NZ752224A - Methods for treating nasal polyposis by administering an il-4r antagonist - Google Patents

Abstract

Disclosed is the use of an antibody or antigen binding fragment thereof, that specifically binds an interleukin-4 receptor (IL-4R) for the preparation of a pharmaceutical composition for treating nasal polyposis in a subject, and wherein the antibody or antigen-binding fragment thereof comprises three HCDRs and three LCDRs, wherein the HCDR1 comprises SEQ ID NO:3, the HCDR2 comprises SEQ ID NO:4, the HCDR3 comprises SEQ ID NO:5, the LCDR1 comprises SEQ ID NO:6, the LCDR2 comprises SEQ ID NO:7, and the LCDR3 comprises SEQ ID NO:8. In a preferred embodiment the pharmaceutical composition is prepared to treat chronic rhinosinusitis with nasal polyposis.

Description

S FOR TREATING NASAL POLYPOSIS BY ADMINISTERING AN |L-4R ANTAGONIST RELATED APPLICATIONS This application claims the benefit of US. Provisional Application No. 61/837,912, filed June 21, 2013 and European Application No. 703, filed May 7, 2014, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to the field of therapeutic treatments of inflammatory conditions. More specifically, the invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists to treat nasal polyposis.

BACKGROUND Nasal polyposis (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, originating from the eatal x. NP is a T helper cell- 2 (Th-2) driven inflammatory process affecting the mucosa of the nose and paranasal sinuses.

Eosinophils and their products are thought to be a hallmark of nasal polyp-associated inflammation as elevated levels of interleukin-5 (IL-5; es eosinophil survival and entiation), eosinophil cationic protein (ECP), and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils, are lly found in nasal polyps. Eosinophils are the predominant inflammatory cell found in the sinuses and nasal polyps, and nasal polyps are also ated with elevated levels of lgE. NP is characterized by long-term symptoms of nasal obstruction and congestion, reduction in 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.

BRIEF SUMMARY OF THE INVENTION

[0004] In one aspect, the invention es a method for ng nasal polyposis, where the method includes administering to a subject in need thereof a pharmaceutical composition containing an interleukin-4 receptor (IL-4R) antagonist, such as an anti-lL-4R antibody or antigen-binding nt thereof. In one embodiment, the lL-4R antagonist is an antibody or antigen-binding nt thereof that specifically binds lL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the dy or antigen binding fragment f 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 e, in one embodiment, 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. In one embodiment, the lL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti- IL-4R dies or antigen-binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

A subject suitable for treatment with an IL-4R antagonist may have one or more of sinusitis, is, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, or have previously undergone surgery to treat nasal polyposis. In some embodiments, the subject has chronic sinusitis or chronic rhinosinusitis. For example, the t may have nasal polyposis with severe symptoms of sinusitis.

In some embodiments, the IL-4R antagonist is administered at a dose of 0.1 mg to 600 mg (e.g., 100 mg to 400 mg, such as 150 mg, 200 mg, 250 mg, 300 mg or 350 mg). In certain embodiments, the ceutical composition is administered to the subject ically or locally. For example, the pharmaceutical ition may be administered subcutaneously, intravenously, or intranasally.

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

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after or concurrent with the pharmaceutical composition comprising the IL-4R antagonist, such as the IL-4R antibody or antigen-binding fragment thereof. For e, in one ment, the one or more additional , such as a second eutic agent can be a TNF inhibitor, an lL-1 inhibitor, an lL-5 inhibitor, an lL-8 inhibitor, an lgE inhibitor, an NSAID (non-steroidal anti-inflammatory drug), an antibiotic, an anti-fungal agent, an asal corticosteroid, an inhaled corticosteroid, a systemic corticosteroid, a long-acting beta2 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 mometasone furoate nasal spray (MFNS). In another embodiment, the second therapeutic agent further includes a cting beta2 t, such as salmeterol or formoterol.

In certain ments, administration of the IL-4R antagonist is followed by an improvement in one or more symptoms of nasal sis. For example, the administration of the antagonist can be followed by an improvement in one or more nasal polyposis-associated parameters, such as an improvement in a 22—item Sinonasal Outcome Test (SNOT-22) score; a nasal symptom score; number of nocturnal awakenings; a Visual Analog Score (VAS), such as for rhinosinusitis symptom severity; a five-item Asthma Control Questionnaire (ACQS) score; nasal peak inspiratory flow (NPIF); the University of Pennsylvania Smell Identification Test (UPSIT); Lund-McKay Score; and three dimensional volumetric measurement of the maxillary sinus. In certain embodiments, administration of the antibody or antigen binding fragment thereof is followed by one or more of an increase in one or both of NPIF and UPSIT, and a decrease in one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay Score and 3D-Volumetric Score. In some embodiments, administration of the lL-4R antagonist is followed by a decrease in nasal polyp score in the patient.

In one , the invention provides a method for treating nasal polyposis, by sequentially administering to a subject in need thereof a single l dose of an interleukin-4 or (IL-4R) antagonist, such as an lL-4R antibody or an antigen-binding fragment thereof, ed by one or more secondary doses of the lL-4R antagonist. In some embodiments, each secondary dose is administered 1 to 15 weeks after the immediately preceding dose. In other ments, at least three secondary doses of the lL-4R antagonist are administered to the subject, and each secondary dose is administered days or weeks (e.g., 1 week or 2 weeks or more) after the immediately ing dose. In another embodiment, the initial dose and the one or more ary doses each include 50 mg to 500 mg of the lL-4R antagonist, e.g., 100 mg to 400 mg of the lL-4R antagonist, e.g., 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg of the lL-4R antagonist. In some embodiments, the initial dose and the one or more secondary doses each n the same amount of the lL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the lL-4R antagonist, and the one or more secondary doses each comprise a second amount of the lL-4R antagonist. For example, the first amount of the lL-4R antagonist can be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x or 5x or more than the second amount of lL-4R antagonist.

[0011] In one embodiment, the subject (e.g., a patient) has one or more of sinusitis, rhinitis, asthma, aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity, or has undergone surgery for nasal . In some embodiments, the subject has chronic sinusitis or c rhinosinusitis. For example, the subject may have nasal polyposis with severe symptoms of sinusitis.

[0012] The initial dose and the secondary doses of the lL-4R antagonist can be administered by the same or different routes of administration. For example, the initial dose and the ary doses can be administered subcutaneously, intravenously, or intranasally.

In certain embodiments, administration of the initial dose and the one or more secondary doses is followed by an improvement in one or more nasal polyposis associated parameters, such as an improvement in a m sal Outcome Test (SNOT-22) score; a nasal symptom score; number of nocturnal ings; a Visual Analog Score (VAS), such as for rhinosinusitis symptom severity; a five-item Asthma Control Questionnaire (ACQ5) score; nasal peak inspiratory flow (NPIF); the University of Pennsylvania Smell Identification Test (UPSIT); Lund-McKay Score; and three dimensional volumetric measurement of the maxillary sinus. In certain embodiments, administration of the antibody or antigen binding fragment thereof is followed by one or more of an increase in one or both of NPIF and UPSIT, and a decrease in one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay Score and 3D-Volumetric Score. In some embodiments, administration of the IL-4R antagonist is followed by a decrease in nasal polyp score in the patient.

In certain embodiments, one or more additional therapeutic agents are administered to the subject before, after or concurrent with the pharmaceutical ition comprising the IL-4R antagonist, such as the IL-4R dy or antigen-binding fragment thereof. For example, in one embodiment, the one or more additional , such as a second therapeutic agent can be a TNF tor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an lgE inhibitor, an NSAID, an antibiotic, an anti-fungal agent, an intranasal corticosteroid, an inhaled corticosteroid, a ic corticosteroid, a long-acting beta2 t, 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 mometasone furoate nasal spray (MFNS).

In another embodiment, the second therapeutic agent further includes a cting beta2 agonist, such as salmeterol or formoterol.

