, or a set of APIs.

[0190] The service layer 613 can provide software services to the computer 602 and other components (illustrated or not) communicatively coupled to the computer 602. The functionality of the computer 602 can be accessible to all service consumers using this service layer. Software services, such as those provided by the service layer 613, can provide reusable, defined functionality through a defined interface. For example, the interface can be software written in JAVA, C++, or a language that provides data in Extensible Markup Language (XML) format. While the API 612 or service layer 613 is illustrated as an embedded component of the computer 602, in alternative implementations, the API 612 or service layer 613 can be a standalone component in relation to other components of the computer 602 and communicatively coupled to the computer 602. Moreover, any or all portions of the API 612 or service layer 613 can be implemented as a child module or sub-module of another software module, enterprise application, or hardware module without departing from the scope of this disclosure.

[0191] Computer 602 includes interface 604. While illustrated in FIG. 5 as a single interface 604, two or more interfaces 604 may be used according to a particular need, desire, or the particular implementation of computer 602 and the described functionality. Interface 604 may be used by computer 602 to communicate with other systems (whether illustrated or not) connected to network 630 in a distributed environment. Generally, interface 604 may be software or hardware (or software) operable to communicate with network 630. The network 630 or interface hardware may include or be implemented using logic coded in software (a combination of software and hardware). More particularly, the interface 604 may include software supporting one or more communication protocols associated with the communication. As such, the network 630 or interface hardware may be operable to communicate physical signals within or outside of the illustrated computer 602.

[0192] Computer 602 includes processor 605. While illustrated in Figure 5 as a single processor 605, two or more processors 605 may be used according to particular needs, desires, or the particular implementation and described functionality of computer 602. Generally, processor 605 can execute instructions and manipulate data to perform the operations of computer 602, including operations using algorithms, methods, functions, processes, flows, and procedures as described in this disclosure.

[0193] Computer 602 also includes a database 606 that can maintain data for computer 602 or other components (illustrated or not) connected to network 630. For example, database 606 can be an in-memory database, a traditional database, or a database that stores data consistent with the present disclosure. In some implementations, database 606 can be a combination of two or more different database types (e.g., a hybrid of an in-memory database and a traditional database) according to particular needs, desires, or the particular implementation and described functionality of computer 602. While illustrated in FIG. 5 as a single database 606, two or more databases (of the same type, different types, or a combination of multiple types) can also be used according to particular needs, desires, or the particular implementation and described functionality of computer 602. While database 606 is illustrated as an internal component of computer 602, in alternative implementations, database 606 can be external to computer 602.

[0194] Computer 602 also includes memory 607, which can retain data for computer 602 or any combination of components (illustrated or not) connected to network 630. Memory 607 can store any data consistent with this disclosure. In some implementations, memory 607 can be a combination of two or more different types of memory (e.g., a combination of semiconductor and magnetic storage) according to a particular need, desire, or specific implementation of computer 602 and the described functionality. While illustrated in FIG. 5 as a single memory 607, two or more memories 607 (of the same type, different types, or a combination of multiple types) can also be used according to a particular need, desire, or specific implementation of computer 602 and the described functionality. While memory 607 is illustrated as an internal component of computer 602, in alternative implementations, memory 607 can be external to computer 602.

[0195] The application 608 may be an algorithmic software engine that provides functionality according to a particular need, desire, or particular implementation of the computer 602 and the described functionality. For example, the application 608 may function as one or more components, modules, or applications. Further, while illustrated as a single application 608, the application 608 may be implemented as multiple applications 608 on the computer 602. Additionally, while illustrated as internal to the computer 602, in alternative implementations, the application 608 may be external to the computer 602.

[0196] The computer 602 may also include a power supply 614. The power supply 614 may include a rechargeable or non-rechargeable battery, which may be configured to be either user-replaceable or non-user-replaceable. In some implementations, the power supply 614 may include power conversion and management circuitry, including recharging, standby, and power management functions. In some implementations, the power supply 614 may include a power plug that allows the computer 602 to be connected to a wall outlet or power source, for example, to power the computer 602 or to recharge a rechargeable battery.

[0197] There may be any number of computers 602 associated with or external to the computer system including computer 602, in which case each computer 602 may communicate via network 630. Furthermore, the terms "client," "user," and other appropriate terminology may be used interchangeably where appropriate without departing from the scope of this disclosure. Moreover, this disclosure contemplates that many users may use one computer 602, and that one user may use multiple computers 602.

[0198] Implementations of the subject matter and functional operations described herein can be implemented in digital electronic circuitry, in tangibly embodied computer software or firmware, in computer hardware including the structures disclosed herein and their structural equivalents, or in one or more combinations thereof. Software implementations of the described subject matter can be implemented as one or more computer programs. Each computer program can include one or more modules of computer program instructions encoded on a tangible, non-transitory, computer-readable computer storage medium for execution by or to control the operation of a data processing device. Alternatively or additionally, the program instructions can be encoded in / on an artificially generated propagated signal. For example, the signal can be a machine-generated electrical, optical, or electromagnetic signal generated to encode information for transmission to a suitable receiving device for execution by a data processing device. The computer storage medium can be a machine-readable storage device, a machine-readable storage substrate, a random-access or serial-access memory device, or a combination of computer storage media.

[0199] The terms “data processing equipment,” “computer,” and “electronic computing device” (or equivalents understood by those skilled in the art) refer to data processing hardware. For example, data processing equipment can encompass all types of equipment, devices, and machines for processing data, such as a programmable processor, a computer, or multiple processors or computers. The equipment can also include special-purpose logic circuitry, such as a central processing unit (CPU), a field programmable gate array (FPGA), or an application-specific integrated circuit (ASIC). In some implementations, the data processing equipment or special-purpose logic circuitry (or a combination of data processing equipment or special-purpose logic circuitry) can be hardware-based or software-based (or a combination of both hardware- and software-based). The equipment can optionally include code that creates an execution environment for a computer program, such as processor firmware, a protocol stack, a database management system, an operating system, or code that constitutes a combination of the execution environment. The present disclosure contemplates the use of data processing equipment with or without a conventional operating system, such as LINUX, UNIX, WINDOWS, MAC OS, ANDROID, or IOS.

[0200] A computer program may also be called a program, software, software application, module, software module, script, or code. A computer program may be described as, or may be written in, any form of programming language. Programming languages ​​may include, for example, compiled, interpreted, declarative, or procedural languages. A program may be arranged for use in a computing environment in any form, including as a stand-alone program, a module, a component, a subroutine, or a unit. A computer program may, but need not, correspond to a file in a file system. A program may be stored in a portion of a file holding other programs or data, e.g., a markup language document, in a single file dedicated to the program of interest, or in one or more scripts stored in multiple linked files that store one or more modules, subprograms, or portions of code. A computer program may be arranged to run on one computer or multiple computers, for example, located at a single site or located across multiple sites interconnected by a communications network. While some of the programs illustrated in the various figures are shown as individual modules that implement various features and functionality through various objects, methods, or processes, the program may instead include several sub-modules, third-party services, components, and libraries. Conversely, the features and functionality of various components may be combined into a single component as desired. The thresholds used to make computational determinations may be determined statically, dynamically, or both statically and dynamically.

[0201] The methods, processes, or logic flows described herein may be implemented by one or more programmable computers executing one or more computer programs to perform functions by manipulating input data and generating output. The methods, processes, or logic flows may also be implemented by, and apparatus may be implemented as, special purpose logic circuitry, such as a CPU, FPGA, or ASIC.

[0202] A computer suitable for running a computer program can be based on one or more general-purpose and special-purpose microprocessors and other types of CPUs. Elements of a computer are a CPU for performing or executing instructions and one or more memory devices for storing instructions and data. Generally, a CPU can receive instructions and data from (and write data to) memory. A computer can also include, or be operatively coupled to, one or more mass storage devices for storing data. In some implementations, a computer can receive data from or send data to a mass storage device such as, for example, a magnetic disk, a magneto-optical disk, or an optical disk. Moreover, a computer can be embedded in another device, such as a mobile phone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a global positioning system (GPS) receiver, or a portable storage device such as a universal serial bus (USB) flash drive.

[0203] Computer-readable media (transient or non-transient, as appropriate) suitable for storing computer program instructions and data can include all forms of permanent / non-permanent, volatile / non-volatile memory, media, and storage devices. Computer-readable media include, for example, semiconductor memory devices, such as random access memory (RAM), read-only memory (ROM), phase-change memory (PRAM), static random access memory (SRAM), dynamic random access memory (DRAM), erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EPROM), and the like. The computer-readable medium may include, for example, magnetic devices, such as tapes, cartridges, cassettes, and internal / removable disks. The computer-readable medium may also include magneto-optical disks and optical storage devices, as well as technologies such as digital video disks (DVDs), CD-ROMs, DVD+ / -Rs, DVD-RAMs, DVD-ROMs, HD-DVDs, and Bluray discs. The memory may store various objects or data, including caches, classes, frameworks, applications, modules, backup data, jobs, web pages, web page templates, data structures, database tables, repositories, and dynamic information. The types of objects and data stored in the memory may include parameters, variables, algorithms, instructions, rules, constraints, and references. Additionally, the memory may include logs, policies, security or access data, and report files. The processor and memory may be supplemented by, or incorporated in, special purpose logic circuitry.

[0204] Implementations of the subject matter described in this disclosure can be implemented on a computer having a display device for providing user interaction, including presenting information to (and receiving input from) a user. Types of display devices can include, for example, cathode ray tubes (CRTs), liquid crystal displays (LCDs), light-emitting diodes (LEDs), and plasma monitors. Display devices can include keyboards and pointing devices, such as mice, trackballs, or trackpads. User input can also be provided to a computer through the use of a touchscreen, such as a tablet computer surface with pressure sensitivity or a multi-touch screen using capacitive or electrical sensing. Other types of devices can be used to provide user interaction and receive user feedback, including, for example, sensory feedback such as visual feedback, auditory feedback, or haptic feedback. Input from a user can be received in the form of auditory input, speech input, or tactile input. Additionally, a computer can interact with a user by sending documents to and receiving documents from devices used by the user. For example, a computer can send a web page to a web browser on a user's client device in response to a request received from the web browser.

[0205] The terms "graphical user interface" or "GUI" can be used in the singular or plural to describe one or more graphic user interfaces and the display of a particular graphic user interface, respectively. Thus, a GUI can refer to any graphic user interface, such as, but not limited to, a web browser, a touch screen, or a command line interface (CLI), that processes information and efficiently presents the resulting information to a user. Generally, a GUI can include multiple user interface (UI) elements, such as interactive fields, pull-down lists, and buttons, some or all of which are associated with a web browser. These and other UI elements can be associated with or represent functionality of the web browser.

[0206] Practices of the subject matter described herein can be implemented in a computing system that includes back-end components (e.g., as a data server) or that includes middleware components (e.g., as an application server). Additionally, the computing system can also include front-end components, e.g., a computer system that allows a user to interact with the computer. The system may include a client computer having a graphical user interface or a web browser, or both. The components of the system may be interconnected in a communications network by any form or medium of wireline or wireless digital data communications (or a combination of data communications). Examples of communications networks include a local area network (LAN), a radio access network (RAN), a metropolitan area network (MAN), a wide area network (WAN), Worldwide Interoperability for Microwave Access (WIMAX), a wireless local area network (WLAN) (e.g., using 802.11a / b / g / n or 802.20 or a combination of protocols), all or part of the Internet, or any other communications system (or combination of communications networks) in one or more locations. The network may communicate, for example, Internet Protocol (IP) packets, frame relay frames, asynchronous transfer mode (ATM) cells, voice, video, data, or a combination of communication types between network addresses.

[0207] The computing system may include clients and servers. Clients and servers may generally be remote from each other and typically interact through a communication network. The relationship of client and server may be created by computer programs running on the respective computers and having a client-server relationship to each other.

[0208] A cluster file system can be any type of file system accessible for reads and updates from multiple servers. Locking or consistency tracking may not be required, since locking for an exchange file system can be done at the application layer. Furthermore, Unicode data files can differ from non-Unicode data files.

[0209] Administration of anti-IL-4Rα antibodies and fragments The present disclosure provides methods of treating certain disorders with therapeutic compositions comprising an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) or a fragment thereof. The present disclosure also provides an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) or a fragment thereof for use in the methods of treating certain disorders with therapeutic compositions.

[0210] The methods used herein are useful for treating a subject in need thereof. As used herein, the terms "subject," "patient," and the like are used interchangeably.

[0211] Disclosed herein in some embodiments is a method for treating a subject with an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder, the subject exhibiting at least one symptom of the disorder, or the subject being determined to be susceptible to the disorder, with an anti-IL-4 receptor antibody. In some cases, the method includes administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject exhibiting at least one symptom of the disorder, the subject being determined to be susceptible to the disorder, the anti-IL-4Rα antibody comprising a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA), a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT), a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV), a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY), a variable light chain CDR2 of SEQ ID NO: 5 (LGS), and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0212] In some cases, the method includes (a) identifying a subject for treatment with an anti-IL-4Rα antibody; and (b) administering a therapeutically effective amount of an anti-IL-4Rα antibody to the subject, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, identifying a subject for treatment includes: (a) selecting a characteristic or characteristics in a set of patients; (b) clustering, by a computer system, a subset of patients having the characteristic or characteristics according to the characteristic or characteristics, wherein the characteristic or characteristics are determined to be associated with at least one symptom of an IL-4Rα-associated disorder or a predisposition to the disorder; (c) identifying, in the subset of patients clustered in step (b), the IL-4Rα-associated disorder based on the characteristic or characteristics associated with the IL-4 / IL-13 pathway; and (d) selecting subjects who exhibit at least one symptom of an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder or a predisposition to the disorder identified in step (c).

[0213] In some cases, the method includes identifying a subject as a candidate for treatment for an anti-interleukin-4 receptor alpha (IL-4Rα) associated disorder with an anti-IL-4Rα antibody, comprising the steps of: (a) selecting, in a data set representing medical records of a plurality of subjects, a characteristic or characteristics associated with the IL-4 / IL-13 pathway; (b) clustering, by a computer system, a subset of subjects from the plurality of subjects according to the characteristic or characteristics associated with the IL-4 / IL-13 pathway, wherein the subset includes the characteristic or characteristics; and (c) identifying, in the subset clustered in step (b), an IL-4 / IL-13 pathway associated characteristic or characteristics. (d) selecting a subject having at least one symptom of or susceptible to an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder identified in step (c), where the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA).

[0214] In some cases, the method includes steps of identifying a subject as a candidate for treatment for an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder with an anti-IL-4Rα antibody, the steps including: (a) selecting a characteristic or characteristics related to the IL4 / IL13 pathway in a data set representing the medical records of a plurality of subjects; (b) clustering a subset of subjects from the plurality of subjects by a computer system according to the characteristic or characteristics related to the IL-4 / IL-13 pathway, wherein the subset comprises the characteristic or characteristics; (c) identifying the IL-4Rα-associated disorder in the clustered subset in step (b) based on a symptom associated with the characteristic or characteristics related to the IL-4 / IL-13 pathway; and (d) selecting a subject identified in step (c) as having at least one symptom of or being susceptible to the anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder. In some cases, the method includes administering to the subject a therapeutically effective amount of an anti-IL-4Rα antibody, wherein the anti-IL-4Rα antibody has a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); (QSLLYSIGYNY); variable light chain CDR2 of SEQ ID NO:5 (LGS); and variable light chain CDR3 of SEQ ID NO:6 (MQALQTPYT).

