JP2019069987A - Methods for treating nasal polyposis by administering il-4r antagonist - Google Patents

Abstract

To provide novel therapeutic treatment methods for treating nasal polyposis.SOLUTION: A method for treating nasal polyposis comprises administering to a subject in need thereof a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), where the antibody or antigen binding fragment thereof comprises heavy chain and light chain CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair.SELECTED DRAWING: None

Description

RELATED APPLICATIONS This application claims the benefit of US Provisional Application No. 61 / 837,912, filed Jun. 21, 2013, and European Application No. 14305670.3, filed May 7, 2014, which are incorporated herein by reference. Each of which is incorporated herein by reference in its entirety.

  The present invention relates to the field of therapeutic treatment of inflammatory conditions. More particularly, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat nasal epilepsy.

  Nasal fin (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity arising from the midnasal passage natural mouth route. NP is an inflammatory process driven by T helper cells-2 (Th-2) that affect the nasal mucosa and the sinuses. Factors that attract and activate eosinophils, high levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), eosinophil cationic protein (ECP) and eotaxin (eosinophils) As acid sphere chemoattractants are typically found in nasal polyps, eosinophils and their products are considered to be characteristic of the inflammation associated with nasal polyps. Eosinophils are the major inflammatory cells found in sinus and nasal polyps, and nasal polyps are also associated with high levels of IgE. NP is characterized by long term symptoms of nasal obstruction and clogging, loss or loss of sense of smell, anterior and posterior rhinorrhea, and facial pain. Current treatment options range from local or systemic corticosteroids to functional endoscopic sinus surgery.

  In one aspect, the invention relates to a method of treating nasal rash, comprising a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen binding fragment thereof, There is provided a method comprising administering to a subject in need thereof. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

  Subjects suitable for treatment with an IL-4R antagonist may have one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity You may have previously received surgery to treat the nose or nose. In some embodiments, the subject has chronic sinusitis or chronic rhinosinusitis. For example, the subject may have a nasal swab that has severe symptoms of sinusitis.

In some embodiments, the IL-4R antagonist is administered at a dose of 0.1 mg to 600 mg (eg, 100 mg to 400 mg, eg, 150 mg, 200 mg, 250 mg, 300 mg or 350 mg). In certain embodiments, the pharmaceutical composition is administered to the subject systemically or locally. For example, the pharmaceutical composition is administered subcutaneously, intravenously or intranasally.

  In one embodiment, the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg.

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist, such as an IL-4R antibody or antigen binding fragment thereof. For example, in one embodiment, the one or more additional agents, such as the second therapeutic agent, is a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, NSAID (non-steroidal anti-inflammatory drug), antibiotic, antifungal agent, intranasal corticosteroids, inhaled corticosteroids, systemic corticosteroids, long-acting beta ₂ agonists, decongestants or any of them It may be a combination. In one embodiment, the second therapeutic agent is an inhaled corticosteroid such as fluticasone or budesonide, or an intranasal corticosteroid such as intranasal spray (MFNS) of mometasone furoate. In another embodiment, the second therapeutic agent further comprises a long acting beta ₂ agonist such as salmeterol or formoterol.

  In certain embodiments, following administration of an IL-4R antagonist, one or more symptoms of nasal blebs are ameliorated. For example, after administration of the antagonist, a 22-item sinus evaluation test (SNOT-22) score; nasal symptom score; number of awakenings at night; visual analogue score (VAS) such as the severity of nasal sinus inflammation symptoms; 5 items Asthma Management Questionnaire (ACQ 5) score; maximum inspiratory flow (NPIF); University of Pennsylvania olfactory identification test (UPSIT); Lund-McKay score; and one or more improvements in maxillary sinus three-dimensional volume measurement, etc. Parameters related to nasal polyps may improve. In certain embodiments, after administration of the antibody or antigen binding fragment thereof, an increase in one or both of NPIF and UPSIT, and SNOT-22 score, nasal symptom score, VAS, Lund-McKay score and 3D-volume score One or more of the one or more reductions occur. In some embodiments, after administration of an IL-4R antagonist, a reduction in nasal polyp score in the patient occurs.

  In one aspect, the invention relates to a single initial dose of an interleukin-4 receptor (IL-4R) antagonist, such as an IL-4R antibody or antigen binding fragment thereof, followed by one or more times an IL-4R antagonist Provides a method of treating nasal polyps by sequentially administering a second dose of the compound to a subject in need thereof. In some embodiments, each secondary dose is administered 1 to 15 weeks after the immediately preceding dose. In other embodiments, at least three secondary doses of the IL-4R antagonist are administered to the subject, each secondary dose lasting several days or weeks of previous dosing (eg, one week or two weeks or more) ) Will be administered later. In another embodiment, each of the initial dose and one or more of the second doses is 50 mg to 500 mg of an IL-4R antagonist, such as 100 mg to 400 mg of an IL-4R antagonist, such as 150 mg, 200 mg, 250 mg, Includes 300 mg or 350 mg of IL-4R antagonist. In some embodiments, each of the initial dose and one or more secondary doses contain the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of an IL-4R antagonist and each of the one or more secondary doses comprises a second amount of an IL-4R antagonist. For example, the first amount of IL-4R antagonist may be 1.5 times, 2 times, 2.5 times, 2.5 times, 3 times, 3.5 times, 4 times or 5 times the second amount of IL-4R antagonist or It may be more than that.

In one embodiment, the subject (eg, a patient) has one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, or the nose I am undergoing surgery for a polyp. In some embodiments, the subject has chronic sinusitis or chronic rhinosinusitis. For example, the subject may have a nasal swab that has severe symptoms of sinusitis.

  The initial and secondary doses of the IL-4R antagonist are administered by the same or different administration routes. For example, the initial and secondary doses are administered subcutaneously, intravenously or intranasally.

  In certain embodiments, after administration of the initial dose and one or more secondary doses, a 22-item sinus evaluation test (SNOT-22) score; nasal symptom score; number of awakenings at night; nasal sinus inflammation symptoms Analogue Scores (VAS), such as the severity of symptoms; Five-item Asthma Management Questionnaire (ACQ 5) score; Nasal Maximum Inspiratory Flow (NPIF); University of Pennsylvania Olfactory Discrimination Test (UPSIT); Lund-McKay Score; An improvement in one or more nasal cavity-related parameters occurs, such as an improvement in three-dimensional volume measurement. In certain embodiments, after administration of the antibody or antigen binding fragment thereof, an increase in one or both of NPIF and UPSIT and SNOT-22 score, nasal symptom score, VAS, Lund-McKay score; and 3D volume score One or more of one or more of the reductions occur. In some embodiments, after administration of an IL-4R antagonist, a reduction in nasal polyp score in the patient occurs.

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist, such as an IL-4R antibody or antigen binding fragment thereof. For example, in one embodiment, the one or more additional agents, such as the second therapeutic agent, is a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, It may be an NSAID, an antibiotic, an antimycotic, an intranasal corticosteroid, an inhaled corticosteroid, a systemic corticosteroid, a long acting beta ₂ agonist, a decongestant or any combination thereof. In one embodiment, the second therapeutic agent is an inhaled corticosteroid such as fluticasone or budesonide, or an intranasal corticosteroid such as intranasal spray (MFNS) of mometasone furoate. In another embodiment, the second therapeutic agent further comprises a long acting beta ₂ agonist such as salmeterol or formoterol.

  In one aspect, the invention is a method of treating a nasal polyp, comprising minimal bilateral nasal polyp score 5, or nasal blockage / obstruction / clogging, anterior or posterior rhinorrhea, facial pain or pressure, and olfactory Selecting a patient having at least two or more of the chronic symptoms of sinusitis selected from the group consisting of reduction or loss; and 2 or 3 of the patient's nasal polyp score is reduced or 2 of the sinusitis Interleukin-4 receptor (IL-4R), such as an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), such that one or more chronic conditions ameliorate A method is provided by administering a pharmaceutical composition comprising an antagonist to a selected patient. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

  In one aspect, the invention is a method of treating a nasal polyp, comprising minimal bilateral nasal polyp score 5, or nasal blockage / obstruction / clogging, anterior or posterior rhinorrhea, facial pain or pressure, and olfactory Selecting a patient having at least two or more of the chronic symptoms of sinusitis selected from the group consisting of reduction or loss; and 2 or 3 of the patient's nasal polyp score is reduced or 2 of the sinusitis Interleukin-4 receptor (IL-4R), such as an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), such that one or more chronic conditions ameliorate The patient is continuously administered a single initial dose of a pharmaceutical composition comprising the antagonist, followed by one or more secondary doses of the antibody or antigen binding fragment thereof. By the process, to provide a method. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

  In one aspect, the invention relates to a method of treating nasal polyp, comprising treating the thymus and activation-modulating chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA) and YKL-40 in a subject. Determining the expression level of one or more genes selected from: specific for an interleukin-4 receptor (IL-4R) if the subject has an improved expression level of one or more genes Selecting a subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody or antigen-binding fragment thereof that binds to the subject; and level of one or more genes An antibody that specifically binds to interleukin 4 receptor (IL-4R) or its antigen binding so as to decrease Pharmaceutical compositions comprising, by step of administering to a subject in the selected provides methods. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention relates to a method of treating nasal polyp, comprising treating the thymus and activation-modulating chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA) and YKL-40 in a subject. Determining the expression level of one or more genes selected from: specific for an interleukin-4 receptor (IL-4R) if the subject has an improved expression level of one or more genes Selecting a subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody or antigen binding fragment thereof that binds to the subject; and level of one or more genes An antibody that specifically binds to interleukin 4 receptor (IL-4R) or its antigen binding so as to decrease Or a single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, followed by one or more secondary doses of the antibody or antigen binding fragment thereof, to the selected subject A method is provided by the step of sequentially administering. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

  In one aspect, the invention relates to a method of treating nasal blebs, comprising determining the level of blood eosinophils or vaginal eosinophils in a subject; For treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), when having an improved level of Selecting a subject as a candidate for the subject; and an antibody or antibody specifically binding to the interleukin-4 receptor (IL-4R) such that the level of blood eosinophils or vaginal eosinophils is reduced. A method is provided by administering a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an antigen binding fragment, to a selected subject. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

In one aspect, the invention relates to a method of treating nasal blebs, comprising determining the level of blood eosinophils or vaginal eosinophils in a subject; the subject is blood eosinophils or vaginal eosinophils For treatment with an interleukin-4 receptor (IL-4R) antagonist, such as an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), when having an improved level of Selecting a subject as a candidate for the subject; and an antibody that specifically binds to the interleukin-4 receptor (IL-4R) or its antibody such that the level of blood eosinophils or vaginal eosinophils is reduced. A single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an antigen binding fragment, followed by one or more of the antibody or antigen binding fragment thereof The following doses, by step of continuously administered to a subject selected, provides a method. In one embodiment, the IL-4R antagonist comprises an antibody or antigen binding fragment etc. comprising heavy and light chain CDR sequences from the heavy chain variable region (HCVR) of SEQ ID NO: 1 and the light chain variable region (LCVR) of SEQ ID NO: 2 Or an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5, and light chain CDR sequences of SEQ ID NOs: 6, 7 and 8. For example, in one embodiment, the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2. In one embodiment, the IL-4R antagonist is dupyrumab or an antigen binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen binding fragments thereof are described, for example, in US Pat. Nos. 7,605,237 and 7,608,693.

  Other embodiments will be apparent from the following drawings and detailed description.

FIG. 1 shows a schematic view of an example of a background treatment withdrawal period in the treatment of asthmatic patients.

  Before describing the present invention, it is understood that the present invention is not limited to the particular methods and experimental conditions described, and thus the methods and conditions may be varied. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" used in connection with a particular stated numerical value means that the numerical value may vary by no more than 1% from the stated value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

  All publications mentioned herein are incorporated herein by reference in their entirety.

Methods of Treating Nasal Moths The present invention provides methods of treating nasal lupus. As used herein, a "nasal polyp" is an overgrowth of tissue in one or more nasal cavities. The condition of the nasal polyps is called "nasal fin". About 80% of nasal polyps are highly edematous and are filled with eosinophils. The nasal polyps may also be present as fibrils, glands or cysts.

  Nasal fin (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity arising from the midnasal passage natural mouth route. NP is an inflammatory process driven by T helper cells-2 (Th-2) that affect the nasal mucosa and the sinuses. Factors that attract and activate eosinophils, high levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), eosinophil cationic protein (ECP) and eotaxin (eosinophils) Because acid sphere chemoattractants are typically found in nasal polyps, eosinophils and their products are considered to be characteristic of the inflammation associated with nasal polyps. Eosinophils are the major inflammatory cells found in sinus and nasal polyps, and nasal polyps are also associated with high levels of IgE.

  NP is characterized by long term symptoms of nasal obstruction and clogging, loss or loss of sense of smell, anterior and posterior rhinorrhea, and facial pain. The presence or absence of nasal polyps is confirmed, for example by performing endoscopy, and the presence and degree of sinus and polyp involvement is confirmed by methods such as coronary computed tomography (CT) scans.

IL-4R antagonists are used to treat nasal swabs associated with various conditions. For example, nasal swabs may include sinusitis, rhinitis (eg, allergic and non-allergic rhinitis), asthma (eg, moderate to severe asthma), NSAID hypersensitivity (eg, aspirin hypersensitivity) and bacterial and fungal infections, etc. Related to the infection of Bacterial infections include, for example, staphylococcal infections. A subject having a nasal swab may have a chronic bacterial infection, eg, a chronic infection, such as a chronic S. aureus infection. In some embodiments, the subject has recurrent nasal polyps, such as those that may be associated with recurrent sinusitis. In another embodiment, the subject has cystic fibrosis or NARES (non-allergic rhinitis with eosinophilia syndrome). In another embodiment, the subject has recurrent nasal polyps after undergoing surgery to treat the polyp. Risk factors for nasal polyps include genetic susceptibility, anatomic abnormalities, mucociliary dysfunction, infection and local immune imbalances.

  IL-4R antagonists are also used to treat nasal blebs in patients who have not previously received treatment or surgery for NP. IL-4R antagonists are also used to treat nasal polyps in patients who have previously undergone surgery, such as nasal surgery such as for the treatment of nasal polyps. In a specific embodiment, the IL-4R antagonist is administered to a subject with nasal lupus relapse after the subject has received prior treatment for polyps, such as prior nasal surgery.

  As used herein, the term "vein sinusitis" is characterized by inflammation of the sinuses, including inflammation of the maxilla, frontal, ethmoid and / or sphenoid sinuses. Refers to an inflammatory condition. The IL-4R antagonist is suitable for the treatment of acute sinusitis, subacute sinusitis, chronic sinusitis and nasal polyps associated with recurrent sinusitis. Acute sinusitis is characterized by the sudden onset of cold-like symptoms such as runny nose, nasal congestion and facial pain that do not heal after 10-14 days. Acute sinusitis typically lasts less than 4 weeks. Subacute sinusitis lasts 4 to 8 weeks. Chronic sinusitis lasts for 8 weeks or more, and recurrent sinusitis is characterized by the appearance of sinusoid inflammation that occurs three or more times a year. More than 80% of patients with chronic sinusitis with nasal polyps have eosinophilic upper airway inflammation.