In one aspect, the invention es a method for treating nasal polyposis, by selecting a patient with a minimum bilateral nasal polyp score of 5, or at least two or more of the chronic symptoms of sinusitis selected from the group consisting of: nasal blockade/obstruction/congestion, anterior or posterior nasal drip, facial pain or pressure, and reduction or loss of smell; and administering to the selected patient a ceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding nt thereof that specifically binds an interleukin-4 receptor (IL-4R), such that the patient’s nasal polyp score is reduced or the two or more chronic symptoms of sinusitis are improved. In one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rd, such as an dy or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the antibody or n 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 f 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. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary L-4R antibodies or antigen-binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention provides a method for ng nasal polyposis, by ing a patient with a minimum bilateral nasal polyp score of 5, or at least two or more of the chronic symptoms of sinusitis selected from the group consisting of: nasal blockade/obstruction/congestion, anterior or posterior nasal drip, facial pain or pressure, and ion or loss of smell; and sequentially administering to the patient a single initial dose of a pharmaceutical ition an interleukin-4 receptor (IL-4R) nist, such as dy or antigen-binding fragment thereof that specifically binds an eukin-4 receptor (IL-4R), ed by one or more secondary doses of the antibody or antigen g fragment thereof, such that the patient’s nasal polyp score is reduced or the two or more chronic ms of sinusitis are improved. In one embodiment, the lL-4R antagonist is an antibody or n- binding fragment thereof that specifically binds lL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the dy 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 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. In one embodiment, the lL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or n-binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention provides a method for treating nasal sis, by ining in a 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; selecting the subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as antibody or n-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), if the subject has an elevated expression level of the one or more genes; and administering to the selected subject a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), such that the level of the one or more genes is reduced. In one embodiment, the lL-4R antagonist is an antibody or antigen-binding fragment f that specifically binds lL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the antibody or antigen binding fragment thereof ses 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 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. In one embodiment, the lL-4R antagonist is dupilumab or an n-binding fragment thereof. Other exemplary anti-IL-4R dies or n- binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention es a method for ng nasal polyposis, by determining in a 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; selecting the subject as a candidate for ent with an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 or (IL-4R), if the t has an elevated expression level of the one or more genes; and sequentially administering to the selected subject a single l dose of a pharmaceutical composition comprising an eukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an eukin-4 receptor (IL-4R), followed by one or more secondary doses of the antibody or antigen binding nt thereof, such that the level of the one or more genes is reduced. In one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that ically binds IL-4Rd, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. 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 f ses 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. In one embodiment, the IL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti-IL-4R antibodies or antigen- binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one aspect, the invention provides a method for treating nasal polyposis, by determining in a t the level of blood eosinophils or sputum eosinophils; selecting the subject as a candidate for treatment with an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 receptor (IL- 4R), if the subject has an elevated level of blood eosinophils or sputum eosinophils; and administering to the selected subject a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as antibody or n-binding fragment thereof that specifically binds an interleukin-4 receptor (IL-4R), such that the level of blood eosinophils or sputum eosinophils is reduced. In one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rd, such as an antibody or n binding fragment that ses heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. 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 e, in one embodiment, the antibody or antigen-binding nt 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. In one embodiment, the lL-4R antagonist is dupilumab or an antigen-binding fragment thereof. Other exemplary anti- IL-4R antibodies or antigen-binding fragments thereof are bed, for example, in US Patent Nos. 7,605,237 and 7,608,693.

In one , the invention provides a method for treating nasal polyposis, by determining in a subject the level of blood eosinophils or sputum eosinophils; selecting the subject as a candidate for ent with an interleukin-4 receptor ) antagonist, such as antibody or antigen-binding nt thereof that ically binds an interleukin-4 receptor (IL- 4R), if the subject has an ed level of blood eosinophils or sputum phils; and tially administering to the selected subject a single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as antibody or antigen-binding fragment thereof that specifically binds an interleukin-4 or (IL-4R), followed by one or more secondary doses of the antibody or n binding fragment thereof, such that the level of blood eosinophils or sputum eosinophils is reduced. In one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL- 4Ror, such as an antibody or antigen binding fragment that comprises heavy and light chain CDR sequences from a heavy chain variable region (HCVR) of SEQ ID NO:1, and a light chain variable region (LCVR) of SEQ ID NO:2. For example, in one embodiment, the dy 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 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. In one embodiment, the lL-4R antagonist is dupilumab or an antigen-binding nt thereof. Other exemplary anti-IL-4R antibodies or antigen-binding fragments thereof are described, for example, in US Patent Nos. 7,605,237 and 7,608,693.

Other embodiments will become apparent from the below figure and the Detailed Description.

BRIEF DESCRIPTION OF THE FIGURES shows the schematic representation of an example of background therapy withdrawal time period in the treatment of an asthma patient.

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

Unless defined otherwise, all technical and ific 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," when used in reference to a particular recited cal value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the sion "about 100" includes 99 and 101 and all values in 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 for Treating Nasal Polyposis

[0026] The present invention provides methods for treating nasal polyposis. As used herein, a "nasal polyp" is an overgrowth of tissue in one or more of the nasal cavities. The condition of nasal polyps is called “nasal polyposis.” About 80% of nasal polyps are highly edematous and filled with eosinophils. Nasal polyps can also present as fibrous, glandular or cystic.

Nasal polyposis (NP) is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, originating from the ostiomeatal complex. NP is a T helper cell- 2 (Th-2) driven inflammatory process affecting the mucosa of the nose and paranasal s.

Eosinophils and their products are thought to be a hallmark of nasal polyp-associated inflammation as elevated levels of interleukin-5 (IL-5; promotes eosinophil survival and differentiation), phil cationic protein (ECP), and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils, are typically found in nasal . Eosinophils are the predominant inflammatory cell found in the sinuses and nasal , and nasal polyps are also associated with ed levels of lgE.

NP is characterized by long-term symptoms of nasal ction and congestion, reduction in or loss of sense of smell, anterior and posterior rhea, and facial pain. The presence or absence of nasal polyps can be med for example by performing endoscopy, and the presence and extent of sinus and polyp involvement can be confirmed by methods such as coronal computed tomography (CT) scans.

An lL-4R antagonist can be used to treat nasal polyposis associated with a variety of conditions. For e, nasal polyposis is associated with tis, rhinitis (e.g., allergic and non-allergic rhinitis), asthma (e.g., moderate-to-severe asthma), NSAID sensitivity (e.g., aspirin sensitivity), and infection, such as bacterial and fungal infection. ial ions include, for example, staphylococcus infections. A subject with nasal polyposis can have a chronic infection, such as a chronic bacterial infection, e.g., a c staphylococcus aureus infection.

In some embodiments, the subject has ing nasal polyposis, such as may be ated with recurring sinusitis. In other embodiments, the subject as cystic fibrosis or NARES (Non- Allergic Rhinitis with Eosinophilia Syndrome). In other embodiments, the subject has a relapse of nasal polyposis after receiving surgery to treat the . Risk factors for nasal sis include genetic susceptibility, anatomic abnormality, mucociliary impairment, infection, and local immunologic nce.

An lL-4R nist can also be used to treat nasal polyposis in patients who have never previously received a treatment or surgery for NP. An lL-4R nist can also be used to treat nasal polyposis in patients who have previously undergone surgery, such as a nasal surgery, such as for treatment of nasal polyps. In certain embodiments, an lL-4R antagonist is administered to a t whose nasal polyposis has relapsed after the subject received prior treatment for the polyps, such as a prior nasal surgery.

As used herein, the term “sinusitis” refers to any matory condition characterized by mation of the paranasal sinuses, including inflammation of the maxillary, l, ethmoid and/or sphenoid paranasal sinuses. An lL-4R antagonist is suitable for treatment of nasal polyposis is associated with acute sinusitis, subacute sinusitis, chronic sinusitis and recurrent sinusitis. Acute sinusitis is characterized by a sudden onset of cold-like symptoms such as runny, stuffy nose and facial pain that does not go away after 10 to 14 days. Acute sinusitis typically lasts less than four weeks. Subacute sinusitis lasts four to eight weeks.

Chronic sinusitis lasts eight weeks or longer, and recurrent sinusitis is characterized by tis episodes that occur three or more times in one year. More than 80% of patients with c sinusitis with nasal polyps have eosinophilic upper airway mation.

Many ts with chronic sinusitis have “chronic hyperplastic eosinophilic sinusitis,” which is characterized by marked inflammation of the sinuses, increased phils and mixed mononuclear cells, and a relative paucity of neutrophils. Some of these patients have one or more of associated nasal polyps, asthma, and aspirin or NSAID sensitivity. In n embodiments, an lL-4R antagonist can be used to treat nasal polyposis in a subject who has chronic hyperplastic eosinophilic sinusitis.

The term “rhinitis” refers to an allergic response, such as to a common allergen (“allergic rhinitis,” e.g., perennial ic rhinitis) or to an environmental irritant (“non-allergic rhinitis”). Symptoms of allergic rhinitis include sneezing; stuffy or runny nose; sinus pressure, and pain or throbbing in the cheeks or nose; and itching in the nose, throat, eyes and ears.

Symptoms of non-allergic rhinitis include constriction or inflammation in the nasal passages which leads to many of the same symptoms of allergic rhinitis. Non-allergic rhinitis can be caused, for example, by strong chemical or smoky environments, or by long-term use of certain medications or dependency on nasal sprays.

As used herein, the term “rhinosinusitis” refers to a condition that has symptoms of both rhinitis and sinusitis. Rhinosinusitis includes acute rhinosinusitis and chronic rhinosinusitis.