[0215] In some cases, the method includes identifying a subject as a candidate for treatment for an anti-interleukin-4 receptor alpha (IL-4Rα) associated disorder with an anti-IL-4Rα antibody, comprising the steps of: (a) selecting, in a data set representing medical records of a plurality of subjects, a characteristic or characteristics associated with the IL-4 / IL-13 pathway; (b) clustering, by a computer system, a subset of subjects from the plurality of subjects according to the characteristic or characteristics associated with the IL-4 / IL-13 pathway, wherein the subset includes the characteristic or characteristics; and (c) identifying, in the subset clustered in step (b), an IL-4 / IL-13 pathway associated characteristic or characteristics. (d) selecting a subject having at least one symptom of or susceptible to an anti-interleukin-4 receptor alpha (IL-4Rα)-associated disorder identified in step (c), where the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA). In some cases, the method further includes administering a therapeutically effective amount of an anti-IL-4Rα antibody to the subject, wherein the anti-IL-4Rα antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT).

[0216] In some cases, a method of treating a subject with an anti-interleukin-4 receptor antibody comprises the steps of: (a) selecting a characteristic or plurality of characteristics in a set of patients; (b) clustering, by a computer system, a subset of patients having the characteristic or plurality of characteristics according to the characteristic or plurality of characteristics, wherein the characteristic or plurality of characteristics is determined to be associated with or predisposing to at least one symptom of an IL-4R-associated disorder; and (c) clustering at least one symptom of an IL-4R-associated disorder. and administering a therapeutically effective amount of an anti-IL-4R antibody to a subject determined to exhibit or be susceptible to the disorder, wherein the anti-IL-4R antibody comprises a variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); a variable heavy chain CDR2 of SEQ ID NO: 2 (ISGSGGNT); a variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); a variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); a variable light chain CDR2 of SEQ ID NO: 5 (LGS); and a variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT). In some cases, the anti-IL-4R antibody is an anti-IL-4R-α antibody. In some cases, the anti-IL-4R antibody is dupilumab. In some cases, the IL-4R-associated disorder is an IL-4R-α-associated disorder. In some cases, the IL-4Rα-associated disorder is a condition listed in Table 9 or Table 10.

[0217] I. Administration Therapeutic compositions can be administered with suitable carriers, excipients, and other agents incorporated into the formulation to provide improved transfer, delivery, tolerance, etc. Many suitable formulations can be found in the formulary: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vehicles ( For example, Lipofectin™, DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowax (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of Excipients for Parenteral Formulations," PDA (1998) J Pharm Sci Technol 52:238-311, which is incorporated herein by reference in its entirety.

[0218] II. Dosage The amount of anti-IL-4Rα antibody (e.g., dupilumab) administered to a subject according to the methods of the present disclosure is generally a therapeutically effective amount. A "therapeutically effective amount" or "therapeutically effective dosage" of an IL-4Rα antibody is any amount of antibody that, when used alone or in combination with other therapeutic agents, promotes disease reversal as manifested by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or prevention of disease-related impairment or disability.

[0219] In some cases, the amount of anti-IL-4Rα antibody (e.g., dupilumab) administered to a subject according to the methods of the present disclosure is a prophylactically effective amount. A "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic result at the necessary dosage and for the necessary period of time. In some embodiments, because a prophylactic dose is used in a subject at or before the early stage of disease, the prophylactically effective amount is less than the therapeutically effective amount.

[0220] The dosage may vary depending on the age and size of the subject, the target disease, condition, route of administration, etc. When an anti-IL-4Rα antibody (e.g., dupilumab) is used to treat various conditions and diseases associated with IL-4Rα in adult patients, it is often advantageous to administer the antibody intravenously in a single dose of about 0.01 mg / kg to about 20 mg / kg of body weight. In some cases, the single dose is about 0.02 mg / kg to about 7 mg / kg of body weight, about 0.03 mg / kg to about 5 mg / kg of body weight, or about 0.05 mg / kg to about 3 mg / kg of body weight. The frequency and duration of treatment can be adjusted depending on the severity of the condition.

[0221] In the case of an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab), the therapeutically effective amount is from about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg The dose may be about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of anti-IL-4Rα antibody. In certain embodiments, 300 mg of anti-IL-4Rα antibody is administered.

[0222] The amount of anti-IL-4R antibody (e.g., anti-IL-4Rα antibody, e.g., dupilumab) contained within an individual dose can be expressed in units of milligrams of antibody per kilogram of patient weight (i.e., mg / kg). Mab) can be administered to a patient at a dose of about 0.0001 mg / kg to about 10 mg / kg of patient body weight (e.g., about 0.001 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, or about 10.0 mg / kg).

[0223] In some cases, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of a treatment regimen as a "loading dose," followed by subsequent doses administered less frequently (e.g., "maintenance doses"). For example, an IL-4R antagonist may be administered to a subject at an initial loading dose of about 200 mg, 400 mg, or about 600 mg, followed by one or more maintenance doses of about 75 mg to about 300 mg. In one embodiment, the initial dose and the one or more secondary doses each contain 50 mg to 600 mg of the IL-4R antagonist, e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg of the IL-4R antagonist. In some embodiments, the initial dose and each of the one or more secondary doses contain the same amount of IL-4R antagonist. In other embodiments, the initial dose includes a first amount of IL-4R antagonist, and each of the one or more secondary doses includes a second amount of IL-4R antagonist. For example, the first amount of IL-4R antagonist can be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times or more the second amount of IL-4R antagonist. In an exemplary embodiment, for a subject weighing less than 30 kg (e.g., ≥ 15 kg to < 30 kg), the IL-4R antagonist is administered to the subject in an initial loading dose of about 200 mg, followed by one or more maintenance doses of about 100 mg, or in an initial loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg. In another exemplary embodiment, for a subject having a body weight of ≥ 30 kg (e.g., ≥ 30 kg to < 60 kg), the IL-4R antagonist is administered to the subject in an initial loading dose of about 400 mg, followed by one or more maintenance doses of about 200 mg, or in an initial loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg.In yet another exemplary embodiment, for a subject having a body weight of ≧60 kg, the IL-4R antagonist is administered to the subject in an initial loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg.

[0224] In some cases, each secondary and / or tertiary dose is administered 1 week to 14 weeks (e.g., 1 week, 1 1 / 2 weeks, 2 weeks, 2 1 / 2 weeks, 3 weeks, 3 1 / 2 weeks, 4 weeks, 4 1 / 2 weeks, 5 weeks, 5 1 / 2 weeks, 6 weeks, 6 1 / 2 weeks, 7 weeks, 7 1 / 2 weeks, 8 weeks, 8 1 / 2 weeks, 9 weeks, 9 1 / 2 weeks, 10 weeks, 10 1 / 2 weeks, 11 weeks, 11 1 / 2 weeks, 12 weeks, 12 1 / 2 weeks, 13 weeks, 13 1 / 2 weeks, 14 weeks, 14 1 The phrase "immediately preceding dose" as used herein means a dose of an IL-4R antagonist administered to a patient before the next dose in a series of multiple doses, with no intervening doses in between.

[0225] In some cases, administration is a single initial dose of 600 mg (two 300 mg injections at different injection sites), followed by 300 mg every other week. In some cases, administration is by pre-filled syringe. In some cases, administration is by pre-filled pen. In some cases, administration is carried out by an autoinjector. In some embodiments, administration is carried out by a 300 mg injection diluted in 2 mL of solution in a single-dose pre-filled syringe with a needle shield. In some embodiments, administration is carried out by a single initial dose of 400 mg (two 200 mg injections at different injection sites), followed by 200 mg every other week. In some embodiments, administration is carried out by a 200 gm injection diluted in 2 mL of solution in a single-dose pre-filled syringe with a needle shield. In some embodiments, administration is carried out by a 300 mg injection diluted in 2 mL of solution in a single-dose pre-filled syringe.

[0226] III. Delivery Various delivery systems are known and can be used to administer pharmaceutical compositions, such as liposomal encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, e.g., by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents. Administration can be systemic or local.

[0227] IV. Combination Therapy Combination therapies are also provided in which an anti-IL-4Rα antibody (e.g., dupilumab) or antibody fragment is administered with a second therapeutic agent. Coadministration and combination therapy include, but are not limited to, simultaneous administration, and include treatment regimens in which an anti-IL-4Rα antibody or antibody fragment is administered at least once during a course of treatment that involves administering at least one other therapeutic agent to a patient. The second therapeutic agent may be another IL-4 antagonist, such as another antibody / antibody fragment, or a soluble cytokine receptor, an IgE antagonist, an antiasthma medication (corticosteroids, nonsteroidal drugs, beta-agonists, leukotriene antagonists, xanthines, fluticasone, salmeterol, albuterol), or a checkpoint inhibitor, which may be delivered by inhalation or other suitable means. In some cases, the anti-IL-4Rα antibody or antibody fragment (e.g., dupilumab) of the present disclosure can be administered together with an IL-1 antagonist, such as rilonacept, or an IL-13 antagonist. The second agent can include one or more leukotriene receptor antagonists to treat disorders such as allergic inflammatory diseases, e.g., asthma and allergies. Examples of leukotriene receptor antagonists include, but are not limited to, montelukast, pranlukast, and zafirlukast. The second agent can be a checkpoint inhibitor. In some cases, the checkpoint inhibitor blocks PD-1, blocks PD-L1, is an anti-PD-1 antibody, or is a PD-1 antagonist (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In some embodiments, the anti-PD-1 antibody is MDX-1106 (also known as nivolumab, MDX-1106-04, ONO-4538, BMS-936558, and Opdivo®), Merck 3475 (pembrolizumab, MK), -3475, lambrolizumab, Keytruda® (also known as SCH-900475), and CT-011 (also known as pidilizumab, hBAT, and hBAT-1). In some cases, the checkpoint inhibitor is a CTLA-4 antagonist, such as Yervoy® (ipilimumab).

[0228] In some cases, the second agent is a cytokine inhibitor, e.g., a TNF (etanercept, ENBREL™), IL-9, IL-5, or IL-17 antagonist. The present invention may include one or more of the following:

[0229] Indications treatable with anti-IL-4Rα antibodies and fragments Pulmonary Indications Lung disorders Provided herein is a method for treating IL-4-induced lung disorders.Such disorders include but are not limited to pulmonary fibrosis, such as chronic fibrotic lung disease, cystic fibrosis, interstitial lung disease, nonspecific interstitial pneumonia, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, idiopathic organizing pneumonia (COP), acute interstitial pneumonia, desquamative interstitial pneumonia, chronic obstructive pulmonary disease, pulmonary alveolar proteinosis, adult respiratory distress syndrome (ARDS), asbestosis, sarcoidosis, tuberculosis and aspirin asthma, other conditions characterized by IL-4-induced fibroblast proliferation or collagen accumulation in the lung, pulmonary diseases in which TH2-type immune response plays a role, the condition characterized by the reduction of lung barrier function (for example, caused by IL-4-induced damage to the membrane) or the condition in which IL-4 plays a role in inflammatory response.

[0230] Cystic fibrosis is characterized by excessive mucus production and the development of chronic infections. Inhibiting IL-4 and Th2 responses reduces mucus production and helps control infections such as allergic bronchopulmonary aspergillosis (ABPA).

[0231] Allergic bronchopulmonary mycosis occurs primarily in patients with cystic fibrosis or asthma when the Th2 immune response is dominant. Inhibition of IL-4 and the Th2 response helps to eliminate and control these infections.

[0232] Chronic obstructive pulmonary disease is associated with mucus hypersecretion and fibrosis. Inhibition of IL-4 and Th2 responses reduces mucus production and the development of fibrosis, thereby improving respiratory function and slowing disease progression.

[0233] Bleomycin-induced lung disease and fibrosis and radiation pulmonary fibrosis are disorders characterized by pulmonary fibrosis, manifested by the influx of Th2, CD4+ cells, and macrophages, which produce IL-4, which mediates the development of fibrosis. Inhibiting IL-4 and Th2 responses reduces the development of these disorders.

[0234] Pulmonary alveolar proteinosis is characterized by disruption of surfactant clearance. IL-4 increases surfactant production. The use of anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can reduce surfactant production, reducing the need for whole lung lavage.

[0235] Adult respiratory distress syndrome (ARDS) can be caused by many factors, one of which is exposure to toxic chemicals. One patient population prone to ARDS is critically ill patients who are on ventilators. ARDS is a common complication in such patients. While anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can alleviate ARDS by reducing inflammation and adhesion molecules, methods of treating such patients according to the present disclosure are not limited by the specific mechanism of action. ARDS can be prevented or treated by using anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab).

[0236] Sarcoidosis is characterized by granulomatous lesions. Sarcoidosis, particularly pulmonary sarcoidosis, can be treated using an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0237] Conditions in which IL-4-induced barrier disruption plays a role (e.g., conditions characterized by decreased epithelial barrier function in the lungs) can be treated with anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab). Damage to the epithelial barrier in the lungs can be induced directly or indirectly by IL-4. The epithelium in the lungs functions as a selective barrier that prevents the contents of the lung lumen from entering the submucosa. A damaged or "leaky" barrier allows antigens to pass through the barrier, and those that do pass can trigger an immune response that can cause further damage to lung tissue. Such an immune response can include, for example, recruitment of eosinophils or mast cells. Administering an anti-IL-4R antibody (e.g., anti-IL-4Rα antibody, e.g., dupilumab) can inhibit the stimulation of such undesirable immune responses.

[0238] Administration of an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) can promote healing of the lung epithelium, thereby restoring barrier function. Administration of an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) can promote healing of the lung epithelium, for example, in asthma patients. IL-4-induced damage to the lung epithelium can be prevented by administering the antibody for prophylactic purposes, instead of or in addition to treatment after the onset of damage.

[0239] Disclosed herein are methods of treating a subject having a pulmonary disorder described herein by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods of ameliorating, alleviating, or preventing reactions associated with a pulmonary disorder described herein by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0240] tuberculosis TH2-type immune responses have been implicated in playing a role in causing tissue damage (necrosis of lung tissue) in tuberculosis (TB) patients. High levels of IL-4 are associated with TB. IL-4 production is particularly increased in cavitary tuberculosis (i.e., in TB patients who have developed lung cavities that can be detected / visualized by techniques such as chest radiographs).

[0241] Anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can benefit TB patients (particularly those with cavitary TB) by suppressing TH2-type immune responses or by binding to (and inactivating) oversecreted IL-4. However, methods of treating such patients according to the present disclosure are not limited by a particular mechanism of action. Anti-IL-4Rα antibodies (e.g., dupilumab) can be advantageously administered in an amount that restores a desired balance between the TH1 and TH2 components of the immune response and reduces IL-4-induced tissue damage in patients.