  Many patients with chronic sinusitis have "chronic hyperplastic eosinophilic sinusitis" characterized by severe inflammation of the sinuses, increased eosinophils and mixed mononuclear cells and relatively small amounts of neutrophils. Have. Some of these patients have one or more of associated nasal polyps, asthma and aspirin or NSAID susceptibility. In a specific embodiment, an IL-4R antagonist is used to treat nasal polyps in a subject with chronic hyperplastic eosinophilic sinusitis.

  The term "rhinitis" refers to an allergic reaction to common allergens ("allergic rhinitis", eg, perennial allergic rhinitis) or environmental irritants (non-allergic rhinitis) and the like. Symptoms of allergic rhinitis include sneezing; nasal congestion or runny nose; pressure and pain in the sinus or buccal or nasal pulsatility; and itchy nose, throat, eyes and ears.

  Symptoms of non-allergic rhinitis include narrowing or inflammation of the nasal passages leading to many of the same symptoms of allergic rhinitis. Non-allergic rhinitis is caused, for example, by a strong chemical or smoke-producing environment, or by reliance on long-term use of certain medications or nasal sprays.

  As used herein, the term "nasal sinusitis" refers to a condition having both rhinitis and sinusitis symptoms. Sinusitis includes acute and chronic rhinosinusitis. Acute rhinosinusitis is caused by an infection such as a bacterial, viral or fungal infection or by chemical stimulation. Cigarette smoke-induced acute rhinosinusitis and chlorine gas-induced chronic rhinosinusitis are examples of acute rhinosinusitis. NP is most commonly associated with chronic rhinosinusitis (CRS) characterized by nasal and sinus mucosal inflammation with symptoms lasting longer than 8 weeks. Chronic eosinophilic rhinosinusitis with nasal polyps lasts longer than 8 weeks.

  Chronic sinusitis (CS) and chronic rhinosinusitis (CRS) are conditions that last longer than 8 weeks. Acute sinusitis and the underlying cause of acute rhinosinusitis can lead to chronic sinusitis or chronic rhinosinusitis if the resulting inflammation persists for more than 8 weeks. Chronic rhinosinusitis includes, for example, eosinophilic chronic hyperplastic rhinosinusitis.

  Further subcategories of chronic sinusitis (and chronic rhinosinusitis) include, for example, superantigen-induced eosinophilic chronic sinusitis (eg, by bacteria such as Staphylococcus aureus) Exotoxins and endotoxins-induced sinusitis); allergic fungal sinusitis (eg, sinusitis induced by a fungus such as Aspergillus or Alternaria); Non-allergic fungal eosinophilic chronic sinusitis; and eosinophilic chronic sinusitis exacerbated by aspirin.

  An IL-4R antagonist is used to treat nasal plaque in a subject with any of the above disorders.

Method of Improving Parameters Associated with Nasal Polyps The present invention is a method of improving parameters associated with one or more nasal polyps in a subject in need thereof, which is an interleukin-4 receptor (IL- 4R) comprising a method comprising administering a pharmaceutical composition comprising an antagonist to a subject. For example, an IL-4R receptor antagonist can reduce endoscopic nasal polyp score in a patient. A nasal polyp score of 0 indicates the absence of polyps. A nasal polyp score of 1 indicates the presence of a small polyp in the middle nasal passage that does not reach below the lower edge of the middle turbinate. A nasal polyp score of 3 indicates a large polyp reaching the lower edge of the inferior turbinate or a polyp intermediate to the middle turbinate. The nasal polyp score of 4 is a large polyp that causes complete occlusion of the lower nasal cavity (see Table 15 below). The maximum score is 8 (4 points per nasal cavity). Treatment with an IL-4R antagonist can reduce nasal polyp score by about 1 to about 8 points. For example, treatment with an IL-4R antagonist can reduce nasal polyp score by about 1 point or more, about 2 points or more, or about 3 points or more. In some embodiments, treatment with an IL-4R antagonist produces a nasal polyp score of about 1 point or percentage; 2 points or percentage; 3 points or percentage; 4 points or percentage; 5 points or percentage; 6 points or percentage thereof; 7 points or percentage thereof; or 8 points or percentage thereof can be reduced. A reduction in nasal polyp score may be correlated with an improvement in one or more other nasal polyp related parameters. However, such a correlation is not always observed in all cases.

  Other examples of “parameters related to nasal polyps”: (a) 22-item sinus evaluation test (SNOT-22) score; (b) nasal congestion / obstruction evaluated by subject, anterior rhinorrhea (nasal runny ), Posterior rhinorrhea (hind rhinorrhea) and loss of sense of smell; (c) the number of nocturnal awakenings; (d) visual analogue score (VAS) to assess the severity of nasal sinus inflammation symptoms associated with the patient (E) 5-item Asthma Management Questionnaire (ACQ 5) score in patients with asthma etc. (f) nasal maximum inspiratory flow (NPIF); (g) olfactory test (University of Pennsylvania olfactory discrimination test (UPSIT)); (h B) Physiological parameters measured by nasal endoscopy and CT scan etc .; (i) Lund-Mackay score; and (j) three-dimensional volume measurement of maxillary sinus.

22 item sinus evaluation test (SNOT-22) score. According to a particular embodiment, administration of the IL-4R antagonist to the patient results in a reduction from baseline in the 22-item sinus evaluation test (SNOT-22). SNOT-22 is a questionnaire to assess the impact of chronic rhinosinusitis (CRS) on quality of life. The questionnaire measures items related to sinus condition and surgery. Scores range from 0 to 110, with higher scores indicating greater influence of CRS on health related quality of life (HRQoL) (Hopkins et al. 2009, Clin. Otolaryngol. 34: 447-454 ).

  The present invention includes methods of treatment that result in a decrease in SNOT-22 score from baseline of at least one point 4 weeks after administration of the IL-4R antagonist. For example, administration of an IL-4R antagonist results in a decrease in SNOT-22 score at 4, 6, 8, 12, 12 or 16 weeks after initiation of treatment. In some embodiments, administration of an IL-4R antagonist to a subject in need thereof comprises about 1, 2, 3, 4, 5, 6, 7, at four weeks, six weeks, eight weeks or twelve weeks. Cause a decrease in SNOT-22 score from baseline of 8, 9, 10, 11, 12, 13 points or more.

  Individual and total nasal symptom scores. Symptoms evaluated by the subject use a 0 to 3 classification scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), clogged / obstructed, Assayed by answering questions of the morning and night individual rhinosinusitis symptoms, including symptoms of anterior rhinorrhea, posterior rhinorrhea and loss of sense of smell. Measures of nighttime awakening are also tracked. For example, the measurement of nocturnal awakening is assessed according to the following score based on the subject's self-assessment: 0 = no symptoms, I slept overnight; 1 = slept well, but some medical condition in the morning; 2 = 1 woke up once for symptoms of rhinosinusitis (including early awakening); 3 = woke up several times for symptoms (including early awakening); 4 = unable to sleep at rest, for symptoms I wake up almost all night. Administration of an IL-4R antagonist may be, for example, an overnight night awakening from at least about 0.10 baselines overnight from 4 weeks to 16 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist This can result in a reduction in the average number of For example, a decrease in the frequency of overnight nocturnal awakening from at least about 0.10 baselines overnight can be seen at 4, 6, 8, 12, 12 or 16 weeks after the start of treatment . Administration of an IL-4R antagonist to a subject in need thereof is, for example, about 0.10 times overnight, 0.15 times overnight, at 4 weeks, 8 weeks, 12 weeks or 16 weeks 0.20 times, 0.25 times overnight, 0.30 times overnight, 0.35 times overnight, 0.40 times overnight, 0.45 times overnight, 0 times overnight .50 times, 0.55 times overnight, 0.60 times overnight, 0.65 times overnight, 0.70 times overnight, 0.75 times overnight, 0.80 overnight Times, 0.85 times overnight, 0.90 times overnight, 0.95 times overnight, 1.0 times overnight, 2.0 times or more overnight, one from the baseline It can cause a reduction in the average number of night awakenings in the evening.

  Visual Analogue Score (VAS). VAS is a scale to assess the severity of nasal sinus symptoms associated with the patient on a scale of 1 to 10. Mild symptoms are indicated by a score of 0 to 3, moderate symptoms are indicated by a VAS score of greater than 3 and 7 and severe symptoms are indicated by a VAS score of greater than 7 to 10. Administration of an IL-4R antagonist to a subject in need thereof is approximately 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points at 4, 6, or 12 weeks Causes a reduction in VAS score from baseline of 3.5 points, 4 points or more. Decreased VAS scores can be seen as early as 4 weeks and at most 12 weeks or later after administration of the IL-4R antagonist.

5-item asthma control questionnaire (ACQ) score. ACQ5 measures both the adequacy of asthma management and the changes in asthma management that occur spontaneously or as a result of treatment. The five questions in ACQ 5 represent the top scoring five asthma symptoms: symptoms awakened at night, symptoms awakened in the morning, restriction of daily activities, breathlessness and wheezing. Patients answered symptom questions on a 7 point scale (0 = no dysfunction, fully managed; 6 = maximal dysfunction, not well managed).

  The present invention includes therapeutic methods that result in a decrease in ACQ5 score from baseline of at least 0.10 points at 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, according to the present invention, administration of an IL-4R antagonist to a subject in need thereof is about 0.10 points, 0.15 points, 0.20 points, at four weeks, six weeks or twelve weeks. 0.25 point, 0.30 point, 0.35 point, 0.40 point, 0.45 point, 0.50 point, 0.55 point, 0.60 point, 0.65 point, 0.70 point, Causes a decrease in ACQ score from baseline of 0.75 points, 0.80 points, 0.85 points or more. Decreased ACQ scores can be seen as early as 4 weeks and at most 12 weeks or later after administration of the IL-4R antagonist.

  Nasal maximum inspiratory flow (NPIF). Nasal maximum inspiratory flow (NPIF) represents a physiological measure of air flow through both nasal passages during inspiratory and / or exhalation, and is expressed in liters / minute. Nasal inspiration is mostly correlated with the subjective sensation of obstruction and is used to monitor nasal leaks. Administration of an IL-4R antagonist to a subject in need thereof will have approximately 0.10 liters / minute, 0.15 liters / minute, 0.20 liters / minute, 0.4, 6, 5 or 12 weeks. 25 liters / minute, 0.30 liters / minute, 0.35 liters / minute, 0.40 liters / minute, 0.45 liters / minute, 0.50 liters / minute, 0.55 liters / minute, 0.60 L / min, 0.65 l / min, 0.70 l / min, 0.75 l / min, 0.80 l / min, 0.85 l / min or more increase in NPIF from baseline cause. An increase in NPIF score can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

  University of Pennsylvania Smell Identification Test (UPSIT). UPSIT is a method for quantitatively evaluating human olfactory function. The test consists of a sample of odorous substances, the subject has to describe the odor. The score is based on the number of correct answers. This test consists of patients with normal olfaction ("normal olfaction") and patients with different levels of loss ("mild, moderate and severe microsmia") or loss ("non-olfactory") It can be distinguished. Administration of an IL-4R antagonist to a subject in need thereof is approximately 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points at 4, 6, or 12 weeks Cause an increase in UPSIT score from baseline of 3.5 points or more. An increase in UPSIT score can be seen as early as 4 weeks and as late as 12 weeks or later after administration of the IL-4R antagonist.

  Physiological parameters. The efficacy of the IL-4R antagonist is assayed by measuring the effects of physiological parameters, such as intranasal, such as by nasal endoscopy or computed tomography (CT) scan.

Lund-Mackay score. The Lund-Mackay scoring system is based on localization by points given for turbidity: 0 = normal, 1 = partial turbidity, 2 = complete turbidity. These points are then applied on each side to the maxilla, anterior ethmoid, posterior ethmoid, sphenoid and frontal sinuses. The middle nasal passage natural mouth route is graded as 0 = no occlusion or 2 = occlusion, and a maximum score of 12 per side is derived. For patients who are deficient in the mid-nasal tract natural oral route (OC) (for previous surgery), the location of the previous OC is considered and scored as if the OC were there. Administration of an IL-4R antagonist to a subject in need thereof has approximately 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points at 4, 6, or 12 weeks. Points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 Causes a reduction in the Lund-Mackay score from the baseline of 0.85 points or more points. A decrease in Lund-Mackay score can be seen as early as 4 weeks and at most 12 weeks or later after administration of the IL-4R antagonist.

  Three-dimensional volumetric measurement of maxillary sinus. This value is used to calculate air volume (mL); mucosal volume (mL); percentage of sinuses occupied by disease; and sidewall thickness in maxillary sinuses. Administration of an IL-4R antagonist to a subject in need thereof causes an increase in three-dimensional volumetric measurement.

  Questionnaire of quality of life (QoL). Various QoL questionnaires including the Short-Form-36 (SF-36) questionnaire, Euroqol-5D (EQ-5D), questionnaires using materials related to nasal polyps and patient qualitative self-assessment Is used to monitor the efficacy of the IL-4R antagonist.

  The SF-36 is a 36-item questionnaire that measures eight multiple-item degrees of health: physical function (10 items), social function (2 items), role restrictions due to physical problems (4 items), Role restriction due to emotional problems (3 items), mental health (5 items), energy / activity (4 items), pain (2 items) and overall health feeling (5 items). For each degree, the scores of the items were coded, summed and converted to a scale of 0 (the worst considered health measured by the questionnaire) to 100 (the highest considered health). Two standardized summary scores can also be calculated from SF-36; Physical Component Summary (PCS) and Mental Health Component (MCS).

  EQ-5D is a standardized health-related quality of life developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic assessments and inter-disease comparisons. Survey sheet. The EQ-5D designed for self-administration by the patient consists of two parts, the EQ-5D Description System and the EQ VAS. The EQ-5D description system includes 5 degrees: movement, personal management, daily activities, pain / discomfort and anxiety / recession; each degree has 3 levels: no problems, some problems, some problems Yes. The EQ Visual Analog Scale (VAS) records the respondent's self-related health against a vertical visual analog scale. The EQ VAS "Thermometer" has endpoints of up to 100 (highest possible health) and 0 (lowest possible health).

  The questionnaire using materials related to nasal polyps is a questionnaire using health management data about nasal polyps, including specialist visits, emergency medical visits, sick leave, holidays, etc.

  The improvement in parameters associated with nasal polyps, such as those associated with nasal polyps described above, can be expressed as a percentage. For example, the score can be improved by 30% or more, 40% or more, 50% or more, 60% or more, 70% or more or 80% or more.

"Improvement of parameters related to nasal polyps" refers to increase from baseline in one or more of NPIF, UPSIT, and / or SNOT-22 score, nasal congestion / obstruction assessed by subject, anterior Rhinorrhea (runny nose), posterior rhinorrhea (back rhinorrhea) and loss of sense of smell; number of awakenings at night; VAS score; Lund-Mackay score; and 3D volume score; and one of the ACQ5 scores in patients with asthma It means a decrease from baseline or more. As used herein, with respect to parameters related to nasal polyps, the term "baseline" refers to the numerical values of parameters related to nasal polyps for the patient prior to or upon administration of the pharmaceutical composition of the present invention. means.