Acute rhinosinusitis can be caused by an infection, such as a bacterial, viral or fungal infection, or by a chemical irritation. Cigarette-smoke-induced acute rhinosinusitis and chlorine fume- induced chronic rhinosinusitis are examples of acute rhinosinusitis. NP is most commonly associated with chronic inusitis (CRS), which is characterized by mucosal inflammation of the nasal cavity and paranasal s with symptoms lasting more than 8 weeks. Chronic eosinophilic rhinosinusitis with nasal polyps is a condition that lasts longer than 8 weeks.

Chronic sinusitis (CS) and chronic rhinosinusitis (CRS) are conditions that last longer than eight weeks. The underlying causes of acute sinusitis and acute rhinosinusitis may lead to chronic sinusitis or chronic rhinosinusitis if the resulting inflammation persists for more than 8 weeks. c inusitis includes for example, eosinophilic chronic hyperplastic rhinosinusitis. onal subcategories of c sinusitis (and chronic rhinosinusitis) include, e.g., superantigen-induced eosinophilic chronic sinusitis (e.g., sinusitis induced by exo- and endo- toxins produced by bacteria such as lococcus ); allergic fungal sinusitis (e.g., sinusitis induced by fungi such as Aspergil/us or Alternaria); non-allergic fungal eosinophilic chronic sinusitis; and aspirin-exacerbated eosinophilic chronic sinusitis.

An lL-4R nist can be used to treat nasal polyposis in subjects having any of the disorders described above.

Methods for Improving Nasal Polyp-Associated Parameters The present invention includes methods for improving one or more nasal polypassociated parameters in a subject in need f, wherein the methods include administering a ceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist to the subject. For example, an lL-4R receptor antagonist can reduce endoscopic nasal polyp score in a patient. A nasal polyp score of 0 indicates the presence of no . A nasal polyp score of 1 indicates the presence of small polyps in the middle meatus not ng below the inferior border of the middle turbinate. A nasal polyp score of 3 indicates large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate. A nasal polyp score of 4 indicates large polyps causing complete obstruction of the inferior nasal cavity (see Table 15 below). The maximum score is 8 (4 points per nasal cavity). Treatment with an lL-4R antagonist can decrease nasal polyp score by about 1 to about 8 points. For example, treatment with an lL-4R antagonist can decrease nasal polyp score by about 1 point or more, by about 2 points or more, or by about 3 points or more. In some embodiments, treatment with an lL-4R antagonist can decrease nasal polyp score by about 1 point, or a fraction thereof; by 2 points, or a fraction thereof; by 3 points, or a fraction thereof; by 4 points, or a fraction thereof; by 5 , or a fraction thereof; by 6 points, or a on thereof; by 7 points, or a fraction thereof; or by 8 points or a on thereof. A ion in nasal polyp score may correlate with an improvement in one or more other nasal polyp-associated parameters. Such a correlation, however, is not arily observed in all cases.

Other examples of "nasal polyp-associated parameters" include: (a) 22-item SinoNasal Outcome Test (SNOT-22) score; (b) subject-assessed nasal congestion/obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post nasal drip) and loss of sense of smell; (c) number of nocturnal awakenings; (d) Visual Analog Score (VAS) to assess patient-rated rhinosinusitis symptom severity; (e) five-item Asthma Control Questionnaire (ACOS) score, such as in patients with asthma; (f) Nasal Peak lnspiratory Flow (NPIF); (g) smell test (University of Pennsylvania Smell Identification Test (UPSIT)); (h) physiological parameters, such as measured by nasal endoscopy and CT scan; (i) Lund-Mackay Score; and (j) Three Dimensional volumetric ement of the maxillary sinus. 22-ltem Sinonasal Outcome Test (SNOT-22) Score. According to n embodiments, administration of an lL-4R antagonist to a t results in a decrease from baseline of 22-item Sinonasal Outcome Test (SNOT-22). The SNOT-22 is a questionnaire to assess the impact of chronic rhinosinusitis (CRS) on y of life. The questionnaire measures items related to sinonasal conditions and surgical treatments. The score ranges from 0 to 110, and higher scores imply greater impact of CR8 on Health Related Quality of Life (HROoL) (Hopkins et al 2009, Clin. yngol. 34: 447-454).

The present invention includes therapeutic s that result in a decrease in SNOT-22 score from baseline of at least 1 point at week 4 to week 16 following administration of the lL-4R antagonist. For example, administration of an lL-4R antagonist will result in a decrease in SNOT-22 score at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment. In some embodiments, administration of an lL-4R antagonist to a subject in need thereof causes a decrease in 2 score from ne of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 13 points, or more at week 4, week 6, week 8 or week 12. , 12, Individual and Total Nasal Symptom Score. Subject-assessed symptoms are d by ding to morning and evening individual rhinosinusitis symptom questions using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate ms and 3 = severe symptoms), and including the symptoms of tion and/or obstruction, anterior rhinorrhea, ior rhinorrhea, and loss of sense of smell. A measure of night-time awakenings can also be tracked. For example, a e of night-time awakenings can be assessed according to the following scores based on subject self-assessment: 0: no symptoms, slept through the night; 1: slept well, but some ints in the morning; 2: woke up once because of rhinosinusitis symptoms (including early awakening); 3= woke up several times because of symptoms (including early awakening); 4: bad night, awake most of the night because of symptoms. Administration of an lL-4R antagonist can result, for example, in a decrease in average number of nighttime awakenings per night from ne of at least about 0.10 times per night at week 4 to week 16 following initiation of treatment with a pharmaceutical composition comprising an anti-lL-4R nist. For example, a se in frequency of nighttime awakenings per night from baseline of at least about 0.10 times per night can be detected at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment. stration of an lL-4R antagonist to a subject in need thereof can cause a decrease in average number of nighttime awakenings per night from baseline by about 0.10 times per night, 0.15 times per night, 0.20 times per night, 0.25 times per night, 0.30 times per night, 0.35 times per night, 0.40 times per night, 0.45 times per night, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 time per night, 2.0 times per night, or more at week 4, week 8, week 12, or week 16, for example.

Visual Analog Score (VAS). The VAS is a measure to assess patient-related rhinosinusitis symptom severity 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 >3 to 7, and severe symptoms are indicated by a VAS score of >7 to 10. Administration of an lL-4R antagonist to a subject in need thereof causes a decrease in VAS score from baseline of about 0.5 point, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points, 4 points, or more at week 4, week 6 or week 12. The decrease in VAS score can be detected as early as week 4, and as late as week 12 or later following stration of the lL-4R antagonist. 5-ltem Asthma Control Questionnaire (ACQ) Score. The A005 measures both the cy of asthma control and change in asthma control, which occurs either spontaneously or as a result of treatment. The five questions on the A005 reflect the top-scoring five asthma symptoms: woken at night by ms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Patients d to the symptom questions on a 7-point scale (0=no impairment, totally controlled; 6: maximum impairment, severely uncontrolled).

The present invention includes therapeutic methods which result in a decrease in A005 score from baseline of at least 0.10 point at week 12 following initiation of treatment with a pharmaceutical composition comprising an anti-lL-4R antagonist. For example, ing to the present invention, administration of an lL-4R antagonist to a subject in need thereof causes a decrease in ACQ score from baseline of about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 , 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more at week 4, week 6 or week 12. The se in ACQ score can be detected as early as week 4, and as late as week 12 or later following stration of the lL-4R antagonist.

[0047] Nasal Peak lnspiratory Flow . The Nasal Peak lnspiratory Flow (NPIF) represents a physiologic measure of air flow through both nasal cavities during forced ation and/or expiration expressed in liters per minute. Nasal inspiration correlates most with the subjective feeling of obstruction and is used to monitor nasal flow. Administration of an lL-4R antagonist to a subject in need thereof causes an increase in NPIF from baseline by about 0.10 liters per minute, 0.15 liters per minute, 0.20 liters per minute, 0.25 liters per , 0.30 liters per minute, 0.35 liters per minute, 0.40 liters per minute, 0.45 liters per minute, 0.50 liters per minute, 0.55 liters per minute, 0.60 liters per minute, 0.65 liters per minute, 0.70 liters per minute, 0.75 liters per minute, 0.80 liters per minute, 0.85 liters per minute, or more at week 4, week 6 or week 12. The increase in NPIF score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist.

University of lvania Smell Identification Test (UPSIT). The UPSIT is a method to quantitatively assess human olfactory function. The test consists of samples of odorants, and the subject has to describe the odor. The score is based on the number of t answers.

This test can distinguish patients with a normal sense of smell ("normosmia") from those with different levels of reduction ("mild, moderate and severe microsmia") or loss ("anosmia").

Administration of an lL-4R antagonist to a subject in need thereof causes an increase in UPSIT score from baseline by about 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 3.5 points or more at week 4, week 6 or week 12. The se in UPSIT score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist.

Physiological parameters. Efficacy of an lL-4R antagonist can be assayed by measuring the effect of physiological parameters, such as within the nasal es, such as by nasal endoscopy or ed tomography (CT) scan.