[0242] Disclosed herein are methods of treating a subject with TB by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods of ameliorating, reducing, or preventing TB-related reactions by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0243] Aspirin asthma Aspirin-exacerbated respiratory AERD, also known as Samter's triad, is a group of three clinical features: asthma, sinus disease with recurrent nasal polyps, and aspirin and cyclooxygenase- AERD is a chronic medical condition consisting of hypersensitivity to other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit an enzyme called NSAID-1. This sensitivity usually manifests as a respiratory reaction when ingesting or inhaling an NSAID, although the exact cause of the reaction is unknown. Approximately 9% of all adults with asthma and 30% of patients with asthma and nasal polyps have AERD. AERD typically begins suddenly in adulthood, usually between the ages of 20 and 50, but the exact cause of the disease is unknown.

[0244] Subjects with AERD usually have asthma, nasal congestion, and recurrent nasal polyps, and these symptoms often do not respond to conventional treatment. Many subjects experience chronic sinus infections, and loss of smell is common.

[0245] AERD is characterized by patients developing reactions to aspirin and other NSAIDs. These reactions classically involve both upper respiratory (stuffy nose, frontal headache or sinus pain, and worsening sneezing) and lower respiratory (cough, wheezing, chest tightness) symptoms, but they can also cause skin flushing, rash, abdominal pain, and occasional vomiting.

[0246] Disclosed herein is a method of treating a subject with AERD by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with AERD by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0247] Allergic bronchopulmonary aspergillosis Allergic bronchopulmonary aspergillosis (ABPA) is an allergic or hypersensitivity reaction to a mold known as Aspergillus fumigatus, which is commonly found in soil. In some cases, subjects with ABPA exhibit inflammation of the airways. Subjects with ABPA often exhibit one or more of the following symptoms: cough, often with brownish, flaky or bloody mucus, fever, wheezing, a generalized cough, shortness of breath, pleuritic chest pain, and general weakness or fatigue. In some cases, subjects with ABPA also suffer from asthma. In some cases, subjects with ABPA also suffer from cystic fibrosis. In some cases, subjects with ABPA also suffer from allergic conditions, such as atopic dermatitis (eczema), hives (rash), allergic rhinitis (hay fever), and sinusitis.

[0248] Disclosed herein is a method of treating a subject with ABPA by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with ABPA by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0249] Extrinsic allergic alveolitis Extrinsic allergic alveolitis (or hypersensitivity pneumonitis) is a lung disorder that occurs as a result of repeated inhalation of organic dust, usually in certain occupational environments. In the acute form, respiratory symptoms and fever begin several hours after exposure to the dust. Symptoms of extrinsic allergic alveolitis include difficulty breathing, wheezing, and a dry cough that appears to vibrate the whole body. In some cases, subjects with extrinsic allergic alveolitis exhibit chills, sweating, pain, weakness, and / or fatigue, which may accompany the pulmonary symptoms. In some embodiments, extrinsic allergic alveolitis is acute. In some cases, extrinsic allergic alveolitis is chronic. In the case of chronic extrinsic allergic alveolitis, subjects may experience fever, crackling sounds (crackling) during breathing, difficulty breathing, a bluish appearance of the skin (cyanosis), and coughing up blood. It is possible.

[0250] Disclosed herein is a method of treating a subject with extrinsic allergic alveolitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with extrinsic allergic alveolitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0251] Upper airway hyperresponsiveness and other respiratory conditions of unknown location resulting from environmental exposures Upper airway hyperresponsiveness reactions of unknown or not otherwise specified (NOS) (also known as upper respiratory allergies; hypersensitive NOS; hypersensitivity reactions; allergic NOS; etc.) include airway and food hypersensitivity. In some cases, upper airway hyperresponsiveness reactions include nasal congestion, rhinorrhea, sneezing, itchy nose and throat, coughing, or wheezing. In some cases, upper airway hyperresponsiveness reactions of unknown or not otherwise specified occur as a result of inhalant allergies. In some cases, upper airway hyperresponsiveness reactions of unknown or not otherwise specified occur as a result of food allergies. In some cases, the subject disclosed herein has upper airway hyperresponsiveness reactions of unknown or not otherwise specified (NOS).

[0252] In some cases, the subject disclosed herein is a subject who experiences respiratory sensitivity when exposed to environmental conditions.For example, in some cases, the subject is exposed to one or more chemicals, one or more gases, one or more fumes, one or more vapors, or a combination thereof.

[0253] Disclosed herein is a method of treating a subject with an upper airway hyperresponsiveness reaction of unknown or not otherwise specified (NOS) by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing a reaction associated with an upper airway hyperresponsiveness reaction of unknown or not otherwise specified (NOS) by administering to the patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0254] Also disclosed herein is a method of treating a subject exposed to one or more chemicals, one or more gases, one or more fumes, one or more vapors, or a combination thereof, by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing a reaction associated with exposure to one or more chemicals, one or more gases, one or more fumes, one or more vapors, or a combination thereof, by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0255] Pharyngitis Pharyngitis (e.g., sore throat) is caused by swelling at the back of the pharynx between the tonsils and the larynx. In some cases, pharyngitis is caused by one or more viruses. For example, in some cases, the virus that causes pharyngitis can include one or more influenza viruses, enteroviruses, such as Coxsackievirus (e.g., in the case of hand, foot, and mouth disease), or Epstein-Barr virus (EBV) (e.g., in the case of mononucleosis). In some cases, pharyngitis is caused by bacteria. For example, in some cases, the subject suffering from pharyngitis is infected by Neisseria species (e.g., Gonorae); Chlamydia species (e.g., Trachomatis), or Streptococcus species (e.g., Group A Streptococcus; e.g., IBD).

[0256] Disclosed herein is a method of treating a subject with pharyngitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with pharyngitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0257] Nasopharyngitis and chronic nasopharyngitis In some cases, the subject disclosed herein has a clinical diagnosis of pharyngitis, particularly nasopharyngitis (also known as the common cold). In some cases, the nasopharyngitis is acute (e.g., the common cold). In some cases, the nasopharyngitis is not acute. Symptoms associated with nasopharyngitis include one or more of: runny or stuffy nose; sneezing; cough; sore throat or scratchy throat; watery or itchy eyes; headache; fatigue; and body aches. In some cases, the nasopharyngitis is viral. In some cases, the nasopharyngitis is bacterial. In some cases, the nasopharyngitis is chronic. In some cases, the nasopharyngitis becomes chronic when one or more symptoms of nasopharyngitis persist for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, or more.

[0258] Disclosed herein is a method of treating a subject with nasopharyngitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with nasopharyngitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0259] Disclosed herein is a method of treating a subject with chronic nasopharyngitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with chronic nasopharyngitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0260] Bronchitis, such as simple chronic bronchitis and mucopurulent chronic bronchitis Bronchitis is inflammation of the bronchi. In some cases, the subject disclosed herein suffers from bronchitis. In some cases, bronchitis is acute. In some cases, bronchitis is chronic. Compared with normal subjects, subjects with chronic bronchitis show increased mucus, increased coughing, and increased difficulty in breathing. Subjects with chronic bronchitis (e.g., simple chronic bronchitis) show symptoms of bronchitis for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months or more.

[0261] In some cases, subjects with mucopurulent chronic bronchitis may also exhibit bronchiectasis, a chronic condition in which the walls of the bronchi thicken from inflammation and infection. In some cases, subjects with mucopurulent chronic bronchitis may also exhibit persistent or recurrent purulent sputum.

[0262] Disclosed herein is a method of treating a subject with uncomplicated chronic bronchitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, reducing, or preventing reactions associated with uncomplicated chronic bronchitis by administering to the patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0263] A method of treating a subject with mucopurulent chronic bronchitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is described herein. Also disclosed herein are methods for ameliorating, reducing, or preventing reactions associated with mucopurulent chronic bronchitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0264] Ear, Nose, and Throat Indications In some cases, methods of treating ear, nose, and throat related indications, such as chronic tonsil and adenoid disease, enlarged adenoids, otosclerosis, mastoiditis and related conditions, or otitis externa, are disclosed.

[0265] Chronic tonsil and adenoid disease Disclosed herein are subjects having one or more chronic conditions of the tonsils. Disclosed herein are subjects having one or more chronic conditions of the adenoids.

[0266] Tonsils are two masses of tissue on either side of the back of the throat. Small pits, called crypts, are often found on the surface of the tonsils. These crypts appear deep and contain stones called tonsil stones. Adenoids are located high in the throat behind the nose and soft palate (roof of the mouth). Unlike tonsils, adenoids cannot be easily seen through the mouth.

[0267] In some cases, chronic tonsil diseases include tonsillitis, an infection of the tonsils. Symptoms of tonsillitis include one or more of the following: swollen tonsils; white or yellow coatings on the tonsils; slight changes in voice due to swelling; sore throat, sometimes with ear pain; unpleasant or painful swallowing; swollen lymph nodes in the neck; fever; or bad breath.

[0268] In some cases, chronic adenoid disease includes enlargement or inflammation of the adenoids. Symptoms include nasal obstruction, sleep disturbances, and middle ear effusion with hearing loss.

[0269] Disclosed herein is a method for treating a subject with one or more chronic diseases of the tonsils and adenoids by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed herein is a method for ameliorating, alleviating, or preventing reactions associated with one or more chronic diseases of the tonsils and adenoids by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0270] Disclosed herein are methods for treating a subject with one or more chronic diseases of the tonsils by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for ameliorating, alleviating, or preventing reactions associated with one or more chronic diseases of the tonsils by administering to the patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0271] Disclosed herein is a method for treating a subject with one or more chronic adenoid disorders by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed herein is a method for improving, alleviating, or preventing reactions associated with one or more chronic adenoid disorders by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0272] Adenoid hypertrophy Adenoid hypertrophy is the abnormal growth of the adenoids. In some cases, most patients are children. In some cases, the adenoids continue to grow larger and obstruct the passage behind the nose. In some cases, this can result in snoring, mouth breathing, and / or a low, nasal voice when speaking. In some cases, adenoid hypertrophy can block the Eustachian tube, resulting in otitis media.

[0273] Disclosed herein is a method of treating a subject with adenoid hypertrophy by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with adenoid hypertrophy by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0274] otosclerosis Otosclerosis is the abnormal growth of bone in the middle ear. This bone prevents structures in the ear from functioning properly, causing hearing loss. Some people with otosclerosis experience severe hearing loss. The condition is caused by abnormal bone remodeling in the middle ear. Bone remodeling is a lifelong process in which bone tissue renews itself by replacing old tissue with new tissue. In otosclerosis, the abnormal remodeling disrupts the ability of sound to travel from the middle ear to the inner ear. Otosclerosis is most often caused when the stapes, one of the bones in the middle ear, becomes stuck in place. If this bone cannot vibrate, sound cannot travel through the ear, and hearing is reduced.

[0275] Disclosed herein are methods for treating a subject with otosclerosis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for ameliorating, alleviating, or preventing reactions associated with otosclerosis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0276] Mastoiditis Mastoiditis is a bacterial infection of the mastoid process. Mastoiditis usually occurs when untreated or inadequately treated acute otitis media spreads from the middle ear into the mastoid process. In some cases, mastoiditis is acute. In some cases, mastoiditis is chronic. Symptoms of mastoiditis include swelling behind the ear, pus discharge from the ear, throbbing pain, and hearing loss. In some cases, the swelling behind the ear may be intermittent.

[0277] Disclosed herein is a method of treating a subject with mastoiditis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with mastoiditis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0278] otitis externa Otitis externa is a condition that causes inflammation of the ear canal, the tube between the outer ear and the eardrum. In some cases, otitis externa is acute. In some cases, otitis externa is caused by a bacterial infection (e.g., Pseudomonas). Symptoms include pain, discharge, and decreased hearing if the ear canal swells and closes; manipulation of the pinna causes pain.

[0279] The subject is administered an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Disclosed herein are methods of treating a subject with otitis externa by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient. Also disclosed herein are methods of ameliorating, alleviating, or preventing reactions associated with otitis externa by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0280] Hematology, rheumatology, and immune-related indications In some cases, methods of treating blood-related indications, such as sickle cell anemia, Churg-Strauss syndrome, autoimmune lymphoproliferative syndrome, lupus (systemic lupus erythematosus), antiphospholipid syndrome (APS), or autoimmune hemolytic anemia, are disclosed.

[0281] Sickle cell anemia Patients with sickle cell anemia typically experience intermittent periods of acute exacerbations called crises, which are classified as anemia or vaso-occlusive disease. Anti-IL-4Rα antibodies (e.g., dupilumab) are used to treat or prevent sickle cell crises, particularly in patients with high IL-4 levels or whose immune response is shifted toward a TH2-type response. Sickle cell anemia (e.g., sickle cell crisis) is associated with increased susceptibility to infectious diseases, such as recent infections. Administering anti-IL-4Rα antibodies (e.g., dupilumab) to patients with sickle cell anemia can help mount an immune response against infectious diseases.

[0282] Disclosed herein are methods of treating a subject with sickle cell anemia by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods of ameliorating, reducing, or preventing reactions associated with sickle cell anemia by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0283] Churg-Strauss syndrome Churg-Strauss syndrome, also known as allergic granulomatous vasculitis or eosinophilic granulomatosis with polyangiitis, is characterized by vascular inflammation and eosinophilia in individuals with a history of asthma or allergies. Administration of anti-IL-4Rα antibodies (e.g., dupilumab) can reduce inflammation in patients with this syndrome. The use of anti-IL-4Rα antibodies to suppress TH2-type immune responses and combat eosinophilia may benefit patients.

[0284] Disclosed herein are methods for treating a subject with Churg-Strauss syndrome by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for ameliorating, reducing, or preventing reactions associated with Churg-Strauss syndrome by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0285] Autoimmune lymphoproliferative syndrome Manifestations of autoimmune lymphoproliferative syndrome involve lymphocyte proliferation and autoantibody production. Patients suffering from this syndrome reportedly have a genetic defect in apoptosis. Anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can benefit patients suffering from this syndrome by suppressing TH2-type immune responses or by binding to (and inactivating) IL-4 secreted at the site of inflammation. However, methods of treating such patients according to the present disclosure are not limited by a particular mechanism of action.

[0286] administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab); Disclosed herein is a method for treating a subject with autoimmune lymphoproliferative syndrome by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject. Also disclosed herein is a method for ameliorating, alleviating, or preventing reactions associated with autoimmune lymphoproliferative syndrome by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0287] Lupus (systemic lupus erythematosus) Systemic lupus erythematosus (or lupus) is an autoimmune disease characterized by the production of unique autoantibodies in the blood. These autoantibodies bind to their respective antigens, forming immune complexes that circulate and ultimately deposit in tissues. This immune complex deposition causes chronic inflammation and tissue damage.