  The parameters are quantified at baseline and at a time after administration of the pharmaceutical composition of the present invention to determine whether the parameters associated with the nasal polyps have been "improved". For example, parameters associated with nasal polyps may be one, two, three, four, five, six, seven, eight, nine, ten days after the start of treatment with the pharmaceutical composition of the present invention. Day 11, Day 12, Day 14, Day 3 or 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 11, Week 11, Week 12, Week 13, Week 14, Week 15, It is measured at 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks or longer. In some embodiments, the parameter is measured daily (eg, once or twice daily) weekly, biweekly or monthly. In another embodiment, the parameters are measured daily, and the mean value determined over the course of one month is compared to the baseline.

  The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is that the parameters associated with the nose are "improving" (e.g., in some cases, to the particular parameter being measured) Are used to demonstrate whether they can be increased or decreased accordingly.

Interleukin-4 Receptor Antagonists In one embodiment, a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist is administered to a subject in need thereof. As used herein, an "IL-4R antagonist" binds to or interacts with IL-4R, when IL-4R is expressed on cells in vitro or in vivo Is any agent that inhibits the normal biological signaling function of IL-4R. Non-limiting examples of the category of IL-4R antagonists include small molecule IL-4R antagonists, peptide-based IL-4R antagonists (eg, "peptibody" molecules), and human IL-4R specifically Included are antibodies or antigen-binding fragments of antibodies that bind.

  The term "human IL-4R" (hIL-4R), as used herein, is a component of the IL-4 receptor types I and II, and the IL-13 receptor system, IL-4Rα. Intended to refer to subunits. IL-4R antagonists, such as anti-IL-4Rα antibodies or antigen binding fragments thereof, block the function of both IL-4 and IL-13 signaling.

The term "antibody" as used herein is an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds, two heavy (H) chains and two light (L) chains, As well as their multimers (eg, IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V _H) and a heavy chain constant region. The heavy chain constant region comprises three _domains, a C H 1, _{C H} 2 and _{C H} 3. 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 contains one domain (C _L 1). The V _H and V _L regions are further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), incorporated into more conserved regions, termed framework regions (FR). Each V _H and V _L is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-Ang-2 antibody (or antigen binding portion thereof) are identical to human germline sequences, or are naturally or artificially modified. Amino acid consensus sequence is a side-by-side analysis of two or more CDRs
It is defined based on ysis).

  The term "antibody" as used herein also includes antigen binding fragments of complete antibody molecules. Terms such as “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, etc., as used herein, are any naturally occurring which specifically bind to an antigen to form a complex? , Enzymatically available, synthetic or genetically engineered polypeptides or glycoproteins. Antigen binding fragments of antibodies may be prepared using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques including manipulation and expression of DNA encoding the variable and optionally constant domains of the antibody. , Derived from a complete antibody molecule. Such DNAs are known and / or are readily available or synthesized, eg, from commercial sources, DNA libraries (eg, including phage-antibody libraries). The DNA may, for example, place one or more variable and / or constant domains in an appropriate configuration, or introduce codons, create cysteine residues, modify, add or delete amino acids, etc. Sequencing, manipulation, etc., chemically or by using molecular biological techniques.

  Non-limiting examples of antigen binding fragments include: (i) Fab fragments; (ii) F (ab ') 2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) (Vi) a dAb fragment; and (vii) a minimal recognition unit consisting of amino acid residues that mimic the hypervariable region of an antibody (eg, an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a restriction Included FR3-CDR3-FR4 peptides. Domain specific antibody, single domain antibody, domain deleted antibody, chimeric antibody, CDR grafted antibody, bispecific antibody, trispecific antibody, quadruple specific antibody, minibody, minibody (eg, Other engineered molecules such as monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, as also used herein Included within the expression "binding fragment".

Antigen binding fragments of antibodies typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition, generally adjacent to one or more framework sequences, or at least one CDR in frame with one or more framework sequences. including. In antigen binding fragments that have a V _H domain associated with a V _L domain, the V _H and V _L domains are positioned relative to one another in any suitable arrangement. For example, the variable region may be a dimer and may contain V _H -V _H , V _H -V _L or V _L -V _L dimers. Alternatively, the antigen binding fragment of the antibody may contain monomeric _VH or _VL domains.

In certain embodiments, an antigen binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains found within the antigen binding fragment of an antibody include: (i) V _H -C _H 1; (ii) V _H -C _H 2; (iii) V _H -C _H 3; (iv) V _H- C _H 1-C _H 2; (v) V _H- C _H 1-C _H 2-C _H 3; (vi) V _H- C _H 2- C _H 3 _{; (vii) V H -C L} ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1- includes and _{(xiv) V L -C L;} C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3. In any of the variable and constant domain configurations, including any of the above listed exemplary configurations, the variable and constant domains are directly linked to each other or linked by a full length or partial hinge or linker region Ru. The hinge region is at least two (eg, 5, 10, 15, 20, 40, etc.) that result in flexible or semi-flexible linkages between adjacent variable and / or constant domains in a single polypeptide molecule. It consists of 60 or more amino acids. Furthermore, the antigen-binding fragments of the antibody are non-covalently linked (e.g., by a disulfide bond) to each other and / or to one or more monomeric V _H or V _L domains, variable and constant as listed above It may comprise any homodimer or heterodimer (or other multimer) of the domain configuration.

  As with whole antibody molecules, antigen binding fragments may be monospecific or multispecific (eg bispecific). Multispecific antigen binding fragments of antibodies typically comprise at least two different variable domains, wherein each variable domain can specifically bind to different antigens or different epitopes on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody format disclosed herein, is an antigen binding fragment of an anti-IL-4R antibody using conventional techniques available in the art. Adapted for use in the context of

  The constant regions of antibodies are important in their ability to fix complement and to mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody is selected based on whether it is desirable for the antibody to mediate cytotoxicity.

  The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies characterized in the present invention, for example in CDRs and particularly in CDR3, amino acid residues not encoded by human germline immunoglobulin sequences (e.g. random or site-directed mutagenesis in vivo or in vivo And the mutation introduced by somatic mutation of However, the term "human antibody" as used herein includes antibodies in which CDR sequences derived from the germline of another mammalian species such as mouse are grafted onto human framework sequences. Not intended to be.

The term "recombinant human antibody" as used herein refers to all human antibodies produced, expressed, produced or isolated by recombinant means, eg, recombinant expression transfected into a host cell Antibodies expressed using vectors (described further below), Antibodies isolated from recombinant combinatorial human antibody libraries (described further below), Animals transgenic for human immunoglobulin genes ( For example, including splicing of antibodies isolated from mice (see, eg, Taylor et al. (1992) Nucl. Acids Res. 20: 6287-6295), or other DNA sequences of human immunoglobulin gene sequences. Intended to include antibodies produced, expressed, produced or isolated by any other means Do. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when animals transgenic for human Ig sequences are used); amino acid sequences of the _{V H} and _{V L} regions of the recombinant antibodies are derived from human germline _{V H} and _{V L} sequences, is related to human germline _{V H} and _{V L} sequences, the human antibody germline repertoire in vivo, It is a sequence which does not have to exist naturally within.

  Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four chain construct of about 150-160 kDa, wherein the dimers are held together by interchain heavy chain disulfide bonds. In the second embodiment, the dimer is not linked via an interchain disulfide bond, and an approximately 75-80 kDa molecule composed of covalently coupled light and heavy chains (half antibody) is It is formed. These forms were very difficult to separate even after affinity purification.

The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of human IgG4 hinge can significantly reduce the appearance of the second form to levels typically observed using human IgG1 hinges (Angal et al. (1993) Molecular Immunology 30: 105). The present invention is a hinge, and include antibodies having one or on a mutation in C H ₂ or C _{H 3} region, which for example, during manufacturing, desirable to improve the yield of the desired antibody form.

  By "isolated antibody" as used herein is meant an antibody that has been identified, separated from at least one component of its natural environment, and / or recovered. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally occurs or is produced naturally is an "isolated antibody". Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular material and / or chemicals.

The term "specifically binds" or the like means that the antibody or antigen binding fragment thereof forms a relatively stable complex with the antigen under physiological conditions. Methods for determining whether an antibody specifically binds 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 “binds specifically” to IL-4R, as used herein, is less than about 1000 nM, less than about 500 nM, as measured by surface plasmon resonance assay on IL-4R or portions thereof. Less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, about 5 nM comprising less than about 4 nM, less than about 3 nM, less than about 2 nM, antibodies that bind at about 1nM or less than about 0.5nM less _{K D.} However, isolated antibodies that specifically bind human IL-4R may have cross-reactivity to other antigens such as IL-4R molecules from other (non-human) species.

Anti-IL-4R antibodies useful in the methods characterized herein are in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequence from which the antibody is derived , One or more amino acid substitutions, insertions and / or deletions. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to, for example, germline sequences available from public antibody sequence databases. The present invention includes methods of using antibodies and antigen binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more framework and / or CDR regions Amino acids within or one of the corresponding residues of the germline sequence from which the antibody was derived, or corresponding residues of another human germline sequence, or conservative amino acid substitutions of the corresponding germline residues Methods are included that are mutated (such sequence changes are collectively referred to herein as "germline mutations"). One skilled in the art can readily prepare numerous antibodies and antigen binding fragments comprising one or more individual germline mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. can do. In certain embodiments, all of the framework and / or CDR residues within the V _H and / or V _L domain are back mutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only specific residues are found, for example, only mutated residues found within the first eight amino acids of FR1 or the last eight amino acids of FR4 or within CDR1, CDR2 or CDR3. Only the mutated residues are back mutated to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are the corresponding residues of a different germline sequence (ie, a germline sequence different from the germline sequence from which the antibody was originally derived). It is mutated to In addition, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, eg, where particular individual residues are of a particular germline sequence. Certain other residues that are mutated to the corresponding residue but that differ from the original germline sequence are either maintained or mutated to the corresponding residue in the different germline sequence. Once obtained, antibodies and antigen binding fragments containing one or more germline mutations may have improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological Properties (optionally) can be easily tested for one or more desired properties, such as reduced immunogenicity. The use of antibodies and antigen binding fragments obtained in this general manner is encompassed within the present invention.

  The invention also includes the use of an anti-IL-4R antibody comprising a variant of any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. Also includes. For example, the present invention provides, for example, 10 or less, 8 or less, 6 or less, 6 or less, 4 or less as compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein. And the like, including the use of anti-IL-4R antibodies having HCVR, LCVR and / or CDR amino acid sequences, including conservative amino acid substitutions such as

  The term "surface plasmon resonance" as used herein, for example, using the BIAcoreTM system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ), is used to Refers to an optical phenomenon that enables analysis of real-time interactions by detecting changes.

The term "K _D " as used herein is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

  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 have more than one epitope. Thus, different antibodies can bind to different regions on the antigen and have different biological effects. Epitopes may be either conformational or linear. Conformational epitopes are generated by spatially adjacent amino acids from different segments of the linear polypeptide chain. Linear epitopes are those generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may comprise a portion of a saccharide, phosphoryl group or sulfonyl group on an antigen.

According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an amino acid of an anti-IL-4R antibody described in US Patent Nos. 7,608,693 and 7,605,237. An anti-IL-4R alpha antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR) and / or a complementarity determining region (CDR) comprising any of the sequences. In a specific exemplary embodiment, the anti-IL-4Rα antibody or antigen-binding fragment thereof used in the context of the method of the invention comprises heavy chain complementation of heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 It comprises the light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the sex determining region (HCDR) and the amino acid sequence of SEQ ID NO: 2. According to a particular embodiment, the anti-IL-4R alpha antibody or antigen binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 is of SEQ ID NO: 3 HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; LCDR3 Contains the amino acid sequence of SEQ ID NO: 8. In yet another embodiment, the anti-IL-4R antibody or antigen binding fragment thereof comprises HCVR comprising SEQ ID NO: 1 and LCVR comprising SEQ ID NO: 2. According to a particular exemplary embodiment, the method of the invention comprises the use of an anti-IL-4Rα antibody, which is referred to as dupyrumab or a biological equivalent thereof and which is known in the art.

The term "bioequivalent" as used herein, administration of the same molecular dose such that the efficacy is considered to be essentially the same as the comparison molecule, both in terms of efficacy and safety Refers to molecules that have similar bioavailability (percentage and degree of availability) after and under similar conditions (eg, the same route of administration). Two pharmaceutical compositions comprising an IL-4R antagonist, when they are pharmaceutically equivalent, are bioequivalents, which are the same amount of active ingredient (e.g. in the same dosage form) for the same route of administration. , IL-4R antagonist), and meet the same or equivalent criteria. Bioequivalence can be determined, for example, by in vivo studies comparing pharmacokinetic parameters for the two compositions. Parameters commonly used in _{bioequivalence} studies include peak plasma concentration (C _max ) and area under the plasma drug concentration time curve (AUC).

  Other anti-IL-4Rα antibodies for use in the context of the method of the invention include, for example, AMG 317 (Corren et al., 2010, Am J Respir Crit Care Med., 181 (8): 788-796), Included are antibodies known in the art, or any of the anti-IL-4Rα antibodies described in US Pat. No. 7,186,809 or US Pat. No. 8,092,804.

  The anti-IL-4Rα antibodies used in the context of the method of the invention may have pH dependent binding properties. For example, anti-IL-4Rα antibodies for use in the methods of the present invention can exhibit reduced binding to IL-4Rα at acidic pH as compared to neutral pH. Alternatively, the anti-IL-4Rα antibodies of the invention can exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH. The expression "acidic pH" is less than about 6.2, for example 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 a pH value lower than that. As used herein, the expression "neutral pH" means a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4 .

In certain cases, "reduced binding to IL-4R [alpha] at acidic pH as compared to neutral pH" of the IL-4R [alpha] in _{the K D} value pairs neutral pH of the antibody binding to IL-4R [alpha] at acidic pH Expressed as the ratio of antibody binding _KD values (or vice versa). For example, an antibody or antigen binding fragment thereof, where the antibody or antigen-binding fragment thereof exhibits an approximately 3.0 or more acidic / neutral K _D ratio, as compared to the "neutral pH for the purposes of the present invention the acidic It is considered to exhibit "reduced binding to IL-4Rα at pH". In certain exemplary embodiments, the acidic / neutral _{K D} ratio for the antibody or antigen-binding fragment of the present invention is 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. It may be 0, 70.0, 100.0 or more.

Antibodies having pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH as compared to neutral pH. Furthermore, modification of the antigen binding domain at the amino acid level can generate antibodies with pH dependent properties. For example, by replacing one or more amino acids of an antigen binding domain (e.g., within a CDR) with a histidine residue to obtain an antibody with reduced antigen binding at acidic pH compared to neutral pH it can. As used herein, the expression "acidic pH" means a pH of 6.0 or less.

Pharmaceutical Compositions The present invention comprises the steps of administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions featured in the present invention are formulated with suitable carriers, excipients and other agents that provide suitable transport, delivery, tolerance and the like. Several suitable formulations can be found in formulations known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These preparations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, Included are oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semisolid gels and semisolid mixtures containing carbowaxes. Powell et al. "Compendium
See also, for exipients for parental formulations "PDA (1998) J Pharm Sci Technol 52: 238-311.