[0050] Lund-Mackay Score. The Lund-Mackay scoring system is based on localization with points given for degree of opacification: 0 = normal, 1 = partial opacification, 2 = total ication. These points are then applied to the maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinus on each side. The osteomeatal complex is graded as 0 = not occluded, or 2 = occluded deriving a maximum score of 12 per side. For patients in whom the osteomeatal complex (00) is missing (because of a previous surgery) the on of the former DC is ered and a score is provided, as if the 00 was there. Administration of an lL-4R nist to a subject in need thereof causes a decrease in Lund-Mackay score from baseline by about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 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 , 0.80 points, 0.85 , or more at week 4, week 6 or week 12. The decrease in Lund-Mackay score can be detected as early as week 4, and as late as week 12 or later following administration of the lL-4R antagonist.

Three-Dimensional volumetric measurement of maxillary sinus. This value is used to calculate the volume of air (mL); the volume of mucosa (mL); the percent sinus occupied by disease; and the thickness of lateral wall in the maxillary sinus. Administration of an lL-4R antagonist to a subject in need f causes an increase in the Dimensional volumetric measurement.

Quality of Life (QoL) Questionnaires. Various QoL Questionnaires can be used to monitor efficacy of an lL-4R antagonist, including Short-Form-36 (SF-36) Questionnaire, the l-5D (EQ-5D), nasal polyp related resource use onnaire, and the patient qualitative ssessment.

The SF-36 is a 36 item questionnaire that measures eight multi-item dimensions of health: physical functioning (10 items) social functioning (2 items) role limitations due to physical problems (4 items), role tions due to nal problems (3 items), mental health (5 , /vitality (4 items), pain (2 items), and general health perception (5 items). For each dimension, item scores are coded, summed, and transformed on a scale from 0 (worst le health state measured by the questionnaire) to 100 (best possible health state). Two standardized summary scores can also be calculated from the SF-36; the physical component summary (PCS) and the mental health component summary (MOS).

The EQ-5D is a standardized health-related quality of life questionnaire developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and ic appraisal and inter-disease comparisons. EQ-5D, designed for self-completion by patients, consists of two parts, the EQ-5D descriptive system and the EQ VAS. The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression; and each dimension has 3 levels: no problem, some problems, severe problems. The EQ Visual Analogue Scale (VAS) records the respondent’s self-rated health on a vertical visual analogue scale. The EQ VAS ometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst imaginable health state) at the .

The nasal polyp related resource use questionnaire is a questionnaire of health care resource utilization for nasal polyposis, including specialist visits, emergency care visits, sick leaves, days off etc.

[0056] Improvement of a nasal polyp-associated parameter, such as a nasal polyp-associated ter described above, can be expressed as a percentage. For example, a score can be improved by 30% or more, by 40% or more, by 50% or more, by 60% or more, by 70% or more, or by 80% or more.

An "improvement in a nasal polyp-associated parameter" means an increase from baseline of one or more of NPIF, UPSIT, and/or a decrease from baseline of one or more of SNOT-22 score, t-assessed nasal congestion/obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post nasal drip) and loss of sense of smell; number of nocturnal awakenings; VAS score; Lund-Mackay score; and 3D volumetric scores; and ACQ5 score in patients with . As used herein, the term "baseline," with regard to a nasal polyp- associated parameter, means the cal value of the nasal polyp-associated parameter for a patient prior to or at the time of administration of a pharmaceutical composition of the present invenfion.

To determine whether a nasal polyp-associated parameter has "improved," the parameter is fied at baseline and at a time point after administration of the pharmaceutical composition of the present ion. For example, a nasal polyp-associated parameter may be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11 , day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer, after the initial treatment with a pharmaceutical composition of the present invention. In some embodiments, the parameter is measured daily (e.g., once or twice per day), weekly, biweekly, or monthly. In other embodiments, the parameter is measured daily and the mean value determined over the course of a month is compared to baseline.

The ence between the value of the parameter at a particular time point following initiation of treatment and the value of the ter at baseline is used to establish whether there has been an "improvement" in the nasal associated parameter (e.g., an se or decrease, as the case may be, depending on the specific parameter being measured).

Interleukin-4 or Antagonists In one embodiment, a subject in need f is administered a therapeutic composition comprising an interleukin-4 or (IL-4R) antagonist. As used , an "IL-4R antagonist" is any agent that binds to or interacts with lL-4R and inhibits the normal biological signaling function of lL-4R when lL-4R is expressed on a cell in vitro or in vivo. Non-limiting examples of categories of lL-4R antagonists include small molecule lL-4R antagonists, peptide- based lL-4R antagonists (e.g., "peptibody" molecules), and antibodies or n-binding fragments of antibodies that ically bind human lL-4R.

[0061] The term "human lL-4R" (hlL-4R), as used herein, is intended to refer to the lL-4Ror subunit, which is a ent of the lL-4 receptors Type | and Type II, as well as the lL-13 receptor system. An lL-4R antagonist, such as an anti-lL-4Roc antibody or antigen-binding nt thereof, blocks the function of both lL-4 and lL-13 signal transduction.

The term "antibody", as used herein, is intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter- connected by disulfide bonds, as well as multimers f (e.g., lgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain nt region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3.

Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypen/ariability, termed complementarity determining regions (CDRs), interspersed with regions that are more consen/ed, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, ed from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDRB, FR4. In some embodiments, the PBS of the anti-Ang-2 antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be lly or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

The term "antibody," as used , also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, e any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that ically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or inant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or is y available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv nts; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the ariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3- CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent dies, etc.), small modular immunopharmaceuticals ), and shark variable IgNAR domains, are also encompassed within the expression "antigen- binding fragment," as used herein.

[0065] An antigen-binding fragment of an antibody will lly se at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL s may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers.

Alternatively, the antigen-binding fragment of an antibody may n a ric VH or VL domain.

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 urations of variable and nt domains that may be found within an antigenbinding fragment of an antibody include: (i) VH-CHf; (ii) ; (iii) VH-CHB; (iv) VH-CHf -CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii)VL-CH1; (ix) VL-CH2; (X) VL-CHS; (xi) VL-CH1- CH2; (xii) VL-CHf-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of le and constant domains, ing any of the ary configurations listed above, the variable and nt domains may be either ly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible e between nt variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody may comprise a imer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more ric VH or VL domain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific dy format, including the exemplary ific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an anti-lL-4R antibody using routine techniques available in the art.

The nt region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of r 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 s derived from human germline immunoglobulin sequences. The human antibodies featured in the invention may nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDRB. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian s, such as a mouse, have been grafted onto human framework sequences.

The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector ected into a host cell (described further below), antibodies ed from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves ng of human immunoglobulin gene sequences to other DNA sequences.

Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain ments, however, such recombinant human antibodies are subjected to in vitro nesis (or, when an animal enic for human lg sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

Human antibodies can exist in two forms that are associated with hinge heterogeneity.

In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held er by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain antibody). These forms have been ely difficult to separate, even after affinity purification.

The frequency of appearance of the second form in various intact lgG isotypes is due to, but not limited to, ural differences associated with the hinge region isotype of the dy. A single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human lng hinge. The instant invention encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in tion, to improve the yield of the desired antibody form.

An "isolated antibody," as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For e, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one cation or isolation step. ing to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.

The term fically binds," or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under logic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" lL-4R, as used herein, es antibodies that bind lL-4R or portion thereof with a KB of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface n resonance assay. An isolated antibody that specifically binds human lL-4R may, however, have cross-reactivity to other antigens, such as lL-4R molecules from other (non-human) species.

The anti-lL-4R dies useful for the methods featured herein may e one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR s of the heavy and light chain le domains as compared to the corresponding germline sequences from which the antibodies were derived. Such ons can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes s involving the use of antibodies, and antigen-binding fragments thereof, which are d from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline ce, or to a consen/ative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as ine mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily e numerous antibodies and antigen-binding fragments which comprise one or more dual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only n residues are d back to the al germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FRf or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1,CDR2 or CDRB. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline ce from which the antibody was originally derived). Furthermore, the antibodies may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline ce while certain other residues that differ from the original germline sequence are maintained or are d to the corresponding residue of a different germline sequence.

Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the t invenfion.

The present invention also includes methods involving the use of anti-lL-4R antibodies comprising ts of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more consen/ative substitutions. For example, the t invention includes the use of anti-lL-4R antibodies having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. consen/ative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein.

[0077] The term "surface plasmon nce", as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BlAcoreTM system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

The term "KD as used herein, is intended to refer to the brium dissociation constant of a ular antibody-antigen interaction.