[0288] Disclosed herein are methods of treating a subject with autoimmune lupus (systemic lupus erythematosus) by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods of ameliorating, alleviating, or preventing reactions associated with lupus (systemic lupus erythematosus) by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0289] Antiphospholipid syndrome (APS) Antiphospholipid syndrome (APS) is an autoimmune disease that appears mostly in young women. People with APS form abnormal proteins called antiphospholipid autoantibodies in their blood. This causes improper blood flow and can lead to dangerous clotting in arteries and veins, problems with the developing fetus, and pregnancy loss. People with this disorder may be otherwise healthy, or they may also have an underlying condition, most often lupus.

[0290] Disclosed herein are methods for treating a subject with antiphospholipid syndrome (APS) by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for ameliorating, alleviating, or preventing reactions associated with APS by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0291] autoimmune hemolytic anemia Excessive IL-4 secretion and deficiencies in TH1-type cytokines are implicated in contributing to the pathogenesis of autoimmune hemolytic anemia. Administration of anti-IL-4Rα antibodies (e.g., dupilumab) can reduce autoantibody production and restore a more normal balance between the TH1 and TH2 components of the immune response.

[0292] Disclosed herein is a method for treating a subject with autoimmune hemolytic anemia, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed is a method for ameliorating, reducing, or preventing reactions associated with autoimmune hemolytic anemia, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0293] eosinophilia Eosinophilia is a disease or disorder characterized by excess eosinophils. In some cases, eosinophilia occurs in the blood. In some cases, eosinophilia occurs in one or more tissues. In some cases, an absolute eosinophil count in peripheral blood greater than 450 cells / μL to 550 cells / μL is considered high. In some cases, a percentage difference greater than 5% is generally considered high eosinophils. In some cases, eosinophilia occurs due to an allergic reaction. In some cases, eosinophilia occurs due to a parasitic infection. In some cases, eosinophilia is mild. In some cases, eosinophilia is Eosinophilia is moderate. In some cases, eosinophilia is severe. In some cases, organ damage occurs. Organ damage typically occurs due to tissue inflammation and a response to cytokines and chemokines released by eosinophils and a response to immune cells recruited to the tissue. Any organ can be involved, but in some cases, the heart, lungs, spleen, skin, and nervous system are typically affected.

[0294] Disclosed herein are methods for treating a subject with eosinophilia, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for ameliorating, alleviating, or preventing reactions associated with eosinophilia, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0295] Systemic mastocytosis Systemic mastocytosis is a disorder in which mast cells abnormally increase in multiple organs, including the bone marrow. Mast cells are immune cells that produce various mediators, such as histamine, which are important in the body's allergic responses. Symptoms of systemic mastocytosis include facial flushing, itching, anemia, and bleeding disorders; gastrointestinal symptoms, such as abdominal pain, diarrhea, nausea, and / or vomiting; anaphylactoid symptoms; and enlarged liver (hepatomegaly), spleen (splenomegaly), and lymph nodes (lymphadenopathy). Other symptoms include dizziness or loss of consciousness. Common triggers include alcohol, temperature changes, spicy foods, and certain drugs. In some cases, subjects with systemic mastocytosis have somatic mutations in the KIT gene.

[0296] Disclosed herein are methods for treating a subject with systemic mastocytosis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for ameliorating, alleviating, or preventing reactions associated with systemic mastocytosis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0297] Graft-versus-host disease Graft-versus-host disease (GvHD) is a condition that can occur after allogeneic transplantation. In GvHD, donated bone marrow or peripheral blood stem cells perceive the recipient's body as foreign, and the donated cells / bone marrow attack the body. In some cases, GvHD is acute graft-versus-host disease (aGvHD). In some cases, GvHD is chronic graft-versus-host disease (cGvHD). Several factors, including donor / recipient HLA (human leukocyte antigen) mismatch, are thought to increase the incidence of acute GvHD (aGvHD). Subjects with aGvHD may exhibit one or more of the following symptoms: skin rash or red areas on the skin; yellowing of the skin and / or eyes; and abnormalities in liver function tests; nausea, vomiting, diarrhea, or abdominal cramps and increased eye dryness / irritation.

[0298] Subjects with aGvHD may exhibit one or more of the following: rash, bumps, or discolored areas, thickened or shrinking skin; abdominal bloating, yellowing of the skin and / or eyes, and abnormal blood test results; dry eyes or vision changes; dry mouth, white patches in the mouth, pain or sensitivity to spicy foods; shortness of breath or changes seen on a chest x-ray; difficulty swallowing, painful swallowing, or weight loss; and fatigue, muscle weakness, or pain.

[0299] Disclosed herein are methods for treating a subject with GvHD by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed are methods for ameliorating, reducing, or preventing reactions associated with GvHD by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient. , as disclosed herein.

[0300] myositis Myositis is the general name for muscle inflammation.Myositis includes dermatomyositis; inclusion body myositis; juvenile myositis; and polymyositis.In some cases, myositis includes chronic progressive inflammation of muscle.Symptoms of myositis include one or more of the following: difficulty standing up; difficulty climbing stairs or lifting arms; fatigue after standing up or walking; difficulty swallowing or breathing; or muscle pain and pain that do not go away after several weeks.

[0301] Disclosed herein is a method of treating a subject with myositis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, reducing, or preventing reactions associated with myositis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0302] Felty syndrome Felty's syndrome (or Felty syndrome) is a rare autoimmune disease characterized by rheumatoid arthritis, an enlarged spleen, and a decrease in neutrophils (i.e., neutropenia). Additional symptoms of Felty syndrome include one or more of the following: fatigue, fever, weight loss, discolored patches on the skin, mild hepatomegaly (enlarged liver), lymphadenopathy (swollen lymph nodes), Sjögren's syndrome, vasculitis, and leg ulcers. The exact cause is unknown, but several risk factors, including autoimmunity, have been proposed.

[0303] Disclosed herein are methods of treating a subject with Felty syndrome by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods of ameliorating, alleviating, or preventing reactions associated with Felty syndrome by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0304] Adult-onset Still's disease Adult-onset Still's disease (AOSD) is a form of Still's disease and is a rare systemic autoinflammatory disease characterized by symptoms including one or more of fever, joint pain, sore throat, muscle pain, and a distinctive salmon-colored, bumpy rash. In some cases, a subject has only one episode of adult-onset Still's disease. In some cases, the condition is persistent or recurrent. The inflammation caused by AOSD can destroy affected joints, especially the wrist.

[0305] Disclosed herein is a method of treating a subject with AOSD by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with AOSD by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0306] Juvenile rheumatoid arthritis Juvenile rheumatoid arthritis (JRA; also known as juvenile idiopathic arthritis) is a form of arthritis in children. Subjects with JRA exhibit arthritis, inflammation, and joint stiffness. In some cases, subjects with JRA are between 6 weeks and 16 years of age. In some cases, JRA affects bone growth in growing children. In some cases, subjects experience symptoms of one or more joints; often a high fever and a skin rash. In some cases, the subject has oligoarticular JRA, which affects one to four joints in the first six months of the disease; in some cases, the subject has polyarticular JRA, which affects five or more joints in the first six months of the disease. In some cases, the subject has enthesitis-associated JRA, which shows arthritis and enthesitis. In some cases, the subject has psoriatic arthritis, which shows arthritis and psoriasis.

[0307] Disclosed herein is a method of treating a subject with juvenile rheumatoid arthritis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, alleviating, or preventing reactions associated with juvenile rheumatoid arthritis by administering to the patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0308] Hyper-IgE (hyperglobulinemia E) syndrome Hyper-IgE (hyperglobulinemia E) syndrome is a group of inherited immunodeficiency disorders characterized by recurrent inflammatory boils, sinus and lung infections, and severe rashes that appear in childhood. Hyper-IgE (hyperglobulinemia E) syndrome is a very rare immunodeficiency syndrome with multisystem involvement, including the immune system, skeleton, connective tissue, and dental development. Hyper-IgE (hyperglobulinemia E) syndrome is characterized by the classic triad of high serum levels of immunoglobulin E (IgE), recurrent staphylococcal cold skin abscesses, and recurrent pneumonia with pulmonary bullae formation. Most cases of hyper-IgE (hyperglobulinemia E) syndrome are sporadic, but it can be inherited as an autosomal dominant or autosomal recessive trait. Although the underlying immune defect in hyper-IgE (hyperglobulinemia E) syndrome is not clearly understood, abnormal neutrophil chemotaxis due to reduced interferon-γ production or secretion plays a major role in the immunopathogenesis of the syndrome, and a skewed Th1 / Th2 cytokine profile toward a Th2 bias also contributes to specific patterns of toxic cellular immunity and infectious disease susceptibility as well as the atopic-allergic predisposition of the syndrome.

[0309] Disclosed herein is a method of treating a subject with hyper-IgE (hyperglobulinemia E) syndrome by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein is a method of ameliorating, reducing, or preventing reactions associated with hyper-IgE (hyperglobulinemia E) syndrome by administering to the patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0310] Severe combined immunodeficiency disease (SCID) Severe combined immunodeficiency (SCID) is a group of rare disorders caused by mutations in various genes involved in development and the function of immune cells that fight infection. Infants with SCID appear healthy at birth but are highly susceptible to severe infections. The condition is usually fatal within the first year or two of life unless the infant receives treatment to correct the immune deficiency, such as hematopoietic stem cell transplantation, gene therapy, or enzyme therapy. More than 80 percent of SCID infants have no family history of the condition. However, the development of newborn screening tests has made it possible to detect SCID before symptoms appear, helping to ensure that patients receive life-saving treatment. Subjects with SCID have difficulty producing white blood cells and are less able to avoid infections, making them more susceptible to bacterial, viral, and fungal infections. In some cases, SCID is linked to the X chromosome. In some cases, SCID is ADA-deficient SCID.

[0311] The subject is administered an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Disclosed herein are methods of treating a subject with SCID by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient. Also disclosed herein are methods of ameliorating, reducing, or preventing reactions associated with SCID by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0312] Ophthalmic indications In some cases, methods of treating ocular-related indications are disclosed, including dry eye, blepharitis, blepharoconjunctivitis, cicatricial pemphigoid, Mooren corneal ulcer, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, anaphylactic lenticular endophthalmitis, keratoconjunctivitis sicca (KCS), or atopic keratoconjunctivitis (AKC).

[0313] Sjögren's syndrome The autoimmune disease known as Sjögren's syndrome or Sicca syndrome typically presents with dry eyes and dry mouth, combined with connective tissue disorders such as rheumatoid arthritis, lupus, scleroderma, or polymyositis. The majority of patients are middle-aged (or elderly) women. Sjögren's syndrome is an inflammatory disease of glands (e.g., lacrimal and salivary glands) and other tissues of the body. This syndrome is typically associated with autoantibody production.

[0314] Anti-IL-4Rα antibodies (e.g., dupilumab) can be administered to reduce inflammatory responses (such as inflammation of glands, including the lacrimal gland) in such patients. Anti-IL-4Rα antibodies (e.g., dupilumab) may be beneficial to patients with Sjögren's syndrome by suppressing TH2-type immune responses or by binding (and inactivating) excess IL-4 in inflammatory lesions. However, methods for treating patients according to the present disclosure are not limited by a particular mechanism of action.

[0315] Disclosed herein are methods for treating a subject with Sjogren's syndrome by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with Sjogren's syndrome by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0316] Autoimmune uveitis Autoimmune uveitis, or uveitis, involves inflammation of the uvea (generally considered collectively to include the iris, ciliary body, and choroid). Excessive IL-4 secretion has been implicated in contributing to the pathogenesis of this sight-threatening inflammatory eye disease. According to the present disclosure, an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is administered to a patient with uveitis to reduce the severity of the disease. In one embodiment, an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is administered to an individual with autoimmune uveoretinitis.

[0317] Disclosed herein are methods for treating a subject with autoimmune uveitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with autoimmune uveitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0318] giant papillary conjunctivitis Giant papillary conjunctivitis (GPC) is an allergic eye reaction that occurs when one or more small, rounded bumps (papillae) develop on the underside of the eyelid. In some cases, GPC is chronic. Symptoms of GPC include bumps that begin to form on the underside of the upper eyelid; itching; and redness of the eye. Symptoms include a feeling of a foreign body in the eye; redness of the eye; excess mucus; swelling; and blurred vision. In some cases, GPC is chronic.

[0319] Disclosed herein are methods for treating a subject with GPC by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with GPC by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0320] Disclosed herein are methods for treating a subject with chronic GPC by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with chronic GPC by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0321] Primary GPC includes atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). Secondary GPC is caused by ocular irritation (e.g., by contact lenses or sutures).

[0322] Atopic keratoconjunctivitis Atopic keratoconjunctivitis (AKC; also called atopic conjunctivitis) is the result of a condition called "atopy." Atopy is a genetic condition in which the immune system produces more antibodies than normal in response to a given allergen. AKC is a perennial (year-round) disease, but symptoms may worsen in the winter. Unlike atopic dermatitis, which is generally seen in early childhood, atopic keratoconjunctivitis appears during late adolescence and early adulthood. Men are more susceptible than women.

[0323] In AKC, the conjunctiva, which lines the eyelids, is usually red and swollen. The lower eyelid is generally more affected than the upper eyelid. This is different from vernal keratoconjunctivitis, in which the upper eyelid is most commonly affected. If left untreated, AKC can progress to ulcers, scarring, cataracts, keratoconus, and corneal neovascularization. Symptoms of AKC include sensitivity to light, itching, burning, tearing, and red, hardened eyelids.

[0324] Disclosed herein are methods for treating a subject with AKC, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing AKC-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0325] Spring conjunctivitis Vernal conjunctivitis is an inflammation of the outer membrane of the eye. In some cases, vernal conjunctivitis is chronic. In some cases, vernal conjunctivitis occurs due to an allergic reaction. In some cases, vernal conjunctivitis indicates asthma. In some cases, the onset of vernal conjunctivitis is seasonal. Vernal conjunctivitis indicates upregulation of IgE-mediated pathways. Subjects with vernal conjunctivitis exhibit symptoms of intense itching, lacrimation, mucous discharge, and severe photophobia.

[0326] Disclosed herein are methods for treating a subject with vernal conjunctivitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with vernal conjunctivitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0327] Eczematous dermatitis of the eyelids Eczematous dermatitis of the eyelid is a common condition in which the skin on or around the eyelid becomes dry, itchy, and inflamed. In some cases, eczematous dermatitis of the eyelid is caused by allergies. In some cases, eczematous dermatitis of the eyelid is caused by irritation. In some cases, eczematous dermatitis is caused by an inherent inflammatory reaction due to damage to the skin (e.g., eyelid). In some cases, subjects with eczematous dermatitis experience symptoms of itching, stinging, or burning, and the eyelids become red and scaly. In some cases, the eyelids become swollen. In some cases, the eyelids become thickened and the skin markings increase.