  The dose of antibody administered to a patient may vary depending on the patient's age and size, symptoms, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment will be adjusted. The effective dosage and schedule for administering the pharmaceutical composition comprising the anti-IL-4R antibody is determined empirically; for example, the progress of the patient is monitored by periodic assessment, and the dose is adjusted accordingly. In addition, interspecies scaling of dosages is performed using methods well known in the art (eg, Mordenti et al., 1991, Pharmaceut. Res. 8: 1351).

  Various delivery systems are known and administering pharmaceutical compositions containing an IL-4R antagonist, including liposome encapsulated, microparticles, microcapsules, recombinant cells capable of expressing the mutant virus, receptor mediated endocytosis (See, for example, 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 composition may be administered by any conventional route, such as by infusion or bolus injection, by absorption through epithelial or mucosal skin linings (eg, oral mucosa, rectal and intestinal mucosa, etc.) and other biologically active It is co-administered with the drug.

The pharmaceutical composition is delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, pen-type delivery devices are readily useful in the delivery of pharmaceutical compositions. Such pen-type delivery devices, including self-injection pen-type delivery devices, may be reusable or disposable. Reusable pen-type delivery devices generally utilize replaceable cartridges containing the pharmaceutical composition. When all of the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge is easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device is then reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition has been emptied from the reservoir, the entire device is discarded.

  A number of reusable pen-type and automatic injection delivery devices have utility in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 /, to name a few. 25 (TM) pen, HUMALOG (TM) pen, HUMALIN 70/30 (TM) pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN (TM) I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BD (trade ) Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN (TM), OPTIPEN PRO (TM), OPTIPEN STARLET (TM) and OPTICLIK (TM) (sanofi-aventis, Frankfurt, Germany) are included. Examples of disposable pen-type delivery devices having utility in subcutaneous delivery of pharmaceutical compositions include, but are not limited to, SOLOSTARTM pen (sanofi-aventis), FLEXPENTM (Novo Nordisk (Novo Nordisk) ) And KWIKPEN (trademark) (Eli Lilly), SURECLICK (trademark) automatic injector (Amgen, Thousand Oaks, CA), PENLET (trademark) (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRA (Trademark) pen (Abbott Labs, Abbott Park IL) is included.

  For direct administration to the sinus, pharmaceutical compositions containing the IL-4R antagonist use, for example, microcatheters (eg, endoscopes and microcatheters), aerosolizers, powder dispensers, nebulizers or inhalers. To be administered.

  In certain situations, the pharmaceutical composition is delivered in a controlled release system. In one embodiment, a pump is used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201). In another embodiment, polymeric materials are used; Medical Applications of Controlled Release, Langer and Wise (ed.), 1974, CRC Pres. See Boca Raton, Florida. In yet another embodiment, the controlled release system is placed in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose (eg, Goodson, 1984, in Medical Applications of Controlled Release, supra, 2 (See pp. 115-138). Other controlled release systems are described in the review by Langer, 1990, Science 249: 1527-1533.

Formulations for injection may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, infusion and the like. These injectable preparations are manufactured by known methods. For example, a preparation for injection is produced, for example, by dissolving, suspending or emulsifying the above-mentioned antibody or a salt thereof in a sterile aqueous medium or oily medium conventionally used for injection. The aqueous medium for injection includes, for example, isotonic solution containing physiological saline, glucose and other adjuvants, which are alcohols (eg ethanol), polyalcohols (eg propylene glycol, polyethylene glycol) And nonionic surfactants [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. are used in combination with a suitable solubilizer. As an oily medium, for example, sesame oil, soybean oil and the like are used, which are used in combination with solubilizers such as benzyl benzoate, benzyl alcohol and the like. The injection prepared in this way is preferably packed in a suitable ampoule.

  Advantageously, the above-mentioned pharmaceutical compositions for oral or parenteral use are manufactured into dosage forms in unit doses adapted to be compatible with the dose of the active ingredient. Such unit dose forms include, for example, tablets, pills, capsules, injections (ampules), suppositories and the like.

Dosage The amount of IL-4R antagonist (eg, anti-IL-4R antibody or antigen binding fragment thereof) administered to a subject in accordance with the methods characterized herein is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" is a dose of an IL-4R antagonist that results in a detectable amelioration of one or more symptoms associated with a nasal polyp, or a nasal polyp or nasal polyp A dose of an IL-4R antagonist that inhibits, prevents, reduces or slows the progression of a condition associated with In the case of anti-IL-4R antibodies, the therapeutically effective amount is about 0.05 mg to about 600 mg, for example about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg , About 20 mg, about 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 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 330 mg, about 340 mg, About 350 mg, about 360 mg, about 370 mg, about 380 mg, about 3 0 mg, about 400 mg, about 410 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 550 mg, about 550 mg It may be about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg of an anti-IL-4R antibody or antigen binding fragment.

  The amount of IL-4R antagonist contained within an individual dose is expressed as milligrams of antibody per kilogram body weight of the patient (ie, mg / kg). For example, an IL-4R antagonist is administered to a patient at a dose of about 0.0001 to about 10 mg / kg patient body weight.

Combination Therapy Methods according to certain embodiments include administering one or more additional therapeutic agents to a subject in combination with an IL-4R antagonist. As used herein, the expression "in combination with" means that the additional therapeutic agent is administered before, after or simultaneously with the pharmaceutical composition comprising the IL-4R antagonist. For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent is about 72 hours, about 60 hours, about 48 hours of administration of the pharmaceutical composition comprising the IL-4R antagonist. About 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes ago Be done. When administered "after" the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent is about 10 minutes, about 15 minutes, about 30 minutes, about 1 of the administration of the pharmaceutical composition comprising the IL-4R antagonist. It is administered after time of about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours. The administration "simultaneously" with the pharmaceutical composition comprising the IL-4R antagonist is separate agent within less than 5 minutes (before, after, or simultaneously) of the administration of the pharmaceutical composition comprising the additional therapeutic agent comprising the IL-4R antagonist. Means administered to the subject in the form or administered to the subject as a single combined dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

Additional therapeutic agents include, for example, other IL-4R antagonists, IL-1 antagonists (including, for example, the IL-1 antagonists described in US Pat. No. 6,927,044), IL-6 antagonists, IL- 6R antagonists (including, for example, anti-IL-6R antibodies described in US Pat. No. 7,582,298), IL-13 antagonists, TNF antagonists, IL-8 antagonists, IL-9 antagonists, IL-17 antagonists , IL-5 antagonist, IgE antagonist, CD48 antagonist, antibiotic (eg, doxycycline), antifungal, leukotriene, antihistamine, α-adrenergic decongestant, mucolytic, NSAID, long acting beta ₂ agonist (E.g. Rumeteroru or formoterol), short-acting beta ₂ agonists, steroids (e.g., oral steroids), intranasal corticosteroids (e.g., mometasone furoate (MFNS; e.g., Nasonex (R))) or inhaled corticosteroids It may be a corticosteroid such as (eg, fluticasone or budesonide), an allergen immunotherapy, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is a combination comprising a long acting beta ₂ agonist and an inhaled corticosteroid (e.g. fluticasone + salmeterol [e.g. Advair (R) (GlaxoSmithKline Or budesonide plus formoterol [e.g., Symbicort (R) (Astra Zeneca)]).

  In some embodiments, the IL-4R antagonist is administered after the subject has undergone surgery to treat a nasal swab.

Administration Regimens According to certain embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a defined time course. The method comprises, for example, sequentially administering to the subject multiple doses of the IL-4R antagonist. As used herein, "sequentially administering" means that each dose of IL-4R antagonist is on different days separated by different time points, eg, predetermined intervals (eg, hours, days, weeks or months) Is meant to be administered to the subject. The present invention provides a patient with a single initial dose of IL-4R antagonist followed by one or more secondary doses of IL-4R antagonist, optionally followed by one or more tertiary doses of IL-4R antagonist A method comprising the steps of sequentially administering

  The terms "initial dose", "second dose" and "third dose" refer to a time series of administration of an IL-4R antagonist. Thus, the "initial dose" is the dose administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary dose" is the dose administered after the initial dose; "the tertiary dose "Is the dose administered after the secondary dose. The initial, secondary and tertiary doses may all contain the same amount of IL-4R antagonist, but generally differ from one another in terms of dosing frequency. However, in certain embodiments, the amount of IL-4R antagonist included in the initial, secondary and / or tertiary doses varies with each other during the course of treatment (eg, adjusted upward or downward as required) ).

  In one exemplary embodiment, the secondary and / or tertiary doses are each for 1 to 14 weeks of the last dose (eg, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12. 5, 13, 13.5, 14, 14.5 or more). The phrase "immediate dosing," as used herein, is a series of multiple administrations, with no intervening medication being administered to the patient prior to the administration of the next dose, in that order immediately prior to the administration of the next dose. Refers to dosing of the -4R antagonist.

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

  In embodiments comprising multiple secondary doses, each secondary dose is administered as frequently as the other secondary doses. For example, each secondary dose is administered to the patient one to two weeks after the last dose. Similarly, in embodiments that include multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose is administered to the patient two to four weeks after the last dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to the patient may be varied over the course of the treatment regimen. The frequency of administration is also adjusted during the course of treatment by the physician depending on the needs of the individual patient after clinical examination.

  In certain embodiments, the initial dose (eg, "loading dose") is greater than either or both of the secondary and tertiary doses. For example, the initial dose may be a loading dose, which is 1.5 times, 2 times, 2.5 times, 3 times or more of the secondary dose.

Treatment Groups The methods characterized in the present invention comprise the step of administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. As used herein, the expression "subject in need thereof" refers to a human who exhibits one or more symptoms or signs of nasal blebs or has been diagnosed with chronic symptoms of nasal blebs or sinusitis. Or means non-human animals. For example, a subject in need thereof has a bilateral nasal polyp, and at least a score of at least 5 to at most 8 for both nares, with a score of at least 2 for each nostril. In a particular embodiment, the polyp is in the middle nasal passage. In certain embodiments, the presence of nasal polyps is confirmed by endoscopy. In some embodiments, the subject also has bilateral mucosal disease, as confirmed by a method such as a CT scan. As used herein, "bilateral mucosal disease" is an infection of the nasal cavity, for example, the mucosal lining of the maxillary nasal cavity. In some embodiments, the nasal polyps (eg, at least 5 to a maximum of 8 nasal polyp scores for both nostrils with a score of at least 2 for each nostril) have at least 6 weeks, at least 7 weeks, at least 8 weeks of INCS It lasts even after treatment regimens of inhaled corticosteroids (INCS), such as when administered, for an extended period of time or longer.

In certain embodiments, the subject in need thereof has anterior and / or posterior mucopurulent drainage, nasal obstruction and reduced olfactory sensation. In certain embodiments, a subject in need thereof has symptoms of nasal swabs for six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks or more. In still other embodiments, the subject has received at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, or more prior to receiving treatment with the IL-4R antagonist. During the above, treatment with an intranasal corticosteroid (eg, MFNS) or the like has previously been received. In some embodiments, the subject continues to receive INCS while undergoing treatment with an IL-4R antagonist. In other embodiments, the subject ceases to receive INCS prior to receiving treatment with an IL-4R antagonist, or the subject is effective to administer nasal IL-4 administration with an IL-4R antagonist, Stop receiving treatment with INCS. In some embodiments, the subject gradually reduces the dose of INCS before completely stopping treatment.

  Subjects in need thereof are further diagnosed with nasal polyps based on one or more of the following: (a) 22-item sinus evaluation test (SNOT-22) score; (b) evaluated by subject Nasal congestion / anterior rhinorrhea, posterior rhinorrhea and loss of sense of smell; (c) number of awakenings at night; (d) visual for assessing the severity of nasal sinus symptoms associated with the patient Analog score (VAS); (e) 5-item Asthma Management Questionnaire (ACQ 5) score in patients with asthma; (f) nasal maximum inspiratory flow (NPIF); (g) olfactory test (University of Pennsylvania Olfactory Identification Test (UPSIT) (H) Physiological parameters measured by, for example, nasal endoscopy and CT scan; (i) Lund-Mackay score; and (k) Three-dimensional volumetric measurement of maxillary sinus.

  For example, in certain embodiments, "a subject in need thereof" is a human patient with chronic symptoms of sinusitis in which at least two of the following symptoms are present: nasal blockage / obstruction / clogs Or nasal discharge (front / rear rhinorrhea); facial pain / pressure sensation; and loss or loss of sense of smell.

  In certain embodiments, the "subject in need thereof" is greater than about 7, about 10, about 15, about 20, about 25, about 30, about 30, about 35, about 40, about 45. Human patients having a SNOT-22 score of over or above about 50. "Subjects in need thereof" are also more than about 4, about 5, more than about 6, more than about 7, more than about 8, more than about 9, more than about 10, more than about 11, more than about 12, or more than about 13. It may be a human patient exhibiting a Lund-Mackay score of

In a related embodiment, the "subject in need thereof" is a subject prior to receiving an IL-4R antagonist, or who has been prescribed or is currently receiving another medication, "background therapy". It may be. Background therapy may be, for example, intranasal corticosteroids (INCS or ICS), such as a nasal spray of mometasone furoate (MFNS; Nasonex®). In some embodiments, the "subject in need thereof" is prescribed INCS prior to receiving an IL-4R antagonist or in combination with a long acting beta ₂ -adrenergic antagonist (LABA) Or is currently receiving asthmatic patients. Examples of INCS / LABA therapies include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. In some embodiments, background treatments include nasal saline, topical decongestants, local anesthetics, leukotriene antagonists or systemic antihistamines. In some embodiments, the “subject in need thereof” continues background therapy after the subject receives an IL-4R antagonist, and in other embodiments, the subject in need thereof is IL Stop receiving background therapy (e.g., once or gradually) before receiving the -4R antagonist.

  The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of methods of making and using the methods and compositions characterized in the present invention, the inventors of the present invention It is not intended to limit the scope of what is considered. Efforts have been made to ensure accuracy with respect to the numbers used (eg, amounts, temperatures, etc.) but some experimental errors and deviations must be taken into account. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric pressure.

Example 1: Subcutaneously administered anti-IL-4R antibody (mAb 1) in patients with persistent moderate to severe eosinophilic asthma including asthmatic patients with chronic hypertrophic eosinophilic sinusitis Clinical trial A. Study Objectives and Overview Randomized, placebo-controlled, double-blind, parallel-group studies were partially managed / managed by inhaled corticosteroids (ICS) and long-acting beta 2 agonist (LABA) treatment Patients who did not have persistent moderate to severe eosinophilic asthma were given a weekly subcutaneous dose of either 300 mg of Dupilumab (“mAb1”) or placebo for 12 weeks. Dupilumab is an anti-IL-4R antibody having a heavy chain variable region of SEQ ID NO: 1 and a light chain variable region of SEQ ID NO: 2. Dupilumab is described in US Pat. No. 7,608,693.

  The main objective of the study was to monitor once-weekly 12 week weekly comparison with placebo for reduced incidence of asthma exacerbation in patients with persistent moderate to severe eosinophilic asthma It was to examine the effect. The secondary objectives of this study were to evaluate the safety and tolerability of mAb1, administered subcutaneously once weekly for 12 weeks, in patients with persistent moderate to severe eosinophilic asthma and The aim was to evaluate mAb1 serum concentrations after subcutaneous dosing once weekly for 12 weeks in patients with moderate to severe eosinophilic asthma.