The term "epitope" refers to an antigenic determinant that interacts with a specific n 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 may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is ed by llyjuxtaposed amino acids from different segments of the linear polypeptide chain. A linear e is one produced by adjacent amino acid residues in a polypeptide chain. In certain stance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

According to certain exemplary ments of the present invention, the lL-4R antagonist is an anti-lL-4Rd antibody, or antigen-binding fragment thereof sing a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-lL-4R dies as set forth in US Patent Nos. 7,608,693 and 7,605,237. In certain exemplary embodiments, the anti-lL-4Rd antibody or antigen-binding fragment f that can be used in the t of the methods of the present invention comprises the heavy chain complementarity determining regions ) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. According to certain embodiments, the anti-lL-4Rd antibody or antigen-binding fragment thereof comprises three HCDRs(HCDR1, HCDR2 and HCDR3) and three LCDRs(LCDR1, LCDR2 and LCDR3), wherein the HCDRf comprises the amino acid sequence of SEQ ID NO:3; the HCDR2 comprises the amino acid sequence of SEQ ID NO:4; the HCDR3 comprises the amino acid sequence of SEQ ID NO:5; the LCDRf comprises the amino acid sequence of SEQ ID NO:6; the LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8. In yet other ments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO:1 and an LCVR comprising SEQ ID NO:2. According to certain exemplary embodiments, the methods of the present ion comprise the use of the anti-lL-4Rd antibody referred to and known in the art as dupilumab, or a bioequivalent thereof.

The term “bioequivalent” as used herein, refers to a molecule having similar bioavaiIabiIity (rate and extent of availability) after stration at the same molar dose and under similar conditions (e.g., same route of administration), such that the effect, with respect to both efficacy and , can be expected to be essentially same as the comparator le.

Two pharmaceutical compositions comprising an lL-4R antagonist are bioequivalent if they are ceutically equivalent, meaning they contain the same amount of active ient (e.g., lL-4R antagonist), in the same dosage form, for the same route of administration and meeting the same or comparable rds. Bioequivalence can be determined, for example, by an in vivo study comparing a pharmacokinetic parameter for the two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration time cun/e (AUG).

Other anti-lL-4Rd antibodies that can be used in the context of the methods of the present invention include, e.g., the antibody referred to and known in the art as AMG317 (Corren etal., 2010, Am J Respir Crit Care Med, 181(8):788-796), or any of the anti-IL-4Rd antibodies as set forth in US Patent No. 7,186,809, or US Patent No. 8,092,804.

The anti-lL-4Rd antibodies used in the context of the methods of the present invention may have pH-dependent binding characteristics. For e, an anti-lL-4Rd antibody for use in the s of the present invention may exhibit reduced binding to lL-4Rd at acidic pH as compared to l pH. Alternatively, an anti-IL-4Ror antibody of the invention may exhibit enhanced binding to its antigen at acidic pH as compared to neutral pH. The expression "acidic pH" includes pH values less than about 6.2, e.g., about 6.0, 5.95, 5,9, 5.85, 5.8, 5.75, 5.7, 5.65, .6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the expression "neutral pH" 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 instances, "reduced binding to lL-4Rd at acidic pH as compared to neutral pH" is expressed in terms of a ratio of the KB value of the dy binding to lL-4Rd at acidic pH to the KB value of the antibody binding to lL-4Rd at neutral pH (or vice versa). For example, an antibody or antigen-binding fragment thereof may be regarded as exhibiting ed g to lL-4Rd at acidic pH as compared to neutral pH" for purposes of the present invention if the dy or antigen-binding fragment thereof exhibits an acidic/neutral KD ratio of about 3.0 or greater. In certain ary embodiments, the acidic/neutral KD ratio for an antibody or antigen-binding fragment of the present invention can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, .0. 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or greater.

Antibodies with pH-dependent binding characteristics may be obtained, e.g., by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH as compared to neutral pH. Additionally, modifications of the antigen-binding domain at the amino acid level may yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an n-binding domain (e.g., within a CDR) with a histidine e, an antibody with reduced antigen-binding at acidic pH relative to neutral pH may be obtained. As used herein, the expression "acidic pH" means a pH of 6.0 or less.

Pharmaceutical Compositions The present invention includes methods which include administering an lL-4R antagonist to a t, where the lL-4R antagonist is ned within a pharmaceutical composition. The ceutical compositions ed in the invention are formulated with suitable carriers, excipients, and other agents that provide suitable er, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all ceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing y, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid nic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing ax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

The dose of antibody administered to a patient may vary depending upon the age and the size of the patient, symptoms, conditions, route of administration, and the like. The preferred dose is lly calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted.

Effective s and schedules for administering ceutical compositions comprising anti-lL-4R antibodies may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly. Moreover, interspecies scaling of s can be performed using well-known methods in the art (e.g., Mordenti eta/., 1991 Pharmaceut. Res. 8:1351).

Various delivery systems are known and can be used to administer a pharmaceutical ition containing an lL-4R antagonist, including encapsulation in liposomes, microparticles, microcapsules, recombinant cells e of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 29-4432).

Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, asal, epidural, and oral routes. The composition may be administered by any ient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.

A pharmaceutical composition can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to aneous delivery, a pen delivery device readily has applications in ring a pharmaceutical composition. Such a pen delivery device, including an autoinjection pen delivery device, can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the dge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be . In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the resen/oir is emptied of the pharmaceutical ition, the entire device is discarded.

Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous ry of a pharmaceutical ition. Examples include, but are not limited to AUTOPENTM (Owen Mumford, lnc., Woodstock, UK), DlSETRONlCTM pen (Disetronic Medical s, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALIN 70/30TM pen (Eli Lilly and 00., Indianapolis, IN), NOVOPENTM I, II and Ill (Novo k, Copenhagen, Denmark), NOVOPEN TM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROT'V', OPTIPEN STARLETTM, and OPTICLIKTM (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition include, but are not d to the ARTM pen (sanofi- aventis), the FLEXPENTM (Novo k), and the KWIKPENTM (Eli Lilly), the SURECLICKTM jector , nd Oaks, CA), the PENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, LP), and the HUMIRATM Pen (Abbott Labs, Abbott Park IL), to name only a few.

For direct administration to the sinuses, the pharmaceutical compositions containing lL- 4R antagonists may be administered using, e.g., a microcatheter (e.g., an endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer or an inhaler.

In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14201). In another embodiment, polymeric materials can be used; see, Medical Applications of lled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another ment, a controlled release system can be placed in proximity of the compositions target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of lled Release, supra, vol. 2, pp. 115-138).

Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known s. For example, the able preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a e s medium or an oily medium tionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in ation with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, hylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

Advantageously, the pharmaceutical itions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

Dosage The amount of lL-4R antagonist (e.g., anti-lL-4R antibody, or antigen binding fragment thereof) administered to a subject according to the methods featured herein is generally a therapeutically effective amount. As used , the phrase "therapeutically ive amount" means a dose of lL-4R antagonist that results in a detectable improvement in one or more symptoms ated with nasal polyps, or a dose of lL-4R antagonist that inhibits, prevents, lessens, or delays the progression of nasal polyps or a ion associated with nasal polyps.

In the case of an anti-lL-4R antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg, of the anti-lL-4R antibody or antigen binding fragment.

The amount of lL-4R antagonist contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg/kg).

For e, the lL-4R antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of patient body weight.

Combination Therapies

[0097] The methods, according to certain embodiments, include administering to the t one or more onal therapeutic agents in combination with the lL-4R antagonist. As used herein, the expression "in combination with" means that the additional eutic agents are administered before, after, or concurrent with the pharmaceutical composition comprising the IL- 4R antagonist. For example, when administered "before" the pharmaceutical composition comprising the lL-4R antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the pharmaceutical composition comprising the lL-4R antagonist. When administered "after" the pharmaceutical composition comprising the lL-4R antagonist, the additional therapeutic agent may be administered about 10 s, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours after the administration of the pharmaceutical composition comprising the lL-4R antagonist.

Administration "concurrent" with the pharmaceutical composition comprising the lL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the lL-4R antagonist, or administered to the t as a single combined dosage formulation sing both the additional therapeutic agent and the lL-4R antagonist.

The additional eutic agent may be, e.g., another lL-4R antagonist, an lL-1 antagonist (including, e.g., an lL-1 antagonist as set forth in US Patent No. 044), an lL-6 antagonist, an lL-6R nist (including, e.g., an anti-lL-6R antibody as set forth in US Patent No. 7,582,298), an lL-13 antagonist, a TNF antagonist, an lL-8 antagonist, an lL-9 antagonist, an lL-17 antagonist, an lL-5 antagonist, an lgE antagonist, a CD48 nist, an antibiotic (e.g., doxycycline), an anti-fungal agent, a leukotriene, an antihistamine, an nergic estant, a mucolytic, an NSAID, a long-acting beta2 t (e.g., salmeterol or formoterol), a short-acting beta2 agonist, a steroid (e.g., an oral steroid), a corticosteroid, such as an intranasal corticosteroid (e.g., mometasone furoate (MFNS; e.g., Nasonex®)), or an inhaled corticosteroid (e.g., fluticasone or budesonide), an allergen immunotherapy, or combinations thereof. For example, in certain embodiments, the pharmaceutical composition comprising an lL-4R antagonist is stered in combination with a combination comprising a cting beta2 t and an inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair® (GlaxoSmithKline)]; or nide + formoterol [e.g., Symbicort® (Astra Zeneca)]).