[0328] Disclosed herein are methods for treating a subject with eczematous dermatitis of the eyelid, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with eczematous dermatitis of the eyelid, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0329] scleritis Scleritis is inflammation of the sclera, the white outer wall of the eye that forms the white of the eye.Scleritis often causes red eye or infectious conjunctivitis, tearing, eye pain and sensitivity, and blurred vision.If left untreated, scleritis becomes a vision-threatening condition that can lead to permanent vision loss.In some cases, the subject with scleritis shows one or more of the following: systemic lupus erythematosus, arthritis, other types of inflammatory arthritis (ankylosing spondylitis, reactive arthritis, gouty arthritis, psoriatic arthritis, relapsing polychondritis), polyarteritis nodosa, mixed connective tissue disease, systemic progressive sclerosis (scleroderma), granulomatosis with polyangiitis, polymyositis, Sjogren's syndrome, giant cell arteritis, inflammatory bowel disease, and allergic vasculitis.

[0330] Disclosed herein are methods for treating a subject with scleritis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing scleritis-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a subject.

[0331] Esophageal indications In some cases, methods of treating esophagus-related indications, including Barrett's esophagus, eosinophilic esophagitis, achalasia, or gastroesophageal reflux disease (GERD), are disclosed.

[0332] Barrett's Esophagus Barrett's esophagus is a condition characterized by cellular changes (after stimulation) in the epithelial tissue lining the lower part of the esophagus. Frequent reflux of stomach contents into the esophagus can lead to Barrett's esophagus over time. Patients with Barrett's esophagus are at risk of developing esophageal cancer (e.g., adenocarcinoma). Without wishing to be bound by a specific mechanism of action, administration of an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) may be beneficial to patients with Barrett's esophagus by suppressing TH2-type immune responses.

[0333] Disclosed herein are methods for treating a subject with Barrett's esophagus, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with Barrett's esophagus, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are treatments in which an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is administered to a patient with esophagitis to inhibit progression to Barrett's esophagus.

[0334] Eosinophilic esophagitis Esophageal strictures (narrowing of the esophagus) result from damage to the lining of the esophagus and can result in, among other things, difficulty swallowing (dysphagia), regurgitation of food or liquids, heartburn, and unintended weight loss. Treatment of esophageal strictures is crucial because dysphagia, weight loss, and nutritional imbalances reduce quality of life. Esophageal strictures can be caused by chronic ulcers or chronic inflammation, or as a complication of chemotherapy, radiation therapy, esophageal cancer or endoscopic surgery, peptic ulcers, or gastroesophageal reflux. Esophageal strictures can also be caused by eosinophilic esophagitis.

[0335] As used herein, "eosinophilic esophagitis" (EoE) refers to an inflammatory disease characterized by abnormal eosinophilic inflammation and esophageal dysfunction within the esophagus. EoE is found to be associated with food allergies in many patients. Some patients may also have concurrent asthma or atopic diseases, such as atopic dermatitis or allergic rhinitis. Primary symptoms of EoE include, but are not limited to, chest and abdominal pain, dysphagia, heartburn, anorexia, vomiting, and food impaction. The clinical pathology of EoE is characterized by the presence of protuberances or trachea-like rings within the esophageal wall and eosinophilic infiltration within the esophageal mucosa. EoE is currently diagnosed by esophageal endoscopy, followed by microscopic and biochemical analysis of the esophageal mucosal lining. EoE is classified as allergic or non-allergic depending on the subject's condition. The present disclosure includes methods of treating both allergic and non-allergic forms of EoE by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0336] As used herein, the term "active EoE" refers to EoE disease in patients with 15 or more eosinophils per high-power field (hpf) in esophageal biopsies even after 8 weeks of treatment with a proton pump inhibitor (PPI). This term also refers to EoE disease in patients with frequent dysphagia, for example, patients with 2, 3, 4, 5, or more episodes of dysphagia per week. The term "active EoE" includes mild EoE and moderate to severe EoE. The term "moderate to severe" refers to EoE disease in patients with eosinophilia (e.g., 15 or more eosinophils per hpf in the esophageal mucosa) and frequent episodes of dysphagia, an SDI score of 2 or more, an EEsAI score of 30 or more, a duration of EoE of at least 2 years, and / or non-responsiveness or resistance to previous treatments (including PPIs or esophageal dilatation).

[0337] Disclosed herein are methods for treating a subject having at least one symptom or indication of EoE, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing a reaction associated with at least one symptom or indication of EoE, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). EoE is further disclosed in US9,290,574 B2 and US-2019-0040126-A1, which are incorporated by reference in their entireties.

[0338] Disclosed herein are methods for treating a subject with EoE, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with EoE, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0339] Eosinophilic gastritis Eosinophilic gastritis is a rare disease in which eosinophils, a type of white blood cell, cause damage and inflammation to the stomach. Symptoms associated with eosinophilic gastritis include vomiting, nausea, difficulty eating, and Symptoms include poor weight gain, poor growth, abdominal pain, anemia (low blood counts), and fatigue.

[0340] Eosinophilic gastroenteritis is a chronic condition. Mild, sporadic symptoms are managed with reassurance and observation, while disabling recurrence of gastrointestinal (GI) symptoms is often controlled with oral corticosteroids. If the disease manifests in infancy and specific food sensitization is identified, disease remission is likely by late childhood. Gastrointestinal obstruction is the most common complication.

[0341] Disclosed herein are methods for treating a subject having at least one symptom or indication of eosinophilic gastritis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing a response associated with at least one symptom or indication of eosinophilic gastritis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0342] Disclosed herein are methods for treating a subject with eosinophilic gastritis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with eosinophilic gastritis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0343] Skin-related indications In some cases, methods of treating skin-related indications are disclosed, including allergic contact dermatitis, dermatitis herpetiformis, dyshidrotic eczema, chronic hand eczema, nummular dermatitis, scleroderma, generalized scleroderma, dermatomyositis, epidermolysis bullosa, hypertrophic scars, hives, skin infections, alopecia areata, prurigo nodularis, bullous pemphigoid, or Netherton syndrome.

[0344] Allergic contact dermatitis (ACD) Allergic contact dermatitis (ACD) is a red, itchy rash caused by direct contact with or an allergic reaction to a substance (e.g., one or more chemicals). ACD can manifest as mild to severe, acute and short-term, or chronic. The rash is not contagious or life-threatening, but it can be very uncomfortable. Many substances, including soaps, cosmetics, fragrances, jewelry, and plants, can cause such a reaction. In some cases, allergic contact dermatitis (ACD) manifests as an adverse event associated with implanted medical devices containing allergenic substances, such as nickel. In some cases, ACD is caused by seasonal exposure. In some cases, ACD occurs due to contact with one or more of poison ivy, poison oak, or poison sumac. In some cases, subjects have been previously exposed and become sensitized to seasonal exposure substances after exposure to the toxic substance.

[0345] In some cases, the allergic contact dermatitis is chronic allergic contact dermatitis (CACD). In some cases, CACD is caused by adverse events associated with implanted medical devices over time. Chronic inflammation from metal joint replacements can cause complications at the implant site, primarily manifesting as chronic joint pain, swelling, loosening, and joint failure. In some cases, CACD is caused by complications from surgical wounds. In some cases, CACD is caused by sun exposure of a subject's skin. In some cases, subjects with ACD or CACD develop skin cancer. See, for example, Demehri et al., J Clin Invest. 2014 Nov 3;124(11):5037-5041, the entire contents of which are incorporated by reference.

[0346] Disclosed herein is a method of treating a subject with allergic contact dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with allergic contact dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0347] Disclosed herein are methods for treating a subject with chronic allergic contact dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with chronic allergic contact dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0348] dermatitis Dermatitis is a condition that has many causes and occurs in many forms. It is usually accompanied by a rash of itchy, dry skin or swollen, red skin. Or it may cause the skin to blister, ooze, crust, or peel. In some cases, the dermatitis is unspecified dermatitis. In some cases, the dermatitis is specified dermatitis.

[0349] Disclosed herein are methods for treating a subject with unspecified dermatitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with unspecified dermatitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0350] Disclosed herein are methods for treating a subject with unspecified dermatitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with specific dermatitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0351] dermatitis herpetiformis Dermatitis herpetiformis, also known as Dühring's disease, is a chronic skin condition characterized by blistering skin lesions, cutaneous IgA deposition, and itching. Patients have an immune-mediated bullous skin disorder with associated gluten-sensitive enteropathy, mediated by a Th2 immune response. Anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) are administered according to the present disclosure to inhibit IL-4 and Th2 responses, thereby promoting the healing of existing lesions and reducing or preventing the formation of blisters on the extensor body surface.

[0352] Disclosed herein are methods for treating a subject with dermatitis herpetiformis, comprising administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with dermatitis herpetiformis, comprising administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0353] nummular dermatitis Nummular eczema (also known as discoid eczema and nummular dermatitis) is a form of eczema that can occur at any age. The cause of nummular eczema (nummular dermatitis) is unknown, but it does not appear to run in families.

[0354] Known triggers for nummular eczema include injuries to the skin such as insect bites, scrapes and scratches, and chemical "burns," reactions to inflammation anywhere on the body (as with atopic dermatitis and / or stasis dermatitis); dry skin, especially in winter; and metals such as nickel. insufficient blood flow or swelling in the lower legs; and medications such as topical antibiotic creams, isotretinoin, and interferon.

[0355] Disclosed herein are methods for treating a subject with nummular dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with nummular dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0356] Eczematous and allergic dermatitis of the eyelids Eczematous dermatitis of the eyelid is a condition in which the skin on or around the eyelid becomes dry, itchy, and inflamed. Allergic dermatitis of the eyelid is an inflammatory reaction involving the skin of the eyelid caused by contact with a trigger substance (e.g., an allergy-inducing substance). It can be caused by allergy (allergic contact dermatitis) or irritation (irritant contact dermatitis). In some cases, dermatitis occurs on the upper eyelid. In some cases, dermatitis occurs on the lower eyelid. In some cases, dermatitis occurs on both the upper and lower eyelids.

[0357] Disclosed herein are methods for treating a subject with eczematous dermatitis of the eyelid by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with eczematous dermatitis of the eyelid by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0358] Also disclosed herein are methods for treating a subject with allergic dermatitis of the eyelid by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with allergic dermatitis of the eyelid by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0359] exfoliative dermatitis Exfoliative dermatitis is widespread erythema and scaling of the skin caused by a pre-existing skin disorder, drugs, cancer, or an unknown cause. Symptoms and signs include itching, diffuse erythema, and epidermal shedding. Exfoliative dermatitis is characterized by spotty and widespread redness and scaling of the skin. The skin begins to peel. This leads to problems with temperature regulation, loss of protein and fluid, and an increased metabolic rate.

[0360] Disclosed herein are methods for treating a subject with exfoliative dermatitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with exfoliative dermatitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0361] seborrheic dermatitis Seborrheic dermatitis is a skin condition that causes an itchy rash with flaky scales. It causes redness on lighter skin and light patches on darker skin. It is also called dandruff, cradle cap, seborrhea, seborrheic eczema, and seborrheic psoriasis. In some cases, seborrheic dermatitis is considered a chronic form of eczema. Seborrheic dermatitis appears on areas of the body with many sebaceous glands, such as the upper back, nose, and scalp. People of all ages, including infants (also known as "cradle cap"), can develop seborrheic dermatitis. However, it is most commonly It typically affects adults aged 30-60 years and infants under 3 months of age.

[0362] Disclosed herein are methods for treating a subject with seborrheic dermatitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with seborrheic dermatitis by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0363] epidermolysis bullosa Disclosed herein is a subject with epidermolysis bullosa. Epidermolysis bullosa is a group of rare diseases that cause fragile, blistered skin. In some cases, blisters appear in response to minor injuries, even heat, friction, scratches, or adhesive tape. In severe cases, blisters may occur internally, such as in the lining of the mouth or stomach. Symptoms of epidermolysis bullosa include one or more of the following: fragile skin prone to blistering, especially on the hands and feet; thick or non-forming nails; blisters in the mouth and throat; thickened skin on the palms and soles; cicatricial alopecia; atrophic skin scars; milia; tooth decay; difficulty swallowing; or itchy, painful skin. In some cases, epidermolysis bullosa develops during infancy or early childhood. In some cases, signs and symptoms appear during adolescence or early adulthood.

[0364] Disclosed herein are methods for treating a subject with epidermolysis bullosa by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with epidermolysis bullosa by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0365] Dyshidrosis and dyshidrotic eczema Dyshidrosis, or dyshidrotic eczema, is a distinct entity often considered a subtype of atopic dermatitis, primarily affecting the palms and soles. It is often associated with significant morbidity and is frequently difficult to treat. Due to its association with seasonal allergies, dyshidrotic eczema blisters are known to eruption more frequently during the spring allergy season. The blisters can last up to three weeks before beginning to dry and can sometimes be large and painful. As the blisters dry, they can transform into cracked skin or make the skin feel thick and spongy. Dyshidrotic eczema is also called palmoplantar dyshidrosis, dyshidrosis, palmoplantar eczema, dyshidrotic eczema, or vesicular eczema, or palmoplantar eczema. In some cases, dyshidrosis is dyshidrotic eczema. Dyshidrotic eczema is a chronic dermatitis characterized by itchy blisters on the palms and sides of the fingers, and sometimes on the soles of the feet.

[0366] Disclosed herein are methods for treating a subject with dyshidrosis or dyshidrotic eczema, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with dyshidrotic eczema, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0367] chronic hand eczema Chronic hand eczema is a frequent chronic inflammatory skin disease that can have a significant physical, mental, and social impact on daily activities. In chronic hand eczema, there is a close relationship between atopic dermatitis (involving approximately 70% of patients), sensitization to environmental antigens, and irritant triggers. Previously, the only systemic treatment indicated for chronic hand eczema, alitretinoin, was associated with moderate efficacy, high dropout rates due to adverse events, and strict adherence to its use in women of childbearing potential. Contraceptive measures are required.

[0368] Disclosed herein are methods for treating a subject with chronic hand eczema, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with chronic hand eczema, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0369] Scleroderma Anti-IL-4Rα antibodies (e.g., dupilumab) can be administered to scleroderma patients according to the present disclosure. They can reduce IL-4-induced collagen synthesis by the patient's fibroblasts. Anti-IL-4Rα antibodies (e.g., dupilumab) can be used to prevent or reduce fibrosis in skin and lung tissues, as well as other tissues where fibrosis occurs in scleroderma patients, inhibit collagen synthesis in such tissues, and treat scleroderma-associated lung disease.

[0370] Scleroderma can be localized scleroderma, an autoimmune disease in which the immune system causes inflammation in the skin. The inflammation can trigger connective tissue cells to overproduce collagen, a fibrous protein that is a major part of many tissues. The excess collagen can lead to fibrosis, which resembles scarring.

[0371] Localized scleroderma may be morphea, an autoimmune disease that causes a skin condition involving hard, thickened, reddish patches of skin in oval areas. The patches most often occur on the abdomen, stomach, and back, and occasionally on the face, arms, and legs.