Prior to screening, patients had to continue on at least one month a stable dose of either of the following doses and prescription of ICS / LABA combination therapy (also called "background therapy"):
Fluticasone / salmeterol combination therapy-Advair® Diskus-Dry Powder Inhaler (DPI): 250/50 ug BID or 500/50 ug BID; or-Advair® HFA-Metered dose inhaler (MDI): 230/42 ug Or budesonide / formoterol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or mometasone / formoterol combination therapy (Dulera® 200/10 ug BID or 400/10 ug) BID).

  Patients who were on budesonide / formoterol or mometasone / formoterol are switched to the equivalent dose of fluticasone / salmeterol at randomization (day 1) and those who are on fluticasone / salmeterol are on background therapy It remained the same.

  Patients who met inclusion and exclusion criteria (see below) were randomly selected for one of the following treatments: mAb1 300 mg subcutaneously for 12 weeks, once weekly; or placebo for 12 weeks It was administered subcutaneously once a week.

  The study included a 12-week treatment period that included a 2-week screening period, a 4-week background treatment stabilization period after randomization and an 8-week background treatment withdrawal period, followed by an 8-week post-treatment follow-up period Was included.

Algorithm for background treatment (ICS / LABA) withdrawal:
Patients remained on BID fluticasone / salmeterol background treatment for 4 weeks after commencing addition therapy or treatment with 300 mg mAb1 (or placebo). Four weeks after randomization, patients were treated with BID fluticasone / salmeterol combination therapy to fluticasone monotherapy (250 ug or 500 ug BI) at equivalent ICS dose
Or with either 220 ug or 440 ug BID Flovent® HFA-MDI formulations. The LABA component (i.e. salmeterol) was interrupted. At the next visit, if the patient did not meet any of the criteria for asthma exacerbation (as defined below), the fluticasone dose was reduced by about 50% starting at week 6. If asthma exacerbation did not occur, ICS withdrawal proceeded according to the following schedule:

  When 12 weeks of treatment with study drug are complete (or after an early discontinuation), fluticasone / salmeterol to manage the patient for an additional 8 weeks of off-study medication prior to final safety assessment. , Budesonide / formoterol or mometasone / formoterol (dose at study entry) and, if necessary, set to the original dose of albuterol or reb albuterol.

  An overview of the study protocol is given in FIG.

Adult patients were included in the study based on the following criteria: (1) Diagnosis of a doctor with persistent asthma for at least 12 months or more based on the Global Initiative for Asthma (GINA) 2009 guidelines, The airway inflammation may be eosinophilic; and (2) the asthma is partially controlled with inhaled corticosteroid / long-acting beta-agonist combination therapy according to the following criteria or Not administered: (i) Fluticasone / salmeterol combination therapy (DPI formulation: 250/50 μg BID or 500/50 μg BID or MDI formulation: 230/42 μg BID or 460/42 μg BID) for at least one month before screening, or budesonide / Ho Stable dose of either moterol combination therapy (160/9 μg BID or 320/9 μg BID), or mometasone / formoterol combination therapy (200/10 μg BID or 400/10 μg BID); Acid sphere ≧ 300 cells / μl or vaginal eosinophil ≧ 3%; (iii) Juniper asthma management questionnaire (5-question edition, ACQ) score at 1.5 or more and 3.0 or less at screening; (iv) screening Expected to be normal with FEV1 50% or greater during the phase (up to 3 trials) and at randomization of the day before the first dose (up to 3 trials); (v) within 2 years before screening Treatment with one or more systemic (oral and / or parenteral) steroid bursts for asthma exacerbation, or Is either hospitalization or emergency treatment visit for asthma exacerbation; and (vi) within 12 months of screening, in the FEV1 after 200 μg to 400 μg (2 to 4 inhalations) of albuterol during the baseline-screening phase Reversible documented history meeting at least 12% and 200 mL (up to 3 trials), or documented history of positive methacholine load (PD20 methacholine 8 mg or less) within 12 months prior to screening. Partially managed or managed with a combination of moderate to high-dose combination therapy with inhaled corticosteroids and long-acting beta agonists (ADVAIR®, SYMBICORT® or DULERA®) Not moderate, but moderate to severe with blood eosinophils equal to or greater than 300 cells per microliter, or vaginal eosinophils equal to or greater than 3%, during the screening phase. Patients with asthma were included in the study.

  Patients meeting all inclusion criteria were screened for the following exclusion criteria: (1) Patients younger than 18 or older than 65 years; (2) Clinically suggestive of unknown disease and require further evaluation Associated abnormal clinical laboratory data; (3) chronic obstructive pulmonary disease (COPD) and / or other pulmonary diseases that impair lung function testing; (4) need for beta adrenergic receptor blockade for any reason (5) current smoker or smoking cessation within 6 months before screening; (6) smoking history more than 10 boxes in 6 years; (7) hospitalization or emergency treatment due to asthma exacerbation during 2 months before screening Visit (8) to start allergen immunotherapy within the study period; (9) period before screening that is less than 5 half life of antibody but more than 30 days, or know half life of antibody If not, exposure to another test antibody within the pre-screening period, which is at least 6 months; (10) Previous enrollment in current study; (11) Patient is investigator, patient (12) known or suspected non-compliance, alcohol or substance abuse; (13) unable to follow test procedures (eg, language problems or psychological disorders) (14) reversal of sleep patterns (eg night workers); (15) treatment with drugs known to prolong QTc intervals; (16) ICS (eg active or non-active) Accompanying severe illness where the use of active pulmonary tuberculosis) or LABA (eg, diabetes, cardiovascular disease, high blood pressure, hyperthyroidism, thyroiditis etc) is contraindicated; (17) screenin Use of glucocorticosteroid or oral systemic glucocorticosteroid for injection more than 3 processes within 2 months before or 6 months before screening; (18) alone or in combination with non-steroidal controller (fluticasone / Pre-treatment with ICS with variable doses of salmeterol combination therapy, budesonide / formoterol combination therapy or mometasone / formoterol combination therapy, either; (19) with banned combination drugs (listed below) (20) known allergies to doxycycline or related compounds; (21) intention to become pregnant in the process of pregnancy or testing, not to use effective methods of breastfeeding or contraception; and (22) parasite infection Recent medical history or 6 months prior to screening Trip to the parasite endemic area in the area.

  For the first four weeks of the study, patients maintain a constant dose of background asthma treatment and then gradually reduce the background treatment dose. First, the long-acting beta agonist component of background therapy was withdrawn at 4 weeks and then the inhaled corticosteroid dose was reduced by half every two weeks to 12 weeks. Patients continued study treatment until the end of the study or until withdrawal due to asthma exacerbation or any other reason.

B. Study Treatment Study Drug: A sterile mAb1 150 mg / mL solution for SC injection was provided in 5 mL glass vials. Each vial contained 2 mL drawable volume. A 300 mg dose was administered subcutaneously at the study site once a week in the morning for 12 weeks. Placebo: A sterile placebo for SC injection was provided in a completely identical 5 mL glass vial. Each vial contained 2 mL drawable volume. A placebo was administered subcutaneously at the study site once a week for 12 weeks in the morning.

  The following combination medications were not permitted during the study period: Fluticasone / Salmeterol combination therapy administered according to protocol or any other than fluticasone (or budesonide / formoterol or mometasone / formoterol) during the screening period Inhaled steroids; systemic or ocular steroids; LABA other than the salmeterol component of fluticasone / salmeterol combination therapy administered according to the protocol; any other ICS / LABA combination product other than those indicated above; any inhaled anticholinergic agent (Eg ipratropium bromide or tiotropium); methylxanthines (theophylline, aminophylline); chromones; anti-IgE treatment; lipoxygenase inhibitors; and leukotriene receptors Tagonisuto or leukotriene synthesis inhibitors.

C. Treatment Efficacy The primary endpoint of this study was the development of asthma exacerbation as defined by any of the following: (1) 30 consecutive days from baseline at peak morning expiratory flow (PEF) for two consecutive days % Or more reduction; or (2) six or more additional seizure therapy puffs of albuterol or levalbuterol (compared to baseline) for two consecutive days, 24 hours (or as compared to baseline); ) Investigative responsibility requiring systemic (oral and / or parenteral) steroid treatment, or (b) a four-fold increase in ICS of the last dose received prior to discontinuation from the study, or (c) hospitalization Deterioration of asthma as determined by a physician.

  Secondary endpoints of the study included the mean change from baseline of the following parameters: Baseline and treatment endpoint (Week 12) to assess upper airway symptoms, (1 ) 1 second Forced expiratory volume (FEV 1) in liters measured at each visit time; (2) morning and night maximum expiratory flow in liters / min measured daily (AM PEF and PM PEF); (3 ) Daily use of albuterol / reb albuterol by inhalation / day; (4) 5-item Asthma Control Questionnaire (ACQ 5) score per visit; and (5) daily awakening at night (counts per night) ), And (6) 22 item sinus evaluation test (SNOT-22). Secondary endpoints were also based on two consecutive days of morning PEF, with six or more additional seizure treatment puffs of albuterol or levalbuterol (compared to baseline) for two consecutive days, 24 hours The proportion of patients with complex asthmatic events defined by a 30% or more reduction from the line was included. PEF, ACQ5, asthma symptom score, nocturnal awakening, and seizure therapy treatment use were obtained in an electronic diary. Average daily nocturnal awakening ranging from 0-10 was averaged from the previous 7 days. Morning and night asthma symptom scores consist of the results reported by non-validated patients rated on a 5-level Likert scale, with higher scores showing worse results (Table 2). Patients recorded a global symptom score twice daily before measuring PEF. Data were stated as an average of 7 days prior to the time point identified.

D. Adverse Event Monitoring Safety was assessed throughout the study by monitoring adverse events and serious adverse events.

  An adverse event (AE) is any adverse medical event in a subject who has received medication or is under clinical consideration. Therefore, AE is not associated with any medication (trial), whether or not it is associated with the use of the medication any undesirable unintended signs (including abnormal laboratory findings), It may be a symptom or a disease. AEs are also: any deterioration of existing conditions (ie, any clinically significant change in frequency and / or intensity) that is temporally related to the use of the study drug; Abnormal laboratory findings considered to be significant; and including any adverse medical events.

  Do serious adverse events (SAEs) result in death at any dose; life-threatening; require hospitalization or prolongation of current hospitalization; cause persistent or significant disability / incompetence A congenital abnormal / congenital defect; or any adverse medical event that is a serious medical event.

E. Statistical Methods For primary analysis of the proportion of patients experiencing asthma exacerbation, SAR groups were compared to placebo using a logistic regression model. This model included terms for treatment and stratification factors (preceding ICS / LABA combined therapeutic doses). Primary analysis was performed based on the modified intent-to-treat (mITT) population, which included all randomized patients who received at least one dose of mAb1. Stratified chi-square test was also used to support primary analysis.

For secondary efficacy endpoints except SNOT-22, changes from baseline were analyzed using a mixed effects model using the repeated measures (MMRM) approach. The model is based on changes from baseline values up to 12 weeks as response variables, and factors for treatment (parameter effects), stratification factors, visits, treatment interactions by visits, baseline values and visits It included baseline interactions. Statistical estimates for treatment comparisons for changes from baseline at 12 weeks were derived from mixed effects models. The change from baseline in SNOT-22 was analyzed using measurements at the end of treatment to impute missing data using analysis using covariance analysis (ANCOVA). Pharmacodynamic effects were assessed using the MMRM model in a post hoc manner. No adjustment was made for multiplicity, as there was only one primary endpoint and analysis. Safety variables, including AE, test parameters, vital signs, ECG, laboratory findings and physical examination, were summarized using descriptive statistics.

  Demographic and clinical features were summarized using descriptive features. Plots of secondary and pharmacodynamic variables are shown as mean change from baseline over time with standard error. Comparison of treatment effects from MMRM analysis is based on the least mean square change (95% confidence interval [CI]) from the 12 week baseline.

F. Results The results observed for all 104 randomized patients (screened from 491) who completed or discontinued the treatment phase of the study are summarized below. All randomized patients were exposed to study treatment and included in the mITT population. Baseline characteristics were similar among groups. Demographic and clinical characteristics were also similar between the two groups (Table 3). As indicated above, patients were treated once weekly with either 300 mg subcutaneous mAb1 or placebo. The study treatment period was completed by 86.5% and 67.3% of mAb1 and placebo patients, respectively. The most common cause of discontinuation was lack of efficacy, which was more frequent with placebo (21.2%) than with mAb1 (1.9%).

(I) Main efficacy endpoint The incidence of asthma exacerbation in the placebo and mAb1 treated groups is shown in Table 4.

  There were a total of 26 asthma exacerbations during the treatment period, and no patients were hospitalized for asthma exacerbations. Twenty-three patients (44.2%) experienced asthma exacerbation in the placebo group, while only 3 patients (5.8%) experienced asthma exacerbation in the mAb1 treated group. The odds ratio was 0.077 (p <0.0001) and the relative risk reduction was about 87%.

  As demonstrated by the need for immediate intervention in the form of treatment with either systemic corticosteroids or inhaled corticosteroids at doses four or more times the dose taken prior to the event, this study Of the 26 asthmatic exacerbations experienced during the period, nine were considered severe. An outline of the incidence of severe asthma exacerbation is shown in Table 5.

  As shown in Table 5, eight severe asthmatic exacerbations were observed in the placebo group, and only one severe asthmatic exacerbation was observed in the mAb1 treatment group. The asthma exacerbation of the remaining 15 people in the placebo group and 2 people in the mAb1 group meets the protocol definition of an exacerbation based on reduced morning PEF use and / or increased albuterol / rev albuterol use. Within the active treatment group, sustained improvement to baseline was observed during the course of the study for all parameters despite steroid withdrawal.

  For mAb1, the time to progression was longer compared to placebo and the risk of progression decreased (hazard ratio 0, 10; 95% CI 0.03, 0.34; P <0.001). Analysis of the time to asthma exacerbation by Kaplan-Meier plot shows that the effect of treatment with mAb1 persists for a long time, including 8 weeks after the patient is at higher risk of developing progression due to steroid withdrawals Revealed that

  Only one patient from the placebo group had a complex asthmatic event. A complex asthmatic event is from a baseline in the morning PEF for two consecutive days, with six or more additional seizure treatment puffs of albuterol or levalbuterol (compared to the baseline) for two consecutive days, 24 hours Defined as 30% or more decline.

(Ii) Other efficacy endpoints Lung function parameters (FEV1, AM PEF and PM PEF), asthma symptoms based endpoints (ACQ score, nocturnal awakening), and albuterol use were assessed for each patient at each visit. In addition, SNOT-22 scores were assessed at baseline and at the end of treatment. For all parameters, mean baseline and week 12 (LOCF) values are summarized in Table 7 (ANOVA model for SNOT-22) along with the mean differences between treatment groups. In Table 7, the column labeled "Differences to placebo" is placebo-corrected from baseline taking into account the observed change in the value of the parameter compared to the observed change for that parameter in the placebo-treated group Indicates a value.