In some ments, the lL-4R antagonist is administered after a subject receives surgery to treat nasal polyposis. stration ns According to certain embodiments, multiple doses of an lL-4R nist may be administered to a subject over a defined time course. The methods include, for example, sequentially stering to a subject multiple doses of an lL-4R antagonist. As used herein, "sequentially administering" means that each dose of lL-4R antagonist is administered to the subject at a different point in time, e.g., on different days separated by a predetermined inten/al (e.g., hours, days, weeks or months). The present invention includes methods which comprise tially administering to the patient a single initial dose of an lL-4R antagonist, followed by one or more secondary doses of the lL-4R antagonist, and optionally followed by one or more tertiary doses of the lL-4R antagonist.

[00101] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the lL-4R antagonist. Thus, the al dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the dary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of lL-4R antagonist, but will generally differ from one another in terms of frequency of administration. In certain ments, however, the amount of lL-4R antagonist contained in the initial, secondary and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment.

[00102] In one exemplary embodiment, each secondary and/or tertiary dose is administered 1 to 14 (e.g., 1, 11/2, 2, 21/2, 3, 31/2, 4, 41/2, 5, 51/2, 6, 61/2, 7, 71/2, 8, 81/2, 9, 91/2, 10, 101/2, 11,111/2, 12, 121/2, 13, 131/2, 14, 141/2, or more) weeks after the immediately preceding dose. The phrase "the ately preceding dose," as used herein, means, in a ce of multiple administrations, the dose of lL-4R nist which is administered to a patient prior to the administration of the very next dose in the sequence with no inten/ening doses.

These methods may include administering to a patient any number of secondary and/or tertiary doses of an lL-4R antagonist. For example, in certain embodiments, only a single secondary dose is stered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, , 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is stered to the patient. In other ments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) ry doses are administered to the patient.

In embodiments ing multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be stered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of stration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical ation.

In certain embodiments, the l dose (e.g., a “loading dose”) is higher than either or both of the secondary and tertiary doses. For e, the initial dose can be a loading dose, which is 1.5x, 2x, 2.5x, 3x or more greater than the secondary dose.

Treatment Populations The methods featured in the t invention ing administering to a subject in need thereof a therapeutic composition comprising an lL-4R antagonist. As used herein, the expression "a subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or indication of nasal polyposis, or who has been sed with nasal polyposis, or chronic symptoms of tis. For example, a subject in need thereof has bilateral nasal polyps, and a nasal polyp score of at least 5 out of a maximum of 8 for both nostrils, with at least a score of 2 for each nostril. In certain embodiments, the polyps are in the middle meatus. In certain embodiments, the presence of nasal polyps is confirmed by endoscopy. In some embodiments, the subject also has bilateral mucosal disease, which is confirmed by a method such as CT scan. As used herein “bilateral mucosal disease” is an infection of the mucous lining of the sinus cavities, e.g., the maxillary sinus cavities. In some embodiments, nasal polyposis (e.g., a nasal polyp score of at least 5 out of a maximum of 8 for both nostrils, with at least a score of 2 for each l) persists even after a treatment regimen of inhaled corticosteroids (INCS), such as where the INCS was administered for at least 6 weeks, at least 7 weeks, at least 8 weeks, or longer.

In certain embodiments, a subject in need thereof has anterior and/or posterior mucopurulent drainage, nasal ction, and a decreased sense of smell. In certain embodiments, a subject in need thereof has had symptoms of nasal polyposis for 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In yet other embodiments, the subject has received a previous treatment, such as with an intranasal corticosteroid (e.g., MFNS), for 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 longer, prior to receiving treatment with an lL-4R nist. In some embodiments the subject will continue to receive the INCS while receiving ent with the lL-4R antagonist. In other ments, the subject stops receiving the INCS before ing treatment with the lL-4R antagonist, or the subject stops receiving treatment with the INCS if stration with the lL-4R antagonist is effective to treat the nasal polyposis. In some embodiments, the subject tapers the dose of the INCS before stopping treatment completely.

A subject in need thereof may further have been diagnosed with nasal polyposis on the basis of one or more of the following: (a) 22—item SinoNasal Outcome Test (SNOT-22) score; (b) subject-assessed nasal congestion/obstruction, anterior rhinorrhea, posterior rhinorrhea and loss of sense of smell; (c) number of nocturnal awakenings; (d) Visual Analog Score (VAS) to assess patient-rated rhinosinusitis symptom severity; (e) five-item Asthma Control Questionnaire (ACQ5) score in patients with asthma; (f) Nasal Peak lnspiratory Flow (NPIF); (g) smell test (University of Pennsylvania Smell Identification Test (UPSIT); (h) physiological parameters, such as measured by nasal endoscopy and CT scan; (i) Lund-Mackay Score; and (k) Three Dimensional volumetric measurement of the maxillary sinus.

For example, in certain embodiments, a “subject in need thereof” is a human patient with chronic symptoms of sinusitis, which are the ce of at least two of the following symptoms: nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); facial ressure; and reduction or loss of smell.

In certain embodiments, a "subject in need thereof" is a human patient with a SNOT-22 score of greater than about 7, greater than about 10, greater than about 15, greater than about , greater than about 25, greater than about 30, greater than about 35, greater than about 40, greater than about 45, or greater than about 50. A "subject in need thereof" may also be a human patient who exhibits a Lund-Mackay score of greater than about 4, greater than about 5, greater than about 6, greater than about 7, greater than about 8, greater than about 9, greater than about 10, greater than about 11, greater than about 12, or greater than about 13.

] In a related ment, a "subject in need thereof" may be a subject who, prior to receiving an lL-4R nist, has been prescribed or is currently taking another tion, “a background therapy.” The background therapy can be, for example, an intranasal corticosteroid (INCS, or 108), such as Mometasone furoate nasal spray (MFNS; Nasonex®). In some embodiments, a “subject in need thereof” is an asthma t who prior to receiving an lL-4R nist, has been prescribed or is currently taking an INCS in combination with a long-acting beta2-adronergic antagonist (LABA). Examples of lNCS/LABA therapies include asone/salmeterol combination y and budesonide/formoterol combination y. In some embodiments, the ound therapy is a nasal saline, a topical decongestant, a topical anesthetic, a leukotriene antagonist or a systemic antihistamine. In some embodiments, the “subject in need thereof” ues the background therapy after the subject receives the lL-4R antagonist, and in other ments, the subject in need thereof stops receiving the background therapy (e.g., at once or gradually) before ing the lL-4R antagonist.

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

Example 1: Clinical Trial of Subcutaneously Administered Anti-IL-4R Antibody (mAb1) In Patients with Persistent Moderate-to-Severe Eosinophilic Asthma, Including Asthma Patients with Chronic Hyperplastic Eosinophilic Sinusitis A. Study Objectives and ew A ized, placebo-controlled, double-blind, parallel group study was conducted with once-a-week aneous administration of either 300 mg dupilumab (“mAb1”) or placebo for 12 weeks to patients with persistent moderate-to-severe eosinophilic asthma who were partially controlled/uncontrolled by inhaled corticosteroid (ICS) and long-acting beta2 agonist (LABA) therapy. Dupilumab is an L-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 7,608,693.

The primary objective of the study was to igate the effects of mAb1 administered subcutaneously once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate-to-severe philic asthma. The secondary objectives of the study were to assess the safety and tolerability of mAb1 administered subcutaneously once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma, and to assess mAb1 serum concentrations following once weekly subcutaneous dosing for 12 weeks in ts with persistent moderate to severe eosinophilic asthma.

Prior to screening, patients were required to be on a stable dose of any of the following doses and formulations of lCS/LABA combination therapy (also called “background therapy”) for at least 1 month: Fluticasone/salmeterol combination therapy - Advair® Diskus — dry powder inhaler (DPI): 250/50 ug BID or 500/50 ug BID; or - Advair® HFA — metered dose r (MDI): 230/42 ug BID or 460/42 ug BID; or nide/formoterol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or Mometasone/formoterol ation therapy (Dulera® 200/10 ug BID or 400/10 ug BID) Patients who were on budesonide/formoterol or mometasone/formoterol were switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1) and patients who had been on fluticasone/salmeterol remained on the same as background y.

Patients who satisfied the inclusion and exclusion criteria (see below) were randomized to one of the following treatments: 300 mg of mAb1 administered aneously once weekly for 12 weeks; or placebo administered aneously once weekly for 12 weeks.

[00118] The study comprised a 2-week screening period, a 12-week treatment period comprising a 4-week background therapy stable phase and an 8-week background therapy withdrawal phase post-randomization, ed by an 8-week post-treatment follow-up .