[0372] Disclosed herein are methods for treating a subject with scleroderma, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing scleroderma-associated reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0373] Limited systemic sclerosis Limited systemic sclerosis, also known as CREST syndrome, is a subtype of scleroderma.In some cases, the skin changes associated with limited systemic sclerosis typically occur only on the forearms and lower legs, below the elbows and knees, and sometimes affect the face and neck.In some cases, limited systemic sclerosis can also affect the digestive tract, heart, lungs or kidneys.In some cases, the symptoms of limited systemic sclerosis include, but are not limited to, tight, hard skin; Raynaud's phenomenon; red spots or lines on the skin; protrusions under the skin; and difficulty swallowing.

[0374] Disclosed herein are methods for treating a subject with limited systemic sclerosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with limited systemic sclerosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0375] systemic sclerosis Systemic sclerosis, including diffuse systemic sclerosis, is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (particularly the esophagus, lower gastrointestinal tract, lungs, heart, and kidneys). In some cases, systemic sclerosis includes localized systemic sclerosis, generalized systemic sclerosis with diffuse skin involvement, and systemic sclerosis without scleroderma. This includes systemic sclerosis sine scleroderma. Patients with localized systemic sclerosis (CREST syndrome - calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) develop skin tightening on the face and distal elbows and knees and may also have gastroesophageal reflux disease. This form is characterized by slow progression and is often complicated by pulmonary hypertension. In generalized systemic sclerosis with diffuse skin involvement, patients have Raynaud's phenomenon and gastrointestinal (GI) complications. This form typically develops rapidly. Interstitial lung disease and scleroderma renal crisis are major complications. In systemic sclerosis without scleroderma, patients have systemic sclerosis-related antibodies and visceral symptoms of the disease but lack skin tightening.

[0376] Disclosed herein are methods for treating a subject with systemic sclerosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with systemic sclerosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0377] Disclosed herein are methods for treating a subject with diffuse systemic sclerosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with systemic sclerosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0378] hypertrophic scar Anti-IL-4Rα antibodies (e.g., dupilumab) can be administered to patients with hypertrophic scars or who are prone to developing hypertrophic scars. For example, anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can be administered to patients with burns. Immune responses to burns and other injuries are thought to contribute to the pathogenesis of hypertrophic scars. Increased production of TH2-type cytokines, including IL-4, and decreased levels of certain TH1-type cytokines have been reported in burn patients with hypertrophic scars. The use of anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can be beneficial to patients with (or at risk of developing) hypertrophic scars by suppressing TH2-type immune responses.

[0379] Disclosed herein are methods for treating a subject with hypertrophic scars, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with hypertrophic scars, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0380] hives Urticaria (e.g., skin rash), particularly its chronic form such as chronic idiopathic urticaria (CIU), can be treated with an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) according to the present disclosure. CIU patients may have higher serum IL-4 levels than controls and a predominantly TH2-type cytokine profile. Mast cells and Th2-type T cells are involved as primary effector cells in chronic urticaria. IL-4 stimulates mast cell proliferation. Mast cell degranulation leads to histamine release, followed by erythema, eosinophilia, skin redness, and itching. In some embodiments, an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is administered to inhibit IL-4 and reduce the TH2-type response, thereby helping to control urticaria in patients.

[0381] administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab); Disclosed herein are methods for treating a subject with chronic idiopathic urticaria (CSU), comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with chronic idiopathic urticaria (CSU), comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). In some embodiments, a patient with CSU has the presence of itching and a rash for more than six consecutive weeks at any time prior to enrollment despite current use of an H1 antihistamine; an Urticaria Activity Score UAS7 score of 16 or greater (range 0-42); and / or has been diagnosed with CSU for at least six months.

[0382] Disclosed herein is a method for treating a subject with cholinergic urticaria (CholU), comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed is a method for reducing, ameliorating, or preventing reactions associated with cholinergic urticaria (CholU), comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). CholU is a type of physical hives (or skin rash) that appears when a person is sweating or has an increased core body temperature. CholU is a type of physical hives characterized by small, itchy welts that follow sweating events, including elevated body temperature, physical exercise, eating spicy foods, and emotional stress.

[0383] Disclosed herein are methods for treating a subject who has CholU and is symptomatic despite H1-antihistamine treatment, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing a CholU-associated reaction that is symptomatic despite H1-antihistamine treatment, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). In some embodiments, an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is administered to a subject who has cholinergic urticaria (CholU) and is symptomatic despite H1-antihistamine treatment.

[0384] Disclosed herein are methods for treating a subject with urticaria, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing urticaria-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0385] Chronic induced urticaria (CIndU) Disclosed herein is a method for treating chronic induced urticaria (CIndU).In some cases, CIndU is chronic urticaria, which has a causative factor or triggering factor and is classified according to the stimulus that causes welts to appear.In some cases, these stimuli that cause welts to appear include rubbing or scratching the skin (dermatographism), exercise, and emotional upset (cholinergic urticaria).In some cases, CIndU is triggered by one or more of cold, heat, pressure, sunlight (for example, in solar urticaria), contact with water or various chemicals (contact urticaria), or vibration.

[0386] In some cases, CIndU exhibits a welt. In some cases, the welt appears anywhere on the body. In some cases, the welt is a few millimeters (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, or 50 mm). In some cases, the welt is about 1, 2, 3, 4, 5 cm, or more. In some cases, the welt appears as white or red, and is often surrounded by a red flare. In some cases, the welt appears within a few minutes (e.g., about 1, 2, 3, 4, 5, 10, or 20 minutes) after stimulation. In some cases, the welt lasts from a few minutes (e.g., about 5, 10, 15, 20, 25, 30, or 45 minutes) to several hours (e.g., about 1, 2, 3, 4, 5 hours, or more). In some cases, the welts are circular. In some cases, the welts form a ring shape.

[0387] Disclosed herein are methods for treating a subject with CIndU, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing CIndU-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0388] Solar urticaria Solar urticaria is a rare condition in which exposure to ultraviolet or UV radiation, or sometimes even visible light, induces cases of hives or a skin rash that can appear on both covered and uncovered areas of the skin. In some cases, a stinging, itchy rash develops within minutes after a brief exposure. In some cases, the rash may look like welts. In some cases, the rash becomes red and / or swollen. In some cases, when large areas of the body are affected, loss of fluid to the skin can lead to lightheadedness, headache, nausea, and vomiting. In some cases, solar urticaria is IgE-mediated.

[0389] Disclosed herein are methods for treating a subject with solar urticaria, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with solar urticaria, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0390] Skin infections (common) Skin infections commonly occur at sites of skin damage caused by, for example, atopic dermatitis, burns, cracked skin, cuts, blisters, insect bites, surgical wounds, intravenous drug injection or intravenous catheter insertion sites, or long-term use of topical steroids. Skin infections can be localized or diffuse, with severe inflammation of the epidermis, dermis, and subcutaneous layers of the skin. They are caused by a variety of microorganisms, including, but not limited to, Staphylococcus aureus, Streptococcus spp., Pseudomonas aeruginosa, Bacteroides spp., herpes simplex virus, coxsackievirus, molluscum contagiosum virus, vaccinia virus, Candida albicans, fungi such as Microsporum spp., and Trichophyton spp., Penicillium spp., Cladosporium spp., Alternaria spp., and Aspergillus spp. Treatment of skin infections is disclosed in US 10,370,449 B2, which is incorporated by reference in its entirety.

[0391] Disclosed herein are methods for treating a subject with a skin infection, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with a skin infection, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0392] Alopecia areata Alopecia areata is a medical condition that causes hair to fall out in patches. Hair can fall out on the scalp or face and other parts of the body. Alopecia areata is an autoimmune condition, meaning the immune system recognizes hair follicles as foreign and attacks them, causing circular patches of hair loss. Alopecia areata is a genetic skin disease that can progress to total scalp hair loss (alopecia totalis) or complete body hair loss (alopecia universalis). The scalp is the most commonly affected area, but the beard or any hair-bearing area may be affected alone or in combination with the scalp. Alopecia areata occurs in men and women of all ages and is a highly unpredictable condition that tends to recur.

[0393] Disclosed herein is a method for treating a subject with alopecia areata, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed is a method for alleviating, ameliorating, or preventing reactions associated with alopecia areata, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0394] Disclosed herein are methods for treating a subject with moderate to severe alopecia areata involving 30-100% of the scalp, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with moderate to severe alopecia areata involving 30-100% of the scalp, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0395] Disclosed herein is a method for treating a subject with alopecia areata and atopic dermatitis (AD) by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed is a method for alleviating, ameliorating, or preventing reactions associated with alopecia areata and AD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0396] Disclosed herein is a method for treating a subject with alopecia areata but without AD by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed is a method for reducing, ameliorating, or preventing reactions associated with alopecia areata without AD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0397] cicatricial alopecia Scarring alopecia, also known as scarring alopecia, scarring alopecia or scarring alopecia planus, is a disease that involves the destruction of hair follicles and their replacement with scar tissue, resulting in permanent hair loss.In some embodiments, hair follicles are the target of destructive inflammatory process.In some embodiments, the destruction of hair follicles is accompanied by the process or trauma that is not directed at hair follicles, such as severe infection, burn, radiation or tumor.In some cases, hair loss is asymptomatic, gradual, and can go unnoticed for a long time.

[0398] In some cases, inflammation occurs at the site of cicatricial alopecia. In some cases, inflammation is primarily accompanied by lymphocyte or neutrophil infiltration. Cicatricial alopecia with primarily lymphocytic inflammation includes lichen planopilaris, frontal fibrosing alopecia, parietal centrifugal alopecia, and atrophic alopecia (Brocq). Cicatricial alopecia caused primarily by neutrophilic inflammation includes bald folliculitis and tufted folliculitis. Sometimes, inflammation shifts from primarily neutrophilic processes to lymphocytic processes. Cicatricial alopecia with mixed inflammatory infiltration includes dissecting cellulitis and capillary papillary dermatitis.

[0399] Disclosed herein is a method for treating a subject with cicatricial alopecia by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed is a method for reducing, ameliorating, or preventing reactions associated with cicatricial alopecia, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). .

[0400] Prurigo nodularis Prurigo nodularis (PN) is a skin disorder that causes hard, itchy lumps (nodules) to form on the skin. The itching (pruritus) can be intense, causing people to scratch themselves until bleeding or pain occurs. Scratching can cause additional skin lesions to appear. The itching is worsened by heat, sweating, or irritation from clothing. In some cases, people with PN have a history of other diseases, including eczema (atopic dermatitis), lymphoma, HIV infection, severe anemia, or kidney disease.

[0401] The diagnosis of PN is based on the observation of symptoms such as extremely itchy skin with the formation of nodules. In some cases, a skin biopsy is used to confirm the diagnosis. Treatment includes corticosteroid creams, oral medications, cryotherapy, or photochemotherapy.

[0402] Disclosed herein are methods for treating a subject with PN, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing PN-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0403] Chronic pruritus of unknown etiology (CPUO) Chronic pruritus of unknown cause (CPUO; also known as chronic idiopathic pruritus of unknown cause and generalized pruritus) manifests as itching that persists for a period of time (e.g., longer than 4, 5, 6, or more weeks) in the absence of a known cause. In some cases, the pruritus of CPUO is localized. In some cases, the pruritus of CPUO is generalized. In some cases, the skin of a subject with CPUO appears normal. In some cases, the skin of a subject with CPUO appears erythematous, rough, or bumpy. Repeated scratching can lead to secondary skin changes, such as lichenification (thickening, hyperpigmentation, and increased skin markings), bleeding, or localized secondary bacterial infection. In some cases, CPUO presents with one or more skin changes selected from localized thickened plaques (lichen simplex, a type of eczema); prurigo nodularis, characterized by pruritic nodules 10-20 mm in diameter; impetigo resulting from secondary bacterial infection after scratching, or any combination thereof.

[0404] Disclosed herein are methods for treating a subject with CPUO, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with CPUO, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0405] Bullous pemphigoid Bullous pemphigoid is a rare skin condition that causes large, fluid-filled blisters. They often develop in areas of the skin that flex, such as the lower abdomen, upper thighs, or armpits. Bullous pemphigoid is most common in older people.

[0406] Bullous pemphigoid occurs when the immune system attacks a thin layer of tissue beneath the outer layer of skin. The reason for this abnormal immune response is unknown, but it is sometimes triggered by taking certain medicines.

[0407] Bullous pemphigoid often goes away on its own within a few months, but it can take as long as five years to resolve. Treatment usually helps heal the blisters and relieves any itching. This includes corticosteroid medications, such as prednisone, and other drugs that suppress the immune system. Bullous pemphigoid can be life-threatening, especially for older people who are already in poor health. It could be threatening.

[0408] Symptoms of bullous pemphigoid include one or more of the following: itchy skin weeks or months before the blisters form; large blisters that do not easily burst when touched, often along skin creases or folds; normal, reddish, or darker-than-normal skin around the blisters; eczema or a honeycomb rash; and / or small blisters or sores inside the mouth or other mucous membranes (benign mucous membrane pemphigoid).

[0409] Disclosed herein are methods for treating a subject with bullous pemphigoid, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with bullous pemphigoid, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0410] Netherton syndrome Netherton syndrome is a disorder that affects the skin, hair, and immune system. Newborns with Netherton syndrome have red, scaly skin (ichthyosiform erythroderma), and the skin may leak fluid. Some affected infants are born with a taut, transparent sheath covering the skin called a collodion membrane. This membrane usually falls off during the first few weeks of life. Because newborns with this disorder lack the protection that normal skin provides, they become dehydrated and are at risk of developing skin or systemic infections (sepsis), which can be life-threatening. Affected babies may also fail to grow and gain weight at the expected rate (failure to thrive). The health of older children and adults with Netherton syndrome usually improves, but they are often underweight and short.

[0411] After childhood, the severity of skin abnormalities varies among people with Netherton syndrome and may fluctuate over time. The skin may continue to become red and scaly, especially during the first few years of life. Some affected individuals experience the development of a unique skin abnormality called flexural linear ichthyosis, which has intermittent redness or patches of multiple circular lesions. The triggering factor for the development is unknown, but researchers suggest that stress or infection may be involved.

[0412] Itching is a common problem for affected individuals, and scratching can lead to frequent infections. Dead skin cells shed at an abnormal rate and often accumulate in the ear canal, potentially affecting hearing if not removed regularly. The skin absorbs substances such as lotions and ointments abnormally, potentially resulting in excessive blood levels of some topical medications. Because the skin's ability to protect against heat and cold is impaired, affected individuals may have difficulty regulating their body temperature.

[0413] People with Netherton syndrome have brittle, easily broken hair. Some hairs vary in diameter, with thicker and thinner areas. This configuration is known as bamboo hair, trichorrhexis nodosa, or intussusceptible trichorrhexis. In addition to scalp hair, eyelashes and eyebrows may also be affected. Hair abnormalities in Netherton syndrome are often not noticeable during infancy because babies often have thin hair.

[0414] Most people with Netherton syndrome have problems related to the immune system, such as food allergies, hay fever, asthma, or an inflammatory skin disorder called eczema.

[0415] Disclosed herein are methods for treating a subject with Netherton syndrome, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with Netherton syndrome, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0416] Atopic dermatitis (AD) Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaly, dry eczematous lesions. AD is often associated with other atopic disorders, such as allergic rhinitis and asthma.