  Treatment with mAb1 resulted in a significant change from baseline in FEV1 at 1 week, which was maintained up to 12 weeks despite LABA and ICS withdrawal, and FEV1 at 5 weeks with LABA withdrawal Decreased slightly. Similar improvements were observed in the morning PEF, but smaller in the night PEF. The least squares (LS) mean change from baseline to week 12 in FEV1 was -0.22 L for placebo and 0.05 L for the mAb1 group (p = 0. 0009).

ACQ5 scores improved at week 1 in both treatment groups. However, although ACQ5 improved further with mAb1 between week 1 and week 4, the placebo effect stabilized and remained differential up to 12 weeks.

  Morning symptom scores increased with placebo from baseline to 12 weeks. For mAb1, there was an initial decrease that remained below baseline until 12 weeks. A similar pattern (greater variation) was observed in the night asthma symptom score.

  Nocturnal awakening was stable from the placebo group until 6 weeks and then increased from 6 weeks to 12 weeks. In contrast, nocturnal awakening was reduced by week 1 in the mAb1 group and remained improved relative to baseline by 12 weeks.

  The change in albuterol / leb albuterol use was similar to other secondary endpoints: returned to baseline after initial reduction with placebo. For mAb1, the initial decline was maintained over time.

  There were non-significant differences at baseline between SNOT-22 values, the mean placebo score was 26.24 and the mean mAb1 score was 39.02. At week 12, the LS mean change was a slight increase of 0.23 points for the placebo group and an average decrease (improvement) of 8.26 points for the mAb1 group. This corresponded to an improvement of 8.49 points for the mAb1 group (p = 0.0027).

For all secondary endpoints, with the exception of nightly PEF and nocturnal awakening, the 12 week measurements were beneficial and significant with mAb1 treatment (Tables 7 and 8). Significant improvement with mAb1 was also observed for the three SNOT-22 items associated with upper respiratory tract disease (Table 9).

(Iii) Safety mAb1 was generally safe and well tolerated. Treatment-induced adverse events (TEAEs) were similarly reported by 40 (76.9%) placebo-treated patients and 42 (80.8%) mAb1-treated patients (Table 10). . TEAE is nonspecific, generally mild to moderate strength, and has mostly recovered by the end of the study. The following increased reports of TEAE were observed for mAb1 compared to placebo: Injection site reactions reported by 15 (28.8%) mAb1 patients and 5 (9.6%) placebo patients Nasopharyngitis was reported by 7 (13.5%) mAb1 patients and 2 (3.8%) placebo patients; 6 (11.5%) headache mAb1 patients and 3 ( Nausea was reported by four (7.7%) mAb1 patients and one (1.9%) placebo patients.

  No deaths were reported during the study period. Serious adverse events (SAEs) that occurred under the 4 treatments reported: 1 mAb1 patient experiences bipolar disorder, 3 placebo patients have asthma with pneumonia, gunshot wound with left pneumothorax and We experienced SAE of right ankle fracture. None of these SAEs were considered to be related to mAb1 and all but the new ankle fracture had recovered by the end of the study. There was no death.

  A total of 6 patients discontinued the study for TEAE: 3 patients in the mAb1 group (bipolar disorder, asthma with asthma and angioedema) and 3 patients in the placebo group (upper respiratory tract infection, psoriasis) And asthma). TEAE of angioedema developed in a 42-year-old African American female after a ninth study treatment dose as a common, generalized pruritus at the injection site and away from the injection site. This lasted one week and resolved after study treatment discontinuation and prednisone and diphenhydramine treatment. This was considered to be treatment related. This AE was after a milder rash at the injection site after the first and sixth study treatment doses.

  Among the most common AEs occurring in more than two patients in any treatment group (Table 10), injection site reactions, nasopharyngitis, nausea and headache occurred more frequently with mAb1 than placebo. No clinically significant changes in vital signs, physical examination, clinical examination or ECG findings were reported in any group.

G. Conclusions Significant improvements have been observed for lung function and other asthma management parameters. Efficacy was observed early and sustained despite background treatment withdrawal. About 87% relative reduction (p <0.0001) in the primary endpoint of the incidence of asthma exacerbation in patients with persistent moderate to severe asthma with eosinophilia, with placebo (44.2% Compared to after 12 weeks of treatment with 300 mg of mAb1 once a week (5.8%). As shown in Table 7, clinically significant (no multiplicity adjustment) improvement in treatment compared to placebo, but with pulmonary function parameters (FEV1, PEF AM), asthma symptom score (ACQ) And albuterol were observed. Beneficial trends were observed for PEF PM (p = 0.0567) and night awakening (p = 0.0518). Statistically significant (no multiplicity adjustment) improvement was also observed for SNOT-22 scores. Within the active treatment group, sustained improvement to baseline was observed during the course of the study for all parameters despite the withdrawal of LABA and ICS. mAb1 was generally safe and well tolerated.

Example 2 Biomarker Studies Biomarker analysis was performed on samples obtained from subjects who participated in clinical trials of mAb1 (see Example 1 above). In particular, it is associated with TH2 inflammation such as thymus and activated chemokine (TARC; CCL17), immunoglobulin E (IgE), eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and blood eosinophils Serum / plasma biomarkers were measured in samples from patients at baseline and at different times after initiation of study treatment. Baseline levels of these biomarkers were assessed for potential predictors of treatment response. In addition, exhaled NO concentration (FeNO) and induced chewing eosinophils and neutrophils were measured as biomarkers of bronchial inflammation. Exhaled nitric oxide assessment was performed using a NIOX instrument (Aerocrine AB, Solna, Sweden) before spirometry and after at least 1 hour of fasting. The biomarkers are analyzed using a mixed model and the least squares mean derived from the model is reported below.

  For asthmatic subjects (N = 104), either mAb1 (300 mg) or placebo, on study days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (ie Administered subcutaneously for 12 weekly doses) (see Example 1 above). Samples for biomarker analysis were taken at 0, 1, 4, 8 and 12 weeks from antibody-treated and placebo-treated subjects. Antigen specific IgE was detected using the Phadiatop® test.

  TARC, eotaxin-3 and IgE remained unchanged in response to placebo. In contrast, TARC (mean% change + -22.7% vs. 0.3%; p = 0.0003) and eotaxin-3 (mean% change-12. 36% vs-39.62%; p A rapid drop of <0.0001) was observed within 1 week in patients treated with mAb1 and lasted up to 12 weeks: TARC: -26.0% vs. 7.6% placebo (p = 0) Eotaxin-3: + 5.13% vs. -45.67% (p <0.0001).

  TARC levels responded within one week after exposure to mAb1 given subcutaneously at 300 mg. TARC levels became constant at approximately 50% of baseline levels in subjects treated with mAb1, regardless of ICS withdrawal. The data show that TARC expression is more directly associated with IL-4R signaling than FEV1 changes (which decreased in parallel with ICS withdrawal [4 weeks later]), and that IL-4R blockade Induces a shift to the TH1 feature, as observed, for example, with IFN gamma administration. In particular, it may be possible to titrate mAb1 doses using TARC (and eg CXCL10) in patients who require long-term treatment and are at risk for TH1-type immune disease.

  Total serum IgE also decreased after mAb1 treatment. The total serum IgE response was more heterogeneous and delayed compared to the TARC response. Mean (SD) baseline IgE levels were 694.68 IU / L (1837.82) for the placebo group (n = 52) and 657.66 (1482.25) for the mAb1 group (n = 52). The median was 169.95 for the placebo group and 206.15 for the mAb1 group. Despite this heterogeneity, a trend towards reduced IgE in mAb1 exposed patients compared to placebo was observed but only began at 4 weeks. Serum IgE is significantly reduced in the mAb1 group compared to placebo (mean% change, 10.1% vs + 13.5%; p = 0.0325), which starts at week 4 and 12 weeks It continued to decrease (mean% change, -36.8% for mAb1 vs. -5.5% for placebo; p <0.0001).

  Changes from baseline and placebo at week 12 for FeNO, TARC, eotaxin-3, and IgE were all favorable for mAb1 (all P <0.001) (Table 11). No differences from baseline or differences between treatments were observed with YKL-40 or CEA.

There was a temporary decrease in periostin levels, followed by an increase with LABA / ICS withdrawal. Administration of mAbl delayed the increase but did not prevent the increase above baseline. Consistent treatment effects were not observed with CEA and YKL-40. The number of blood eosinophils remained unchanged until 6 weeks, but increased at 8 and 12 weeks thereafter. Peripheral blood eosinophil counts did not change with placebo throughout treatment. The differences between treatments were not significant, and only in some patients treated with mAb1 a larger increase in blood eosinophilia promoted a borderline increase. Little to no increase was observed in most of the patients.

  As only 3 mAb1 patients experienced asthma exacerbation during the study, no conclusions were drawn as to the association between baseline biomarker levels and asthma exacerbation.

  mAb1 treatment was also associated with a significant decrease from baseline at week 4 FeNO, and despite ICS withdrawal, FeNo remained below baseline by week 12 (mean% week 12) Change: -28.7 for mAb1 vs. 35.0 for placebo; p <0.0001). In contrast, placebo FeNo values remained stable until week 8 and then increased at week 12 consistent with ICS withdrawal.

The improvement in forced expiratory volume (FEV ₁ ) for ₁ second was significantly correlated with FeNO reduction (r = −0.408, p = 0.009) at 12 weeks. Similarly, improvements in AM-PEF and PM-PEF were correlated with FeNO reduction. Other correlations with FeNO were not significant. See Table 13.

  Scatter plot analysis of changes from baseline in baseline eosinophils versus week 12 at baseline, as measured by changes from baseline at week 12 in FEV1 in the study population, baseline eosinophils and treatment effects It did not seem to show any relationship with (baseline eosinophil ≧ 0.3 giga / L). Baseline eosinophils were correlated with decreased ACQ and decreased albuterol / leb albuterol use. Baseline periostin and YKL-40 were correlated with decreased ACQ.

  The FEV1 change from the 12th week baseline was exacerbated by the withdrawal of the ICS (on the 4th week). A similar analysis does not suggest an association between baseline TARC or IgE and changes from baseline of FEV1 at 12 weeks in the study population (baseline eosinophils 0.3 0.3 giga / l) The

H. Summary These results indicate that mAb1 significantly reduced serum biomarkers associated with Th2 inflammation (TARC, Eotaxin-3 and IgE) and bronchial inflammation (FeNO) in adult asthmatic patients. The correlation between FeNO reduction and FEV ₁ improvement suggests a relationship between IL-4 / IL-13 mediated anti-inflammatory activity and improvement of lung function in moderate to severe uncontrolled asthma.

Example 3 Clinical Trials of Anti-IL-4R Antibody (mAb1) Administered Subcutaneously in Patients with Chronic Symptoms of Bilateral Sinusitis and Sinusitis Research Objectives and Summary The positive effect of mAb1 on the SNOT-22 test described in Example 1 suggested that anti-IL-4R antibodies may also be effective in treating nasal polyps. In addition, nasal polyps were most commonly driven by eosinophilic / TH2, and mAb1 significantly reduced biomarkers associated with Th2 inflammation (see Example 2). Therefore, a clinical trial was designed to test the therapeutic effect of mAb1 on nasal polyps.

  A randomized, double-blind, phase 2, placebo-controlled study of two treatment groups, once weekly for 16 weeks (QW) in patients with chronic signs of bilateral rhinocephaly and sinusitis, Conducted to evaluate mAb1 administered subcutaneously (SC). The main objective of the study was to evaluate the efficacy of mAb1 in the treatment of bilateral nasal polyp (NP) by evaluation of endoscopic nasal polyps score compared to placebo. Secondary objectives of the study were based on symptoms of sinusitis, computed tomography (CT) scan changes, nasal polyp score in subgroups of patients with co-existing asthma, safety and tolerability, suppression of TH2 biomarkers Bilateral nasal polyps with respect to the scale of the pharmacodynamic response, the concentration of mAb1 in serum, the immune response to mAb1 (anti-drug antibody (ADA)) and the effect and quality of life (QoL) of mAb1 in the results reported by the patient It included the assessment of mAb1 in patients with.

  mAb1 was administered simultaneously with a nasal spray of mometasone furoate (MFNS). Also, because there is asthma, aspirin / non-steroidal anti-inflammatory drug (NSAID) hypersensitivity and high comorbidity rates of NP with previous surgery, patients do not have any of the exclusion criteria described below , Registered for study was allowed. Approximately 56 patients were randomized into two treatment groups of 28 patients per group. If approximately 28 patients without asthma were randomized to ensure that at least 28 patients with co-existing asthma were included in this study, NP patients without co-existing asthma were Stop mobilization. They were blinded to treatment groups to which both the patient and investigator were assigned.

  The study consisted of three periods: 1) a 4-week screening period with MFNS (visit 1); (2) a 16-week randomized mAb1 or placebo treatment period (visits 2-18); 3) A 16 week post-treatment period to assay pharmacokinetics, immunogenicity, safety and efficacy (visits 19-22). The total duration of the study was up to 36 weeks.

  The primary endpoint changed from baseline at 16 weeks in bilateral nasal polyp score (NPS).

A number of secondary efficacy endpoints were measured to assess the efficacy of mAb1 more comprehensively. Studies have shown improvement in nasal sputum and related sinusitis in CT scans, condition-specific and global medical questionnaires to gain a better understanding of the impact of severe nasal splints on the subject's quality of life (QOL) I examined the improvement.

  Together with trial subgroup analysis and biomarkers, these endpoints provided information for the therapeutic value of mAb1 to reduce nasal polyps score and improve symptoms in NP and its subsets. Persistence of effects was also examined throughout the four month post treatment evaluation period.

  The 300 mg QW dose regimen was predicted to saturate apparent target-mediated clearance levels (10-15 mg / L). This regimen has been tested and provided statistically significant, clinically relevant responses in two previous lines of conceptual studies conducted with mAb1 in asthma and atopic dermatitis (eg, above See Example 1, USSN 61/805797 and USSN 61/816191). The first dose utilized a 600 mg loading dose to more rapidly achieve steady state concentrations. This loading dose range was supported by the allowable loading profile of the highest loading dose (600 mg) demonstrated in previous studies conducted in healthy Japanese subjects.

In addition, Cmax after loading dose of 600 mg is about 70 mg / L, steady-state Ctrough of 300 mg QW is about 150 mg / L, and the proposed dosing regimen (ie loading dose of 600 mg followed by 300 mg QW ) After Cmax 12mg / kg
The highest single dose tested in well-tolerated healthy subjects, considering that it is less than the mean Cmax of the IV dose (421 mg / L), has a safety profile that this dose regimen allows Provided further confidence that it should be.

  Patient inclusion criteria include: (i) a physician's endoscopic diagnosis (ie, despite previous INCS (intranasal corticosteroids) treatment) by the physician for bilateral rhinorrhoids for at least 8 weeks prior to screening. Minimal bilateral polyps score 5 to max score 8 for both nostrils, with a score of at least 2 for each nostril, and (ii) the following symptoms before screening: nasal obstruction / obstruction / clog or nasal discharge (front / back) Rhinorrhea); facial pain / pressure sensation; and chronic symptoms of sinusitis in which there is at least two of olfactory loss or loss.