Algorithm for background therapy (ICS/LABA) withdrawal: Patients remained on BID fluticasone/salmeterol background y for 4 weeks after starting add-on therapy or treatment of 300 mg mAb1 (or placebo). At 4 weeks post- randomization, patients were switched from the BID fluticasone/salmeterol combination therapy to an equivalent ICS dose of fluticasone monotherapy (comprising either t® Diskus — DPI formulation of 250ug or 500 ug BID; or Flovent® HFA — MDI formulation of 220 ug or 440 ug BID). The LABA component (i.e., salmeterol) was discontinued. At subsequent visits, beginning with week 6, the fluticasone dose was reduced by approximately 50%, provided the patient did not meet any of the criteria for an asthma exacerbation (as defined below). If no asthma exacerbations occurred, the ICS withdrawal proceeded according to the following dosing schedule: Background therapy Background therapy withdrawal phase stable phase Week 4 Week 6 Week 7 Week 8 Week 9 Fluticasone/salmeterol Fluticasone 100 pg 50 ug BID 0 ug BID 0 ug (DPI): 250/50 pg BID (DPI): 250 ug BID BID BID Fluticasone/salmeterol Fluticasone 250 pg 100 pg 50 ug BID 0 ug (DPI): 500/50 pg BID (DPI): 500 ug BID BID BID BID Fluticasone/salmeterol Fluticasone 110 pg 44 ug BID 0 ug BID 0 ug (MDI): 230/42 ug BID (MDI): 220 ug BID BID asone/salmeterol Fluticasone 220 pg 110 pg 44 ug BID 0 ug (MDI): 460/42 ug BID (MDI): 440 ug BID BID BID Upon completing 12 weeks of treatment with investigational product (or after early discontinuation), patients were placed on their original dose of fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol (dose at study entry) and albuterol or levalbuterol as-needed to control their symptoms for an additional 8 weeks off study medication before a final safety evaluation.

A tic of the study protocol is provided in Figure 1.

Adult patients were included in the study based on the following criteria: (1) physician’s diagnosis of persistent asthma for at least 2 12 months based on the Global Initiative for Asthma (GINA) 2009 Guidelines, whose y mation is likely to be eosinophilic; and (2) whose asthma is partially controlled or uncontrolled in inhaled corticosteroids/long acting beta-agonists combination therapy ing to the following criteria: (i) stable dose of either fluticasone/salmeterol combination therapy (DPI formulation: 250/50 pg BID or 500/50 pg BID or MDI formulation: 230/42 pg BID or 460/42 pg BID), or budesonide/formoterol ation y (160/9 pg BID or 320/9 pg BID), or mometasone/formoterol combination therapy (200/10 pg BID or 400/10 pg BID) for at least 1 month prior to screening; (ii) blood eosinophils 2 300 cells/pl or sputum phils 2 3% during the screening phase; (iii) Juniper asthma control questionnaire (5-question version, ACQ) score of 2 1.5 and s 3.0 at screening; (iv) FEV1 2 50% predicted normal during the screening phase (3 attempts maximum) and on the ization day prior to the first dose (3 ts maximum); (v) has had within the 2 years prior to screening either treatment with one or more systemic (oral and/or parenteral) steroid bursts for worsening asthma or in-patient hospitalization or an ncy care visit for worsening asthma; and (vi) documented history of reversibility within 12 months of screening that meets the criterion — at least 12% and 200 mL in FEV1 after 200 pg to 400 pg (2 to 4 inhalations) of albuterol during the screening phase (3 attempts maximum), or documented history of a positive methacholine challenge (PD20 methacholine S 8 mg) within 12 months prior to screening.

Patients with moderate-to-severe asthma that is partially controlled or uncontrolled with te to high doses of combination therapy with inhaled corticosteroids and long-acting beta agonists (ADVAIR®, SYMBICORT® or DULERA®) and with blood eosinophils greater than or equal to 300 cells per microliter, or sputum eosinophils greater than or equal to 3% during the screening phase, were included in the study.

Patients who met all the inclusion criteria were screened for the following exclusion criteria: (1) patients less than 18 years of age or greater than 65 years of age; (2) clinically relevant abnormal laboratory values suggesting an n e and requiring further evaluation; (3) chronic obstructive ary disease (COPD) and/or other lung es impairing pulmonary function tests; (4) patients requiring beta-adrenergic receptor blockers for any reason; (5) current smoker or cessation of smoking within the 6 months prior to ing; (6) previous smoking with a smoking history > 10 cigarette pack-years; (7) in-patient hospitalization or emergency care visit due to asthma exacerbation in the 2 months prior to screening; (8) plans to begin allergen immunotherapy within the study period; (9) exposure to another investigative antibody within a time period prior to screening that is less than 5 half-lives of the antibody but not less than 30 days, or if the half life of the antibody is not known, then a time period prior to screening that is at least 6 ; (10) previous enrollment into the current study; (11) patient was the investigator, his/her family member or an ee at the investigational site; (12) known or suspected non-compliance, alcohol or drug abuse; (13) inability to follow the procedures of the study (e.g., due to ge problems or logical disorders); (14) reversal of sleep pattern (e.g., night shift worker); (15) ent with drugs known to prolong QTc inten/al; (16) concomitant severe disease(s) for which the use of ICS (e.g., active or inactive pulmonary tuberculosis) or LABA (e.g., diabetes, cardiovascular diseases, hypertension, hyperthyroidism, thyrotoxicosis, etc) are contra-indicated; (17) use of injectable glucocorticosteroids or oral ic glucocorticosteroids within 2 months prior to screening or more than 3 s within the 6 months prior to screening; (18) pre-treatment with variable doses of ICS, either alone or in combination with a non-steroidal controller (other than fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy, or mometasone/formoterol combination therapy); (19) patients receiving prohibited concomitant medications (listed below); (20) known allergy to doxycycline or related compounds; (21) pregnancy or intention to become pregnant during the course of the study, breast feeding or unwillingness to use an effective method of contraception; and (22) recent history of a parasitic ion or travel to a parasitic endemic area within 6 months prior to screening.

Patients remained on a constant dose of the background asthma therapy for the first four weeks of the study after which the dose of background therapy was reduced gradually.

First, the long-acting beta agonist component of the background y was awn at week 4, and then the inhaled corticosteroid dose was reduced by half every 2 weeks until week 12.

Patients continued on study treatment until the end of the study or until they were withdrawn due to an asthma exacerbation or for any other reason.

B. Study Treatments lnvestigational Product: Sterile mAb1 150 mg/mL solution for SC injection was ed in a 5 mL glass vial. Each vial contained a withdrawable volume of 2 mL. A 300 mg dose was administered subcutaneously at the study site once weekly in the morning for 12 weeks.

Placebo: Sterile placebo for SC injection was provided in an identically matched 5 mL glass vial.

Each vial contained a awable volume of 2 mL. Placebo was administered subcutaneously at the study site once weekly in the morning for 12 weeks.

[00126] The following itant medications were not d during the duration of the study: any other inhaled steroid other than fluticasone/salmeterol combination therapy or asone administered per the protocol (or budesonide/formoterol or mometasone/formoterol during the screening period); ic or ocular steroids; LABAs other than the salmeterol component of the fluticasone/salmeterol ation therapy administered per the ol; any other ICS/LABA combination products other than those given above; any inhaled anti- cholinergic agents (e.g., opium bromide or tiotropium); methylxanthines (theophylline, aminophyllines); cromones; anti-lgE therapy; |ipoxygenase inhibitors; and leukotriene receptor antagonists or leukotriene synthesis inhibitors.

C. Efficacy of treatment The primary endpoint of this study was the occurrence of an exacerbation of asthma as defined by any of the following: (1) a 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on two consecutive days; or (2) six or more additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days; or (3) deterioration of asthma, as determined by the Investigator, requiring: (a) systemic (oral and/or parenteral) steroid treatment, or (b) an increase in ICS 24 times the last dose ed prior to discontinuation from the study, or (c) hospitalization.

[00128] Secondary endpoints of the study included mean changes from baseline of the ing parameters: (1) Forced expiratory volume in 1 second (FEV1) in liters measured at every visit; (2) Morning and evening peak expiratory flow rate (AM PEF and PM PEF) in liters/minute ed daily; (3) Daily Albuterol/Levalbuterol use in inhalations/day; (4) Five- item Asthma Control Questionnaire (ACQ5) score at every visit; and (5) Nighttime awakenings (no. of times per night) measured daily and (6) a 22-item Sino-Nasal Outcome Test (SNOT-22), evaluated at baseline and end of treatment (at Week 12), to assess upper ainNay symptoms.

Secondary endpoints also included proportion of patients with a composite asthma event defined by a 30% or greater reduction from baseline in morning PEF on two consecutive days er with 2 6 additional reliever puffs of albuterol or levalbuterol in a 24-hour period 9compared to baseline) on 2 utive days. PEF, ACQS, asthma ms , nocturnal ings, and reliever medication use were captured in an electronic daily diary.