[0417] The pathophysiology of AD is influenced by a complex interplay between immunoglobulin E (IgE)-mediated sensitization, the immune system, and environmental factors. Primary skin defects can be immunological disorders that cause IgE-mediated sensitization, with epithelial barrier dysfunction resulting from both genetic mutations and local inflammation. AD often begins in childhood, before the age of 5, and can continue into adulthood.

[0418] Disclosed herein are methods for treating a subject having symptoms of AD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). In some embodiments, the AD is not moderate to severe atopic dermatitis. Disclosed herein are methods for treating an adult subject with AD (but not moderate to severe atopic dermatitis). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with symptoms of AD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Treatments for AD are disclosed in US-2017-0333557-A1 and US 10,370,449 B2, each of which is incorporated by reference in its entirety.

[0419] Also disclosed herein are methods for treating patients with severe AD that is resistant to treatment or inadequately controlled by systemic therapy (including systemic immunosuppressants). In some cases, the present disclosure includes methods for treating patients with severe AD that is uncontrolled despite treatment with a systemic therapeutic agent. In some cases, the present disclosure includes methods for treating patients with severe AD for which treatment with a systemic therapeutic agent (e.g., a systemic immunosuppressant) is medically inadvisable.

[0420] Disclosed herein are methods for treating a subject with severe AD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with severe AD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). In other embodiments, the anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) is administered in combination with a topical therapy (such as a topical corticosteroid or a topical calcineurin inhibitor). In certain embodiments, the systemic therapeutic agent is an immunosuppressant selected from cyclosporine A, methotrexate, mycophenolate mofetil, azathioprine, oral corticosteroids, and / or interferon-gamma. Methods for treating a subject who does not adequately respond to systemic therapy are further disclosed in US-2018-0078603-A1, which is incorporated by reference in its entirety.

[0421] Ichthyosis and congenital ichthyosis Ichthyosis is a family of inherited skin disorders characterized by dry, scaling skin that can thicken or become very thin. Ichthyosis usually appears at birth or within the first year of life and continues to affect patients throughout their lives. Congenital ichthyosis is an autosomal recessive disorder (also called autosomal recessive congenital ichthyosis (ARCI)) that includes a heterogeneous group of keratinization disorders primarily characterized by abnormal desquamation of the skin over the entire body. In some cases, individuals with congenital ichthyosis The main skin phenotypes in subjects with congenital ichthyosis are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE). In some cases, subjects with congenital ichthyosis have scales covering the entire body surface, including flexural folds, and the scales vary greatly in size and color. In some cases, the erythema is very mild and barely visible. In some cases, subjects with congenital ichthyosis exhibit cicatricial alopecia, and many have secondary anhidrosis. In some cases, the ichthyosis includes one or more of ichthyosis vulgaris, lamellar ichthyosis, epidermolytic hyperkeratosis, congenital ichthyosiform erythroderma, or X-linked ichthyosis.

[0422] Disclosed herein are methods for treating a subject with ichthyosis or congenital ichthyosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with ichthyosis or congenital ichthyosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0423] erythema nodosum Erythema nodosum is a type of skin inflammation located in the fatty layer of the skin. It is characterized by soft, red bumps, usually symmetrically located on the shins; fever; joint pain; and enlarged lymph nodes in the chest. Erythema nodosum may also indicate other conditions, including streptococcal infection, sarcoidosis, coccidioidomycosis, histoplasmosis, tuberculosis, psittacosis, ulcerative colitis or Crohn's disease, cancer, and pregnancy. In some cases, erythema nodosum is acute. In other cases, erythema nodosum is chronic.

[0424] Disclosed herein are methods for treating a subject with erythema nodosum, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with erythema nodosum, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0425] Pyoderma gangrenosum Pyoderma gangrenosum is a rare condition that often causes large, painful ulcers to develop on the skin. Classic pyoderma gangrenosum can occur on any skin surface. In some cases, the ulcers develop on the subject's legs. In some cases, pyoderma gangrenosum begins as a small, red bump on the skin that may resemble a spider bite. In some cases, within a few days, this bump can develop into a large, painful open wound. In some cases, pyoderma gangrenosum is chronic. In some cases, subjects with pyoderma gangrenosum exhibit fever and / or joint pain.

[0426] Disclosed herein are methods for treating a subject with pyoderma gangrenosum, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with pyoderma gangrenosum, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0427] erythema multiforme Erythema multiforme (EM) is an acute, sometimes self-limited, sometimes recurrent skin condition associated with certain infections and various other triggers. In some cases, EM is a skin condition caused by a hypersensitivity reaction to an infection or drug. It consists of a polymorphous rash of macules, papules, and characteristic "target" lesions that tend to be symmetrically distributed on the distal extremities. Minimal mucosal involvement is present.

[0428] administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab); Disclosed herein are methods for treating a subject with EM, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with EM, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0429] hemangioma Hemangiomas of the skin and subcutaneous tissue are benign lesions with an increased number of blood vessels on or below the surface of the skin. Cutaneous hemangiomas are generally deep red or bluish purple in color. They appear as raised lesions or tumors on the skin. The deeper the hemangioma, the darker its color. Hemangiomas can affect many tissue types (individually or in combination), including skin, subcutaneous tissue, internal organs, muscle, synovium, and bone. In some cases, hemangiomas do not spread to avascular tissues such as cartilage. In some embodiments, hemangiomas occur in infants. In some embodiments, hemangiomas occur in premature or low birth weight infants.

[0430] Disclosed herein are methods for treating a subject with a hemangioma of the skin and / or subcutaneous tissue, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with a hemangioma of the skin and / or subcutaneous tissue, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0431] lichen planus Lichen planus is a condition that can cause swelling and inflammation in skin, hair, nails and mucous membranes.On the skin, lichen planus usually appears as purplish, itchy, flat bumps that develop over several weeks.In the mouth, vagina, and other areas covered by mucous membranes, lichen planus forms lace-like white spots, sometimes painful sores.In some cases, the subject with lichen planus shows one or more of the following symptoms: purplish, flat bumps, most often on the inner forearm, wrist or ankle, and sometimes on the genitals; itching; blisters that break and form scabs or crusts; lace-like white spots in the mouth or on the lip or tongue; painful sores in the mouth or vagina; hair loss; scalp color change; and / or nail damage or loss. In some cases, lichen planus is triggered by hepatitis C infection, influenza vaccines, certain dyes, chemicals, and metals; painkillers such as ibuprofen and naproxen, and certain medicines for heart disease, high blood pressure, or arthritis.

[0432] Disclosed herein are methods for treating a subject with lichen planus, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with lichen planus, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0433] Facial granuloma Facial granuloma is a rare, benign skin condition characterized by single or multiple erythematous (red) papules, plaques, or nodules. In some cases, facial granuloma is characterized by chronic leukocytoclastic vasculitis with a dense infiltrate of polymorphonuclear vesicles. In some cases, facial granuloma affects the facial area of ​​a subject. In some cases, subjects with facial granuloma develop single or multiple skin nodules in sun-exposed areas.

[0434] Disclosed herein are methods for treating a subject with facial granuloma, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with facial granuloma, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0435] exfoliative dermatitis Exfoliative dermatitis (also called erythroderma) is widespread erythema and scaling of the skin. In some cases, exfoliative dermatitis involves redness and peeling of the skin over large areas of the body. In some cases, it is caused by a pre-existing skin disorder, a drug, or cancer. In some cases, symptoms and signs are itching, diffuse erythema, epidermal shedding, discomfort, and chills. In some cases, the diffuse erythema begins in patches but spreads to involve all or nearly all of the body. In some cases, widespread epidermal shedding leads to abnormal thermoregulation, nutritional deficiencies due to widespread protein loss, increased metabolic rate with a hypercatabolic state, and hypovolemia due to transcutaneous fluid loss.

[0436] Disclosed herein are methods for treating a subject with exfoliative dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with exfoliative dermatitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0437] Eccrine sweat disorder Eccrine sweat disorders are a group of dysregulation disorders of the human body's primary sweat glands (i.e., eccrine sweat glands). Eccrine sweat glands are found in virtually all skin, with the highest density on the palms and soles, followed by the head, but rarely on the trunk and extremities. Eccrine sweat glands are sympathetically innervated, distributed throughout the body, and active from birth. Their secretions are watery and help cool the body in hot environments or during activity. Eccrine sweat disorders include, but are not limited to, hyperhidrosis, hypohidrosis, and miliaria. In some cases, alterations in the electrolyte composition of eccrine sweat are observed in several systemic diseases, most notably cystic fibrosis.

[0438] Disclosed herein are methods for treating a subject with an eccrine sweat disorder, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with an eccrine sweat disorder, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0439] Non-suppurative otitis media Non-suppurative otitis media, also known as acute otitis media (AOM) or secretory otitis media, is otitis media that involves leakage of fluid into the middle ear without suppuration. In some cases, subjects with non-suppurative otitis media are children.

[0440] Disclosed herein are methods for treating a subject with non-suppurative otitis media, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with non-suppurative otitis media, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0441] acne Acne is a skin condition that occurs when hair follicles become clogged with oil and dead skin cells. This often results in whiteheads, blackheads, or pimples, which usually appear on the face, forehead, chest, upper back, and shoulders. Acne affects people of all ages, but is most common among teenagers. In some cases, acne can cause emotional distress and skin scarring. Symptoms associated with acne include whiteheads (closed, clogged pores), ); blackheads (open, clogged pores); small, red, soft bumps (papules); whiteheads (pustules), which are papules with pus at the top; large, painful, solid lumps (nodules) under the surface of the skin; and painful, pus-filled lumps (cystic lesions) under the surface of the skin.

[0442] Disclosed herein are methods for treating a subject with acne, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing acne-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0443] Pityriasis rosea Pityriasis rosea (or pityriasis rosea; or rosea) is a rash that usually begins as large, round or oval spots on the chest, abdomen, or back. In some cases, the spots can be up to 4 inches (10 centimeters) in diameter.

[0444] In some cases, pityriasis rosea begins with large, slightly raised, scaly patches called herald patches on the back, chest, or abdomen. In some cases, before the herald patches appear, the subject experiences headache, fatigue, fever, or sore throat. In some cases, several days to weeks after the herald patches appear, the subject develops smaller, scaly dots resembling a pine tree pattern across the back, chest, or abdomen. In some cases, the rash causes itching, which can sometimes become severe. In some cases, pityriasis rosea is triggered by a viral infection. In some cases, the viral infection is caused by a herpes virus.

[0445] Disclosed herein are methods for treating a subject with pityriasis rosea, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with pityriasis rosea, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0446] Melanocytic nevus Melanocytic nevi are benign neoplasms or hamartomas composed of melanocytes. In some cases, subjects with melanocytic nevi are disclosed herein. Melanocytic nevi can be congenital or acquired. Melanocytic nevi are neoplasms resulting from the proliferation of melanocytes, the normal pigment-producing cells in the skin. Nevi are growth-arrested clonal neoplasms of melanocytes that initiate from a clearly defined oncogenic mutation in the mitogen-activated protein kinase (MAPK) pathway, most commonly the BRAFV600E activating mutation. Furthermore, they are naturally pigmented and located in the skin, making them easily identifiable by visual inspection and allowing for real-time monitoring.

[0447] Disclosed herein are methods for treating a subject with melanocytic nevus by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with melanocytic nevus by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0448] Itching Pruritus (e.g., itchy skin) is defined as a cutaneous discomfort that provokes the urge to scratch. It is a characteristic feature of many skin disorders and an unusual manifestation of some systemic diseases. In some cases, pruritus is localized. In some cases, pruritus is generalized. In some cases, pruritus is an acute condition. In some cases, pruritus is a chronic condition. Itching is a common symptom of dermatological diseases, including eczema, atopic dermatitis, and allergic contact dermatitis.

[0449] Disclosed herein are methods for treating a subject with pruritus by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing pruritus-related responses by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0450] vitiligo Vitiligo is a long-term skin condition characterized by patches of skin that have lost pigment. The affected patches of skin turn white and usually have sharp edges. In some cases, the hair from the skin of a subject with vitiligo turns white. In some cases, the inside of the mouth and nose turn white. Usually, hair and skin color is determined by melanin. Vitiligo occurs when skin or hair cells stop producing melanin or reduce the amount of melanin they produce. In some cases, discoloration first appears in areas exposed to sunlight, such as the hands, feet, arms, face, and lips. In some cases, subjects under the age of 20 exhibit vitiligo.

[0451] Disclosed herein are methods for treating a subject with vitiligo by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing vitiligo-related reactions by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0452] Nevus not otherwise classified Phacomats are a group of neurocutaneous disorders characterized by the involvement of structures arising from the embryonic ectoderm. They are a heterogeneous group of disorders primarily involving structures derived from the embryonic neuroectoderm. However, they commonly exhibit pathology related to tissues derived from all three germ cell layers, most notably the ectoderm (skin) and mesoderm (connective tissue). All phacomats involve the central nervous system (CNS); some also affect the peripheral nervous system. Most are associated with cutaneous manifestations, and many have alterations of the visceral and connective tissues (mesoderm).

[0453] Disclosed herein is a method for treating a subject with one or more unclassified nevus diseases by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to the subject. Also disclosed herein is a method for reducing, ameliorating, or preventing reactions associated with one or more unclassified nevus diseases by administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) to a patient.

[0454] Stevens-Johnson syndrome Stevens-Johnson syndrome (STS) is a rare, serious disorder of the skin and mucous membranes. It is typically a reaction to a medication or an infection. It often begins with flu-like symptoms, followed by a painful, spreading red or purplish rash and the development of blisters. The top layer of the affected skin then dies, peels, and heals. Symptoms associated with STS include fever; unexplained, widespread skin pain; a widespread red or purple skin rash; blisters on the skin and mucous membranes of the mouth, nose, eyes, and genitals; and peeling of the skin within a few days after the blisters form.

[0455] Disclosed herein are methods for treating a subject with Stevens-Johnson syndrome by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with Stevens-Johnson syndrome by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0456] Gastrointestinal indications Disclosed are methods of treating gastrointestinal-related indications, including gastrointestinal-related disorders that in some cases are ulcerative colitis, Whipple's disease, Behcet's disease, Wegener's granulomatosis, or GERD.

[0457] ulcerative colitis IL-4 is involved in the pathogenesis of ulcerative colitis. Th2 cytokines, including IL-4, may be predominant in the colonic mucosa of patients with this disorder. The use of anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) to suppress TH2 responses can alleviate this condition.

[0458] In addition to ulcerative colitis, other disorders of the gastrointestinal tract or digestive system can be treated with anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab). Examples of such disorders include, but are not limited to, inflammatory bowel disease (IBD), of which ulcerative colitis and Crohn's disease are forms, gastritis, ulcers, and mucosal inflammation.

[0459] Any gastrointestinal condition in which IL-4 plays a role can be treated with an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab) in accordance with the present disclosure. For example, conditions involving IL-4-induced inflammation of a portion of the gastrointestinal tract can be treated with an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Certain embodiments are directed to the treatment of chronic inflammatory conditions in the gastrointestinal tract.