Patients meeting these criteria were screened for the following exclusion criteria: age under 18 or over 65 years; any technical / administrative reasons for which patients can not be randomized in the study; any of mAb1 Previous participation in any clinical trial; SNOT 22 score less than 7; drug in any other trial study or therapy prohibited for this study within 2 months or 5 half-lives prior to screening, whichever is longer Receiving oral corticosteroids (OCS) or intranasal corticosteroids drops within 2 months or 1 month prior to screening, or receiving OCS for a period of study for another condition Are planned; treatment with mAB or immunosuppressive therapy; anti-immune glob within 130 days of visit 1 Treatment with E (IgE) treatment (eg, omalizumab); treatment with a leukotriene antagonist / modulator for patients who did not continue treatment for more than 30 days prior to Visit 1; within 3 months prior to Visit 1 Plan to start treatment during the start or screening or randomization treatment period of allergen immunotherapy of any of the nose within 6 months before screening or have had more than 5 sinus surgery in the past, up to 2 The procedure was surgery to change the sidewall structure of the nose; or conditions or comorbidities in which the patient can not be evaluated for the primary efficacy endpoint (eg, retronasal nasal polyps; at least one nasal obstruction occlusion); at screening or Acute sinusitis, nasal infection or upper respiratory tract infection two weeks before screening; ongoing drug rhinitis; Yagu-Strauss syndrome, Young's syndrome, Kartagener syndrome or cilia dyskinesia syndrome, cystic fibrosis, suggested by signs or CT scan of allergic fungal rhinosinusitis). Patients with co-existing asthma were excluded if: Patients had less than 60% forced expiratory volume (FEV1); systemic (oral and / or parenteral) steroid treatment or hospitalization (24 for treatment of asthma) An exacerbation requiring more than a hour occurred within 3 months prior to screening; or the patient had received fluticasone at doses greater than 1000 μg or equivalent inhaled corticosteroids. Other exclusion criteria include: patients whose life expectancy is expected to be short (less than 6 months); patients undergoing concomitant treatment prohibited in the study; women who are pregnant or intend to become pregnant during the study Or include lactating women. Other exclusion criteria include concurrent severe disease (eg, active and inactive pulmonary tuberculosis, diabetes, etc.); diagnosed active parasitic infection; suspected or high risk of parasitic infection; human immunodeficiency History of viral (HIV) infection or positive HIC screening at Visit 1; evidence of acute or chronic infection; invasive opportunistic infection (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidosis, regardless of whether the infection has healed) Known or suspected immunosuppression, including a history of pneumocystis, aspergillosis; planned for live vaccination or research within 12 weeks prior to Visit 1; active autoimmune disease Or autoimmune disease (eg, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, Patients using immunosuppressive therapy for lupus erythematosus, multiple sclerosis, psoriasis vulgaris, rheumatoid arthritis); positive or indeterminate hepatitis B surface antigen (HBsAg) at Visit 1, hepatitis B Included are patients with core antibody (HB cAb) or hepatitis C antibody; patients with liver injury related criteria (eg, underlying hepatobiliary disease or ALT> 3ULN).

B. Study Treatment Study Drug: Various concentrations of sterile mAb1 were provided in 5 mL glass vials. Each vial contained 2 mL withdrawal volume: 150 mg / mL solution (300 mg dose / 2 mL). The sterile placebo was provided in 5 mL vials of a completely identical glass match, each vial containing a deliverable volume of 2 mL.

  mAb1 was administered every 7 ± 2 days (QW). Dosing of mAb1 was separated by over 5 days to avoid overdosing. Two injections were performed at Visit 2 (V2). After V2, a single injection of mAb1 was performed once weekly at the trial site throughout the randomized treatment period. MAb1 was administered after clinical treatment and blood collection. After each dose, patients were monitored for at least 1 hour for any signs or symptoms of local injection or hypersensitivity reactions. The subcutaneous injection site was alternated between a quarter of the abdomen (avoiding the navel and waist) or the upper thigh so that the same site was not injected twice a week consecutively.

  Every day during the study, subjects recorded their daily use of MFNS using an electronic diary. An actuation of 50 micrograms / nasal spray of furan carboxylic acid mometasone (NASONEX®) was included in the bottle, which contained 18 g (140 actuations) of the formulation.

  Screening period: Before screening, subjects must continue a stable dose of intranasal corticosteroids (INCS) at least 2 months prior to Visit 1. Patients switched to MFNS if they used an alternative INCS preparation other than MFNS at V1 prior to the screening visit. After V1, all patients will be enrolled for a 4-week study period, and patients will be able to remain on the low dose (QD) regimen, unless they can not tolerate BID INCS: Two actuations (50 μg / actuation) (a total daily dose of 400 μg) were administered to each of the twice daily (BID) nostrils. In order to be accepted for this study, patients have the following symptoms before screening: nasal blockage / obstruction / clog or nasal discharge (pre / post nasal rhinorrhea); +/- facial pain / pressure or +/- loss of sense of smell Or at least two of the losses must be present.

  Treatment Period: The treatment period proceeded as shown in the study flow chart of Table 14.

  During the treatment period, the patient continued on a steady dose of mometasone furoate: 2 actuations of MFNS at BID or QD in each nostril (if the patient can not tolerate high doses). At Visit 2, patients were enrolled in the SNOT-22 trial in patients with asthma, VAS and QoL questionnaires (SF-36, EQ-5D, questionnaires using data related to nasal polyps), olfactory examination and ACQ- Received 5

Clinical laboratory examinations at Visit 2 were limited to hematology, pharmacokinetics, anti-drug antibodies, biomarkers in serum and plasma, allergen specific IgE panel sampling. Blood samples were obtained prior to administration of mAb1. Nasal sampling for biomarkers. Blood samples were collected for DNA and RNA sampling (prior to administration of study drug during randomized treatment period) for those patients who signed a particular informed consent form.

  Temporary discontinuation of treatment due to suspected AE was considered by the investigator. If the role of mAb1 in the occurrence of related events is unlikely to occur, the investigator should carefully consider resuming treatment with mAb1 if it further meets the selection criteria for the study, taking into account optimal medical judgment. Conducted under appropriate clinical and / or laboratory monitoring.

  An adverse event (AE) is any adverse medical event in a patient or clinical trial patient to whom the medication is administered and which may not necessarily have a causal relationship with this treatment.

  A serious adverse event (SAE) is any adverse medical event at any of the doses: either resulting in death or life threatening, ("life-threatening" in the definition of "serious" The term refers to an event that is at risk of death at the time of the event; if it is more severe it does not refer to an event that can cause death on an assumption); hospitalization of hospitalized patients or prolongation of existing hospitalizations Needs or produces persistent or serious disability / impairment, or is birth error / birth disorder; processed reports do not immediately threaten life risk, or death or hospitalization While not leading to the need for intervention (ie specific measures or corrective treatment) to endanger the patient or to prevent one of the other consequences described in the definition above. It is the medical and scientific judgment of medically important events that should be made in determining whether it is suitable in other situations, such as important medical events that may be (medically important events The following list is intended to serve as a guideline for determining that a condition should be considered as a medically significant event). The list is not intended to be comprehensive: Emergency treatment room or intensive treatment in the home: allergic bronchospasm, anaphylaxis, blood disease (ie agranulocytosis, aplastic anemia, bone marrow aplasia, bone marrow aplasia, bone marrow) Dysplasia, pancytopenia, etc.), convulsions (seizure, epilepsy, seizures of epilepsy, absence, etc.), development of drug dependence or substance abuse; ALT> 3 × ULN + total bilirubin> 2 × ULN or no syndrome ALT increase> 10 x ULN; suggestion of any event of suicide attempt or suicidality; syncope, loss of consciousness (except as documented as a result of blood sampling); bullous skin rash; diagnosed during study or study Cancer that has been exacerbated during: chronic neurodegenerative disease (newly diagnosed) or exacerbated during the study (especially to evaluate the effects of research drugs in these diseases) Oite investigator if it is determined that the abnormality / significant by the physician only).

  Post-treatment period: At the completion of the randomized treatment period (or after an early discontinuation of mAb1), the patient continued treatment with a stable dose of MFNS maintained over the randomized treatment period, or medicine Treatment was modified based on the subjective judgment.

  The following combination treatments were not permitted during the screening and randomized treatment periods: Intranasal medications (antihistamines, nasal atropine, ipratropium bromide, nasal) which prevent the symptoms of the disease except for saline for nasal administration For use with cromolyn); INCS drops; systemic corticosteroids; decongestants (local or systemic) excluding previous endoscopy; long-term use of systemic antibiotics (2 weeks or more); lipoxygenases Inhibitors; any immunosuppressive treatment including, but not limited to, methotrexate, cyclosporin, mycophenolic acid, tacrilomus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, cyclophosphamide; anti-immunoglobulin E (IgE) Treatment (omalizumab); and ass Aspirin or NSAID in patients with hypersensitivity to phosphorus.

  The following combination treatments were tolerated: MFNS during screening and throughout the study; Saline for nasal use; Topical hyper-congestive agent (eg oxymeta-hydrochloride to reduce swelling and widen passage for endoscopes Zorin), and local anesthetics (eg lidocaine accepted before endoscopy); short-term (less than 2 weeks) use of antibiotics; and for patients with asthma, SABA, LABA and methylxanthines (eg , Theophylline, aminophylline). The following inhaled corticosteroids are acceptable for patients continuing with a stable dose of 1000 μg or less of fluticasone (or another CS with equivalent dose; see Table 16), 30 days before Visit 1 Allowed only for patients who had continued above stable doses: Leukotriene antagonists / modifiers were only tolerated during the study, only for patients who continued treatment for at least 30 days prior to Visit 1; synthetic anti Histamine; and start of allergen immunotherapy (for at least 3 months prior to Visit 1, predetermined allergen immunotherapy was tolerated).

C. Treatment Efficacy The primary endpoint of this study is the change from baseline at Week 16 in bilateral endoscopic nasal polyp scores.

  A nasal endoscopy was performed at the end of the planned visit and preceded the topical administration of an anesthetic in combination with a decongestant. You have downloaded a standard video sequence or sent it to a centralized reader. Centralized image data evaluation and scoring by independent physician reviewers for image data was performed for all endoscopy. Only V1 centered reads were made available to the site to confirm eligibility in V2. The final results of the central reading were made available after the study.

  For analysis of the primary endpoint, a V2 central reading was used for comparison with the EOT reading. The site removed the information that the subject identified from the image data header before sending the image data to the central reader.

Secondary endpoints of the study included patient-reported symptoms (including 22-item sinus evaluation test (SNOT-22)); nasal congestion / obstruction assessed by subject, anterior rhinorrhea (nasal discharge), posterior nose Leakage (hind rhinorrhea) and loss of olfactory sense (daily diary of AM and PM) monthly average; number of awakenings at night; severe symptoms of nasal sinus inflammation associated with patients using Visual Analog Scale (VAS) Degree; 5-item asthma control questionnaire in asthma subgroup (ACQ-5); nasal maximum inspiratory flow (NPIF); olfaction test (UPSIT); NPS in patients with coexisting asthma; CT scan evaluation; spirometry (total and Subgroup with asthma) time to first response in NPS (more than 1 point improvement) time to study treatment discontinuation; and due to the need for OCS or nasal surgery Including change from baseline at 16 weeks in the development of treatment interruption.

  The quality of life (QoL) endpoint is based on the 36-term short form health survey (SF 36); the European Quality of Life scale (EQ-5D); and at 16 weeks in questionnaires using materials related to nasal polyps Includes changes from the line.

  Disease-specific efficacy measures include: computed tomography (CT). The sinus CT should be performed at EOT before V2. The same acquisition (sequence) was used for central image data evaluation for both maxillary sinus Lund-Mackay score and 3D volumetric measurements, and image data was scored by independent physician reviewers. Center reading of V2 was used for comparison with EOT. The final results of the central reading were made available after the study.

  For three-dimensional volume measurements of maxillary sinuses, pre-V2 center readings were used for comparison with EOT readings. The site removed the information that the subject identified from the image data header before sending the image data to the central reader. The% change in turbidity from BL to EOT was calculated.

  At screening (visit 1), patients issued NPIF measurements to record morning (AM) and night (PM) NPIF. Patients were instructed to record the following changes in their daily electronic diary: AM NPIF performed within 15 minutes prior to receiving MFNS (between 6am and 10am); and night before receiving MFNS NPIF of PM performed between 6pm and 10pm.

  Three NPIF trials were performed by the patient; all three values were recorded by the patient in an electronic diary and the highest value was used for evaluation. AM NPIF baseline is the mean AM measurement recorded during the 28 days prior to the first dose of study drug, and PM NPIF baseline is recorded during the 28 days prior to the first dose of study drug It was an average PM measurement.

  To assess the daily symptoms specific to the disease, the patient has: 0 to 3 classified scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms Questions of the morning and night individual nasal sinus inflammation symptoms, including symptoms of clogs and / or obstruction, anterior rhinorrhea (nasal drainage), posterior rhinorrhea (posterior rhinorrhea) and loss of sense of smell, using I used an electronic diary to answer the question. The number of awakenings at night was also recorded.

  The same safety assessment was applied across all treatment groups. Adverse events, including serious adverse events (SAE) and adverse events of particular interest (AESI), were collected at each visit.

  Pre-dose blood samples were taken to determine serum functional mAb1 and anti-mAb1 antibodies specified in Table 14.

  Optional sampling for preliminary analysis of DNA and RNA requiring alternative pharmacogenetics informed consent.

Pharmacokinetics. Functional mAb1 and anti-mAb1 antibodies in serum were assayed by ELISA. Pre-dose functional mAb1 concentrations in serum at Visit 2 (1 day), mAb1 trough concentrations at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, and 20 weeks, 24 weeks, 28 weeks and 32 weeks Provided follow-up serum mAb1. The anti-mAb1 antibody status (negative or potency) at Visit 2 (1 day), 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks and 32 weeks was also provided.
At the end of the study visit patients with over 1000 ADA titers were planned to return after about 6 months for further evaluation of ADA titers. Further follow-up was considered based on the overall assessment of antibody titers and clinical findings.

  Pharmacodynamics. Because secretion of specific proteins is at least partially dependent on Th2 cytokines and is associated with chronic inflammation of airway mucus, including sinus tissue, expression of specific biomarkers was assayed to monitor the therapeutic effect of mAb1. These biomarkers were also evaluated for their value in predicting toxicity and / or recording the time course of drug response. Values used as baseline were collected on day 1 (pre-dose assessment).

  Nasal fluid was obtained by inserting a nasal swab into the nasal cavity for 5 minutes. Nasal fluid was saved for additional biomarkers associated with nasal swabs and possible analysis of response to mAb1 treatment.

  Nasal polyp tissue was optionally obtained by biopsy at selected clinical sites, with specific informed consent. Baseline biopsies were obtained at V2 of the study. After randomization, another biopsy of nasal polyp tissue was obtained at the end of the treatment visit (16 weeks).

  Biopsy nasal polyp tissues were evaluated for various biomarkers of inflammation and disease processes or responses. For example, RNA was extracted and used for expression profiling (eg, microarray, transcriptome sequencing or quantitative RT-PCR).