[0460] Other embodiments are directed to conditions in which IL-4-induced barrier disruption plays a role, e.g., conditions characterized by reduced epithelial barrier function in at least a portion of the gastrointestinal tract. Such conditions may involve, for example, damage to the epithelium induced directly or indirectly by IL-4.

[0461] The intestinal epithelium forms a relatively impermeable barrier between the lumen and the submucosa. Disruption of the epithelial barrier is associated with conditions such as inflammatory bowel disease. See the discussion in Youakim, A. and M. Ahdieh (Am. J. Physiol. 276 (Gastrointest. Liver Physiol. 39): G1279-G1288, 1999), which is incorporated herein by reference in its entirety. A damaged or "leaky" barrier can allow antigens to cross the barrier, which in turn elicits an immune response that can cause further damage to gastrointestinal tissue. Such an immune response can include, for example, the recruitment of neutrophils or T cells. Anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) can be administered to inhibit undesired stimulation of the immune response.

[0462] Colitis is a chronic digestive system disease characterized by inflammation of the lining of the colon. Infection, loss of blood supply to the colon, inflammatory bowel disease (IBD), and infiltration of the colon wall with collagen or lymphocytic leukocytes are all possible causes of an inflamed colon.

[0463] In some cases, the colitis is viral colitis. In some cases, the colitis is bacterial colitis. In some cases, the colitis is caused by an allergic reaction. In some cases, colitis is caused by a reaction to food.

[0464] Disclosed herein are methods for treating a subject with colitis by administering to the subject an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed herein are methods for reducing, ameliorating, or preventing reactions associated with colitis by administering to a patient an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0465] Also disclosed herein are methods for treating a subject with ulcerative colitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with ulcerative colitis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0466] Whipple disease Tropheryma whippelii is the bacterial causative agent of Whipple's disease, also known as intestinal lipodystrophy and lipophagia granulomatosis. This disease is characterized by steatorrhea, frequent generalized lymphadenopathy, arthritis, fever, and cough. Patients with Whipple's disease have also been reported to have abundant "foamy" macrophages in the jejunal lamina propria and lymph nodes containing periodic acid-Schiff-positive particles that appear rod-shaped by electron microscopy (Steadman's Medical Dictionary, 26th ed., Williams & Wilkins, Baltimore, Md., 1995).

[0467] The use of anti-IL-4R antibodies (e.g., anti-IL-4Rα antibodies, e.g., dupilumab) may benefit patients with (or at risk of developing) Whipple's disease by restoring the normal balance between the TH1 and TH2 components of the patient's immune response. Increased production of IL-4 (a TH2-type cytokine) and decreased levels of certain TH1-type cytokines are associated with Whipple's disease. While TH2 cytokines may contribute to bacterial persistence, TH1 responses play a role in eliminating pathogenic bacteria. Anti-IL-4Rα antibodies (e.g., dupilumab) can be administered to patients infected with T. whipplei, regardless of whether the patient exhibits clinical symptoms of Whipple's disease.

[0468] Disclosed herein are methods for treating a subject with Whipple's disease, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with Whipple's disease, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0469] Behçet's disease Behçet's disease, or Behçet's syndrome, is a rare disorder that causes vascular inflammation. Behçet's disease presents with a variety of signs and symptoms, including abdominal pain, diarrhea, and bleeding in the digestive system.

[0470] Disclosed herein are methods for treating a subject with Behçet's disease, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with Behçet's disease, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0471] Wegener's granulomatosis Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)) is a rare multisystem autoimmune disease. Its hallmarks include necrotizing granulomatous inflammation and pauci-immune vasculitis in small- and medium-sized vessels.

[0472] Disclosed herein are methods for treating a subject with Wegener's granulomatosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing reactions associated with Wegener's granulomatosis, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0473] Gastroesophageal reflux disease (GERD) Gastroesophageal reflux disease (GERD) occurs when stomach acid frequently backs up into the tube connecting the mouth and stomach. This reflux (acid reflux) can irritate the lining of the esophagus. In some cases, GERD involves acid reflux.

[0474] Disclosed herein are methods for treating a subject with GERD, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab). Also disclosed are methods for reducing, ameliorating, or preventing GERD-related reactions, comprising administering an anti-IL-4R antibody (e.g., an anti-IL-4Rα antibody, e.g., dupilumab).

[0475] Eosinophilic colitis Eosinophilic colitis (EC) is a rare form of primary eosinophilic gastrointestinal disease with a bimodal peak in prevalence in newborns and young adults. In contrast to increasingly recognized eosinophilic esophagitis, EC remains poorly understood. The clinical manifestations of EC vary widely depending on the mucosal, transmural, or serosal predominance of the inflammation. Colonic tissue eosinophilia often occurs in parasitic infections, drug-induced allergic reactions, inflammatory bowel disease, and various connective tissue disorders. This makes EC subject to a broad differential diagnosis, necessitating a thorough investigation for secondary causes that are specifically treated with antibiotics or dietary and drug therapy.

[0476] Disclosed herein are methods for treating a subject with EC by administer...

Claims

1. 1. A method of treating a subject with an anti-interleukin-4 receptor alpha (IL-4Rα) antibody, the subject exhibiting at least one symptom of or determined to be susceptible to an anti-IL-4Rα associated disorder, the method comprising: (a) selecting a feature or features associated with the IL-4 / IL-13 pathway in a data set representing the medical records of a plurality of patients; (b) clustering, by a computer system, a subset of patients from said plurality of patients according to said characteristic or characteristics associated with said IL-4 / IL-13 pathway, said subset comprising said characteristic or characteristics; (c) identifying the IL-4Rα-associated disorder in the subset clustered in step (b) based on symptoms associated with the trait or traits associated with the IL-4 / IL-13 pathway; (d) selecting the subject who exhibits at least one symptom of or is determined to be susceptible to the IL-4Rα-associated disorder identified in step (c), provided that the IL-4Rα-associated disorder is not selected from the group consisting of atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, peanut allergy, grass allergy, chronic obstructive pulmonary disease (COPD), prurigo nodularis, bullous pemphigoid, chronic idiopathic urticaria (CSU), and allergic bronchopulmonary aspergillosis (ABPA); (e) administering a therapeutically effective amount of the anti-IL-4Rα antibody to the subject, The anti-IL-4Rα antibody is Variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); Variable heavy chain CDR2 of SEQ ID NO:2 (ISGSGGNT); Variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); Variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); Variable light chain CDR2 of SEQ ID NO: 5 (LGS); and Variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT) and The method comprising:

2. 1. A method of treating a subject with an anti-IL-4Rα antibody, the subject exhibiting at least one symptom of or determined to be susceptible to an IL-4Rα-associated disorder, the method comprising: (a) selecting a characteristic or characteristics in a set of patients; (b) clustering, by a computer system, a subset of patients having the trait or traits according to the trait or traits, wherein the trait or traits are determined to be associated with or predisposed to at least one symptom of the IL-4Rα-associated disorder; (c) identifying the IL-4Rα-associated disorder in the subset of patients clustered in step (b) based on the symptoms associated with the trait or traits associated with the IL-4 / IL-13 pathway; (d) selecting the subject identified in step (c) as exhibiting at least one symptom of or susceptible to the IL-4Rα-associated disorder; (e) administering a therapeutically effective amount of the anti-IL-4Rα antibody to the subject, The anti-IL-4Rα antibody is Variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); Variable heavy chain CDR2 of SEQ ID NO:2 (ISGSGGNT); Variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); Variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); Variable light chain CDR2 of SEQ ID NO: 5 (LGS); and Variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT) and The method comprising:

3. 3. The method of claim 1 or 2, wherein the IL-4Rα-associated disorder is a skin-related disorder, an allergic reaction, asthma, arthritis, a nasal-related disorder, a lung-related disorder, a blood-related disorder, an eye-related disorder, an esophageal-related disorder, a gastrointestinal-related disorder, a kidney-related disorder, a prostate-related disorder, Kawasaki disease, a thyroid-related disorder, a vascular-related disorder, a pregnancy-related disorder, or cancer.

4. 1. A method of treating a subject with an anti-interleukin-4 receptor alpha (anti-IL-4Rα) antibody, comprising administering a therapeutically effective amount of an anti-IL-4Rα antibody to a subject exhibiting at least one symptom of or determined to be susceptible to a disorder selected from the group consisting of a skin-related disorder, an allergic reaction, asthma, arthritis, a nasal-related disorder, a lung-related disorder, a blood-related disorder, an eye-related disorder, an esophageal-related disorder, a gastrointestinal-related disorder, a kidney-related disorder, a prostate-related disorder, Kawasaki Disease, a thyroid-related disorder, a vascular-related disorder, a pregnancy-related disorder, and cancer; The anti-IL-4Rα antibody is Variable heavy chain CDR1 of SEQ ID NO: 1 (GFTFRDYA); Variable heavy chain CDR2 of SEQ ID NO:2 (ISGSGGNT); Variable heavy chain CDR3 of SEQ ID NO: 3 (AKDRLSITIRPRYYGLDV); Variable light chain CDR1 of SEQ ID NO: 4 (QSLLYSIGYNY); Variable light chain CDR2 of SEQ ID NO: 5 (LGS); and Variable light chain CDR3 of SEQ ID NO: 6 (MQALQTPYT) The method comprising:

5. 5. The method of claim 3 or 4, wherein the skin-related disorder is selected from atopic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, dyshidrotic eczema, chronic hand eczema, nummular dermatitis, scleroderma, generalized scleroderma, hypertrophic scarring, urticaria, skin infections, focal alopecia, prurigo nodularis, bullous pemphigoid, Netherton syndrome, or a combination thereof.

6. 5. The method of claim 3 or 4, wherein the allergic reaction is a hypersensitivity to a food selected from dairy products, eggs, wheat, soy, corn, fish, shellfish, peanuts, tree nuts, beef, chicken, oats, barley, pork, green beans, apples, pineapples, or combinations thereof.

7. 5. The method of claim 3 or 4, wherein the allergic reaction is hypersensitivity to insect venom, plant-derived substances, chemicals, pharmaceuticals, animal dander, or a combination thereof.

8. The method according to claim 3 or 4, wherein the IL-4Rα-associated disorder is asthma.

9. The method according to claim 3 or 4, wherein the IL-4Rα-associated disorder is arthritis.

10. 5. The method of claim 3 or 4, wherein the nasal-related disorder is nasal polyps, sinusitis, rhinitis, or a combination thereof.

11. 5. The method of claim 3 or 4, wherein the lung-related disorder is pulmonary fibrosis or cirrhosis.

12. 5. The method of claim 3 or 4, wherein the lung-related disorder is chronic fibrotic lung disease, cystic fibrosis, allergic bronchopulmonary mycosis, chronic obstructive pulmonary disease, bleomycin-induced pulmonary disease and fibrosis, pulmonary alveolar proteinosis, adult respiratory distress syndrome, sarcoidosis, tuberculosis, aspirin-induced asthma, or a combination thereof.

13. 5. The method of claim 3 or 4, wherein the blood-related disorder is sickle cell anemia, Churg-Strauss syndrome, autoimmune lymphoproliferative syndrome, lupus (systemic lupus erythematosus), antiphospholipid syndrome (APS), autoimmune hemolytic anemia, or a combination thereof.

14. 5. The method of claim 3 or 4, wherein the ocular-related disorder is Sjogren's syndrome, autoimmune uveitis, autoimmune lymphoproliferative syndrome, dry eye, blepharitis, blepharoconjunctivitis, cicatricial pemphigoid, Mooren corneal ulcer, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, anaphylactic lenticular endophthalmitis, conjunctivitis sicca (KCS), atrophic keratoconjunctivitis (AKC), or a combination thereof.

15. 5. The method of claim 3 or 4, wherein the esophagus-related indication is Barrett's esophagus, eosinophilic esophagitis, eosinophilic gastritis, achalasia, gastroesophageal reflux disease (GERD), or a combination thereof.

16. 5. The method of claim 3 or 4, wherein the gastrointestinal-related disorder is ulcerative colitis, Whipple's disease, Behcet's disease, Wegener's granulomatosis (GERD), or a combination thereof.

17. 5. The method of claim 3 or 4, wherein the kidney-related disorder is nephrosis, glomerulonephritis, Goodpasture's syndrome, or a combination thereof.

18. 5. The method of claim 3 or 4, wherein the prostate-related disorder is benign prostatic hyperplasia, chronic prostatitis syndrome, or a combination thereof.

19. The method according to claim 3 or 4, wherein the IL-4Rα-associated disorder is Kawasaki disease.

20. 5. The method of claim 3 or 4, wherein the pregnancy-related disorder is pre-eclampsia, antiphospholipid syndrome, immune thrombocytopenia, or a combination thereof.

21. The method of claim 3 or 4, wherein the cancer is cutaneous T-cell lymphoma.

22. The method according to any one of claims 1 to 21, wherein the anti-IL-4Rα antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

14.

23. The method of any one of claims 1 to 22, wherein the IL-4Rα-associated disorder is a condition listed in Table 9 or Table 10.

24. The method of any one of claims 1 to 23, wherein the subject is a human.

25. The method of any one of claims 1 to 24, wherein the administering step is intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, or epidural administration.

26. The method of any one of claims 1 to 25, wherein the administering step is subcutaneous.

27. The method of any one of claims 1 to 26, wherein the administering step is carried out by a pre-filled syringe.

28. 27. The method of any one of claims 1 to 26, wherein the administering step is performed by a prefilled pen.

29. The method according to any one of claims 1 to 26, wherein the administration step is carried out by an autoinjector. Law.

30. The method of any one of claims 1 to 29, wherein the anti-IL-4Rα antibody is administered in multiple doses.

31. The method of any one of claims 1 to 30, wherein the anti-IL-4Rα antibody is administered in two doses.

32. The method of any one of claims 1 to 31, wherein the anti-IL-4Rα antibody is administered at a dose of about 0.0001 to about 10 mg / kg of patient body weight.

33. 33. The method of any one of claims 1 to 32, further comprising administering a second therapeutic agent.

34. 34. The method of claim 33, wherein the second therapeutic agent is a second antibody or antigen-binding fragment thereof, a soluble cytokine receptor, an IgE antagonist, an anti-asthma medication, or a checkpoint inhibitor.

35. 35. The method of claim 34, wherein the anti-asthma medication is a corticosteroid, a nonsteroidal agent, a beta agonist, a leukotriene antagonist, a xanthine, fluticasone, salmeterol, or albuterol.

36. 36. The method of claim 35, wherein the checkpoint inhibitor is a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist.

37. The method of any one of claims 33 to 36, wherein the anti-IL-4Rα antibody is administered before the second therapeutic agent is administered.

38. The method of any one of claims 33 to 36, wherein the anti-IL-4Rα antibody is administered simultaneously with the administration of the second therapeutic agent.

39. The method of any one of claims 33 to 36, wherein the anti-IL-4Rα antibody is administered after the administration of the second therapeutic agent.

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