  DNA and RNA samples could be used to determine the possible relationship between the gene and the response to treatment with mAb1 and the possible side effects on mAb1.

  Analysis of the proportion of patients with bicomponent events. The proportion of patients with bicomponent events was assessed: one or more point improvement (decrease) in NPS at 16 weeks (read centrally); 10% or more improvement in CT turbidity from baseline at 16 weeks; A drop due to oral CS or surgery; or an increase in INCS after 8 weeks, as a response variable and treatment group, pooled country / region and pre-study stratification factor as a covariate, respectively with logistic model with the above responses It analyzed using.

  Analysis of time-event changes. Time-events (eg, initial response with one or more point improvement (decrease) in NPS, etc., study treatment discontinuation, etc. Were analyzed using the Cox regression model along with asthma co-morbidities. The Kaplan-Meier method was used to derive the percentage of patients with events specific to each treatment group at 4, 8, 12 and 16 weeks. For analysis during the treatment period, if the patient did not have an event prior to treatment discontinuation / completion, the patient was considered to have no event until the end of the treatment period (day of last dose + 7 days).

  Analysis of changes from baseline for continuous variables. NPS for patients with coexisting asthma; Lund Mackay score; 22-item sinus evaluation test (SNOT-22); blockage and / or occlusion score assessed by subject; nasal maximum inspiratory flow (NPIF); comorbid asthma Changes from baseline at week 16 in patients with ACQ-5; QoL (SF36, EQ-5D) and VAS were analyzed using the same MMRM as the primary endpoint. Descriptive statistics were provided including number of patients, mean, standard error and LS mean. In addition, differences in LS mean, corresponding 95% Cl and p values were provided for comparison of each dose to placebo.

  Analysis of efficacy at baseline biomarkers of defined subsets. Analysis of changes in NPS is also used to examine baseline biomarkers for their potential value to predict treatment response, the following subsets and total ITT population by each dosing group and selected pooled doses It carried out about a group.

  Subgroup analysis. Preliminary subgroup analysis, age group, gender, area, to assess consistency treatment effects across subgroup levels and to examine baseline biomarkers for their potential value to predict treatment response The change from baseline in NPS was performed on race, INCS dose level, baseline NPS, baseline CT scan score, asthma co-morbidities and biomarkers selected prior to study.

  Items of anti-mAb1 antibody results (negative or antibody titer) were represented by patient, time point and treatment group. ADA titer levels were classified into categories: low, medium and high. Low level ADA titer defined as titer less than 1000; medium level ADA titer defined as titer between 1000 and 10,000; high level ADA titer greater than 10,000 power It was defined as the value.

  Anti-mAb1 antibody assay results were definitively described. The following summary was provided: patients with any positive ADA assay response during the TEAE period; patients with positive ADA assay response induced by treatment during the TEAE period; treatment induced during the TEAE period Patients with positive ADA assay response were further described as patients with transient positive response and patients with persistent positive response. During the TEAE period, patients with any positive ADA assay response were defined as having at least one sample that was positive in the ADA assay.

  Treatment-induced positive ADA assay response: with no positive assay response at baseline, but with a positive assay response during a TEAE period, with a positive ADA assay response at baseline, and also with a TEAE period During that time, patients were defined as having at least a 4-fold increase in titer.

  Sustained positive responses were treatment-induced positive that at least two consecutive post-baseline samples from the patient were positive in the ADA assay, or the last post-baseline sample taken was positive in the ADA assay. ADA assay reaction. A transient positive response is defined as a positive ADA assay response induced by any treatment not considered persistent.

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

Claims (61)

  A method of treating nasal polyps, comprising administering a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to a subject in need thereof. Said method, wherein said antibody or antigen binding fragment thereof comprises heavy and light chain CDR sequences from heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pairs of SEQ ID NO: 1 and 2;   2. The method of claim 1, wherein the antibody or antigen binding fragment thereof comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5.   The subject has one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, or is undergoing surgery for a nasal polyp. The method of claim 1.   The method of claim 1, wherein the subject has chronic rhinosinusitis.   The method according to claim 1, wherein the antibody or antigen binding fragment thereof is administered at a dose of 0.1 mg to 600 mg.   6. The method of claim 5, wherein the antibody or antigen binding fragment thereof is administered at a dose of 100 mg to 400 mg.   6. The method of claim 5, wherein the antibody or antigen binding fragment thereof is administered at a dose of 300 mg.   The method according to claim 1, wherein the antibody or antigen binding fragment thereof comprises HCVR having the amino acid sequence of SEQ ID NO: 1 and LCVR having the amino acid sequence of SEQ ID NO: 2.   The method according to claim 1, wherein the antibody is dupyrumab or an antigen-binding fragment thereof.   The method according to claim 1, wherein the pharmaceutical composition is administered to the subject systemically or locally.   11. The method of claim 10, wherein the pharmaceutical composition is administered to the subject subcutaneously, intravenously or intranasally.   2. The method of claim 1, wherein the pharmaceutical composition is administered subcutaneously to the subject at a dose of 300 mg.   The method according to claim 1, wherein the second therapeutic agent is administered to the subject before, after or simultaneously with the pharmaceutical composition.   14. The method of claim 13, wherein the second therapeutic agent is selected from the group consisting of an IgE inhibitor, an antibiotic preparation and an antifungal agent.   14. The method of claim 13, wherein the second therapeutic agent comprises an intranasal corticosteroid.   The method according to claim 15, wherein the intranasal corticosteroid is a nasal spray (MFNS) of mometasone furoate.   16. The method of claim 15, wherein the second therapeutic agent comprises inhaled corticosteroids.   18. The method of claim 17, wherein the inhaled corticosteroid is fluticasone or budesonide. 16. The method of claim 15, wherein the second therapeutic agent further comprises a long acting beta ₂ agonist. 20. The method of claim 19, wherein the long acting beta ₂ agonist is salmeterol or formoterol.   2. The method of claim 1, wherein one or more nasal swab-related parameters improve after administration of the antibody or antigen binding fragment thereof. The parameters associated with one or more of the nasal passages are:
a) 22 item sinus evaluation test (SNOT-22) score;
b) nasal symptom score;
c) number of awakenings at night;
d) Visual Analogue Score (VAS) for the severity of nasal sinus symptoms;
e) 5 item asthma control questionnaire (ACQ 5) score;
f) nasal maximum inspiratory flow (NPIF);
g) University of Pennsylvania Smell Identification Test (UPSIT);
22. The method of claim 21, wherein the method is selected from the group consisting of h) Lund-McKay score; and i) three-dimensional volume measurement of maxillary sinus.   2. The method of claim 1, wherein one or both of NPIF and UPSIT are increased after administration of the antibody or antigen binding fragment thereof.   2. The method according to claim 1, wherein one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay score and 3D-volume score decrease after administration of the antibody or antigen binding fragment thereof. .   2. The method of claim 1, wherein nasal polyp score in the patient is reduced after administration of the antibody or antigen binding fragment thereof.   A method of treating nasal polyps, comprising a single initial dose of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), followed by the antibody or antigen-binding thereof Sequentially administering one or more secondary doses of the fragment to a subject in need thereof, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region (HCVR) of SEQ ID NOs: 1 and 2 and A method as described above comprising heavy and light chain CDR sequences from a light chain variable region (LCVR) sequence pair.   27. The antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises the light chain CDR sequences of SEQ ID NOs: 6, 7 and 8 and the heavy chain CDR sequences of SEQ ID NOs: 3, 4 and 5. Method described.   27. The method of claim 26, wherein the antibody or antigen binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO: 2.   27. The method of claim 26, wherein the antibody is dupyrumab or an antigen binding fragment thereof.   27. The method of claim 26, wherein each secondary dose is administered 1 to 15 weeks after the immediately preceding dose.   27. The method of claim 26, wherein at least three secondary doses of the antibody or antigen binding fragment thereof are administered to the subject, and each secondary dose is administered one week after the last dose.   27. The method of claim 26, wherein each of the initial dose and one or more secondary doses comprises 50 mg to 500 mg of an antibody or antigen binding fragment thereof.   33. The method of claim 32, wherein each of the initial dose and one or more secondary doses comprises 100 mg to 400 mg of an antibody or antigen binding fragment thereof.   33. The method of claim 32, wherein each of the initial dose and one or more secondary doses comprises 300 mg of an antibody or antigen binding fragment thereof.   27. The method of claim 26, wherein each of the initial dose and one or more secondary doses comprises the same dose of antibody or antigen binding fragment thereof.   27. The initial dose comprises a first amount of antibody or antigen binding fragment thereof, and wherein one or more secondary doses each comprise a second amount of antibody or antigen binding fragment thereof the method of.   The first amount of antibody or antigen binding fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times or 5 times the second amount of antibody or antigen binding fragment thereof 37. The method of claim 36.   37. The method of claim 36, wherein the first amount of antibody or antigen binding fragment thereof is twice the second amount of antibody or antigen binding fragment thereof.   The subject has one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, or is undergoing surgery for a nasal polyp. 27. The method of claim 26.   27. The method of claim 26, wherein the subject has chronic rhinosinusitis.   27. The method of claim 26, wherein the initial dose and the secondary dose are administered by the same or different routes of administration.   27. The method of claim 26, wherein the initial dose and the second dose are administered subcutaneously, intravenously or intranasally.   27. The method of claim 26, wherein after administration of the initial dose and one or more secondary doses, one or more nasal cavity-related parameters improve. The parameters associated with one or more of the nasal passages are:
a) 22 item sinus evaluation test (SNOT-22) score;
b) nasal symptom score;
c) number of awakenings at night;
d) Visual Analogue Score (VAS) for the severity of nasal sinus symptoms;
e) 5 item asthma control questionnaire (ACQ 5) score;
f) nasal maximum inspiratory flow (NPIF);
g) University of Pennsylvania Smell Identification Test (UPSIT);
44. The method of claim 43, wherein the method is selected from the group consisting of h) Lund-McKay score; and i) three-dimensional volume measurement of maxillary sinus.   27. The method of claim 26, wherein one or both of NPIF and UPSIT are increased after administration of the antibody or antigen binding fragment thereof.   27. The method of claim 26, wherein one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay score and 3D-volume score is decreased after administration of the antibody or antigen binding fragment thereof. .   27. The method of claim 26, wherein nasal polyp score in the patient is reduced after administration of the antibody or antigen binding fragment thereof.   27. The method of claim 26, wherein the second therapeutic agent is administered to the subject before, after or simultaneously with the initial dose or one or more secondary doses.   49. The method of claim 48, wherein the second therapeutic agent is selected from the group consisting of an IgE inhibitor, an antibiotic preparation and an antifungal agent.   49. The method of claim 48, wherein the second therapeutic agent comprises an intranasal corticosteroid.   51. The method of claim 50, wherein the intranasal corticosteroid is a nasal spray (MFNS) of mometasone furoate.   51. The method of claim 50, wherein the second therapeutic agent comprises inhaled corticosteroids.   53. The method of claim 52, wherein the inhaled corticosteroid is fluticasone or budesonide. 51. The method of claim 50, wherein the second therapeutic agent further comprises a long acting beta ₂ agonist. 55. The method of claim 54, wherein the long acting beta ₂ agonist is salmeterol or formoterol. A method of treating nasal polyps, comprising
a) A sinusitis selected from the group consisting of at least a bilateral nasal polyp score of 5, or nasal blockage / obstruction / clogs, anterior or posterior rhinorrhea, facial pain or pressure, and loss or loss of smell Selecting a patient who has at least two or more of the chronic symptoms of b); and b) reducing the patient's nasal polyp score or ameliorating two or more chronic symptoms of sinusitis Administering a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) to a selected patient, said antibody or antigen-binding fragment Comprises heavy and light chain CDRs from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pairs of SEQ ID NOs: 1 and 2; Notation method. A method of treating nasal polyps, comprising
a) A sinusitis selected from the group consisting of at least a bilateral nasal polyp score of 5, or nasal blockage / obstruction / clogs, anterior or posterior rhinorrhea, facial pain or pressure, and loss or loss of smell Selecting a patient who has at least two or more of the chronic symptoms of b); and b) reducing the patient's nasal polyp score or ameliorating two or more chronic symptoms of sinusitis A single initial dose of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), followed by one or more of the antibody or antigen-binding fragment thereof Sequentially administering to the patient a second dose of the antibody, or the antibody or antigen binding fragment thereof, comprising the heavy chain variable region (HCVR) and the light chain of SEQ ID NO: 1 and 2 Said method comprising the step comprising heavy and light chain CDR sequences from a variable region (LCVR) sequence pair. A method of treating nasal polyps, comprising
a) In the subject, the expression level of one or more genes selected from the group consisting of thymus and activation regulated chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA) and YKL-40 Determining steps;
b) as a candidate for treatment with an antibody or antigen-binding fragment thereof that selectively binds to the interleukin-4 receptor (IL-4R) if the subject has improved expression levels of one or more genes Selecting an object; and c) a medicament comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) such that the level of one or more genes is reduced Administering the composition to a selected subject, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR) sequence pair of SEQ ID NOs: 1 and 2; Said method comprising the steps described above comprising chain and light chain CDR sequences. A method of treating nasal polyps, comprising
a) In the subject, the expression level of one or more genes selected from the group consisting of thymus and activation regulated chemokine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA) and YKL-40 Determining steps;
b) Candidates for treatment with an antibody or antigen-binding fragment thereof that selectively binds to the interleukin-4 receptor (IL-4R) if the subject has improved expression levels of one or more genes Selecting the subject as; and c) comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) such that the level of one or more genes is reduced. Sequentially administering to the selected subject a single initial dose of the pharmaceutical composition, followed by one or more secondary doses of the antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment is Said method comprising the above steps comprising heavy and light chain CDR sequences from heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pairs of SEQ ID NO: 1 and 2 . A method of treating nasal polyps, comprising
a) determining the level of blood eosinophils or vaginal eosinophils in the subject;
b) for treatment with an antibody or antigen-binding fragment thereof that selectively binds to interleukin-4 receptor (IL-4R) if the subject has an elevated level of blood eosinophils or vaginal eosinophils Selecting a subject as a candidate for (c); and c) an antibody that specifically binds to interleukin-4 receptor (IL-4R) such that the levels of blood eosinophils or vaginal eosinophils are reduced. Or administering a pharmaceutical composition comprising an antigen-binding fragment thereof to a selected subject, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region of SEQ ID NOs: 1 and 2 (LCVR) said method comprising the step comprising heavy and light chain CDR sequences from a pair of sequences. A method of treating nasal polyps, comprising
a) determining the level of blood eosinophils or vaginal eosinophils in the subject;
b) for treatment with an antibody or antigen-binding fragment thereof that selectively binds to interleukin-4 receptor (IL-4R) if the subject has an elevated level of blood eosinophils or vaginal eosinophils Selecting a subject as a candidate for (c); and c) an antibody that specifically binds to interleukin-4 receptor (IL-4R) such that the levels of blood eosinophils or vaginal eosinophils are reduced. Or sequentially administering a single initial dose of a pharmaceutical composition comprising the antigen-binding fragment thereof, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, to the selected subject, said antibody Or the antigen-binding fragment thereof comprises heavy and light chain CDR sequences derived from the heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pairs of SEQ ID NOs: 1 and 2;

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