Mean daily nal awakenings, ranging from 0-10, were averaged from the previous 7 days.

Morning and evening asthma symptom scores consisted of a non-validated patient-reported e assessed on a 5-point -type scale, with higher scores indicating worse outcomes (Table 2). Patients recorded overall symptom scores twice a day prior to measuring PEF. Data were described as the average for the 7 days prior to the specified time point.

Table 2: Asthma Symptom Score Assessment A) Morning symptom score: 0 = No asthma symptoms, slept through the night 1 = Slept well, but some complaints in the morning. No nighttime awakenings 2 = Woke up once because of asthma (including early ing) 3 = Woke up several times because of asthma (including early awakening) 4 = Bad night, awake most of the night because of asthma B) Evening m score: 0 = Very well, no asthma symptoms 1 = One episode of ng, cough, or breathlessness 2 = More than one episode of wheezing, cough, or breathlessness without interference of normal activities 3 = ng, cough, or breathlessness most of the day, which interfered to some extent with normal activities 4 = Asthma very bad. Unable to carry out daily activities as usual D. Adverse Events Monitoring Safety was assessed throughout the study by monitoring Adverse Events and Serious Adverse Events.

An Adverse Event (AE) is any rd medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product. An AE can, therefore, be any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, r or not ered related to the nal (investigational) product. AEs also include: any worsening (i.e., any clinically significant change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study drug; abnormal laboratory findings considered by the Investigator to be clinically significant; and any untoward medical occurrence.

A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose s in death; is life-threatening; requires in-patient hospitalization or prolongation of existing alization; results in persistent or significant disability/ incapacity; is a ital anomaly/ birth defect; or is an important l event.

E. Statistical methods

[00132] For the primary analysis of proportion of patients experiencing an asthma exacerbation, a ic regression model was used to compare SAR group with placebo. The model included terms for treatment and stratification factor (prior lCS/LABA combination therapy dose). The primary analysis was performed based on modified intent-to-treat (mlTT) population which included all randomized patients who received at least one dose of mAb1. A stratified chi- square test was also used to corroborate the primary analysis.

For secondary efficacy endpoints except SNOT-22, the change from baseline was analyzed using a mixed-effect model with ed measures (MMRM) approach. The model included change from baseline values up to week 12 as response les, and factors (fixed effects) for treatment, stratification factor, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction. Statistical inferences on treatment isons for the change from baseline at week 12 were derived from the mixed-effect model. Change from baseline in SNOT- 22 was analyzed using an analysis of covariance (ANCOVA), with end of treatment measurements used to impute g data. Pharmacodynamic effects were evaluated using MMRM models in a post hocfashion. No adjustments were made for multiplicity, since there was only one primary endpoint and analysis. Safety variables including AEs, laboratory parameter, vital signs, ECG, clinical laboratory observations and physical examinations were summarized using descriptive statistics.

Demographic and clinical characteristics were summarized using ptive characteristics. Plots of secondary and pharmacodynamic variables are presented as mean change from baseline over time with standard error. Comparison of treatment effects from the MMBM analyses are based on least square mean change (95% confidence inten/als [Cl]) from baseline at Week 12.

F. Results The results obsen/ed with all 104 randomized patients (from 491 screened) who either completed or tinued the treatment phase of the study are summarized below. All randomized patients were exposed to study treatment and included in the mlTT population.

Baseline characteristics were r between groups. The aphic and clinical characteristics were also similar between the two groups (Table 3). As noted above, patients were treated either with 300 mg aneous mAb1 once a week, or with placebo. The study treatment period was completed by 86.5% and 67.3% of the mAb1 and placebo patients, tively. The most common cause of tinuation was lack of cy, which was more frequent with placebo (21.2%) than mAb1 (1.9%).

Table 3. Baseline Demographic and Clinical Characteristics of Treatment Groups.* Variable Placebo mAb1 300 mg (N : 52) (N : 52) Age (yr) 41.6 i 13.1 37.8 i 13.2 Male sex, no. (%) 26 (50.0) 26 (50.0) Race or ethnic group, no. (%) White 38 (73.1) 45 (86.5) Black or African American 9 (17.3) 5 (9.6) Asian 3 (5.8) 1 (1.9) Other 2 (3.8) 1 (1.9) Body mass index Mean (kg/m2) 31.6 i 7.0 31.3 i 8 0 2 30, no. (%) 25 (48.1) 24 (46.2) Duration of asthma (yr) 26.9 :r 14.8 24.2 :r 12.6 Number of asthma bations in prior 2 years 1.4 :r 1.3 1.4 :r 1.0 Prior lCS/LABA combination therapy dose, no. (%) High Dose 41 (78.8) 42 (80.8) Low Dose 11 (21.2) 10 (19.2) Blood eosinophils (x10'/|) 0.47 i 0.21 0.55 i 0.19 FEV, (l) 2.54 i 0.66 2.47 i 0.65 FEV, (% of predicted value) 72.0 :r 12.7 72.0 :r 12.6 PEF (l/min) Morning 406.9 i 110.7 393.0 i 101.1 Variable Placebo mAb1 300 mg (N : 52) (N : 52) Evening 416.6 1r 116.8 414.6 1r 102.3 ACQ5 score 2.1 :r 0.5 2.1 :r 0.5 Asthma symptom score Morning 0.73 i 0.63 0.75 i 0.81 Evening 1.12 1r 0.73 0.92 1r 0.71 Nocturnal awakenings per day 0.21 :r 0.50 0.44 :r 0.80 SNOT-22 26.2 1r 15.6 30.9 1r 14.8 Inhalations of albuterol or levalbuterol/24-hour period 2.0 :r 1.8 2.2 :r 2.4 FeNO (ppb) 35.0 1r 27.1 37.6 1r 28.1 TARC (pg/ml) 470.5 1r 204.7 496.1 1r 342.4 Eotaxin-3 (pg/ml) 117.3 i 349.2 75.4 i 44.0 lgE (lU/ml) 694.7 1r 1837.8 657.7 1r 1482.3 *Plus—minus values are means i SD, except as otherwise noted. ACQ5 denotes the Asthma Control Questionnaire (5 question n), FeNO on of exhaled nitric oxide, FEV, forced tory volume in 1 second, IgE immunoglobulin E, PEF peak expiratory volume, SNOT-22 the 22-item Sinonasal e Test, and TARC thymus and activation ted chemokine. (i) Primary Efficacy Endpoint The incidence of asthma exacerbations in the placebo and mAb1 treatment groups is ted in Table 4.

Table 4. Incidence of Asthma Exacerbations in mlTT population Placebo (N=52) mAb1 (N=52) Patients With No Asthma 29 (55.8%) 49 (94.2%) Exacerbations Patients With Asthma Exacerbations 23 (44.2%) 3 (5.8%) Odds Ratio vs Placebo (95% Cl) -- 0.077 , 0.279) There were a total of 26 asthma exacerbations during the treatment period, and no patients were alized for asthma exacerbations. There were 23 patients (44.2%) who experienced an asthma exacerbation in the placebo group, s only 3 patients (5.8%) experienced an asthma exacerbation in the mAb1 treatment group. The odds ratio is 0.077 (p <0.0001) and the relative risk reduction is approximately 87%.

Out of the 26 asthma exacerbations experienced during this study, 9 were considered severe as demonstrated by a need for immediate inten/ention in the form of treatment with either systemic corticosteroids or with inhaled corticosteroids at 4 or more times the dose taken prior to the event. A summary of the incidence of severe asthma exacerbations is presented in Table 5.

Table 5. Incidence of Severe Asthma Exacerbations in mlTT population Placebo (N=52) mAb1 (N=52) Patients With No Asthma Exacerbations 29 (55.8%) 49 (94.2%) Patients WIth Severe Asthma 8 (154%) 1 (1.9%) Exacerbations Patients With Non-Severe Asthma (28's /°)o 2 (3'8 /°)o Exacerbations As shown in Table 5, eight severe asthma exacerbations were observed in the o group, and only 1 severe asthma exacerbation was ed in the mAb1 treatment group. The ing 15 asthma exacerbations in the placebo group and 2 in the mAb1 group met the protocol definition of exacerbation based on decreased morning PEF and/or sed albuterol/levalbuterol use. Within the active treatment group, a sustained ement versus baseline was observed during the course of the study for all parameters, despite steroid withdrawal.

Table 6. Exacerbation Events Outcome Placebo mAb1 (N : 52) ( N : 52) 2 30% reduction from ne 10* (19.2) 1 (1.9) in morning PEF in a 24-hr period on 2 consecutive days 2 6 additional inhalations of 10 (19.2) 1 (1.9) albuterol/levalbuterol in a 24-hr period on 2 consecutive days ic steroid treatment 5 (9.6) 1 (1.9) 2 4-fold increase in 108 from 3 (5.8) 0 the previous dose Hospitalization *4 Placebo patients met both PEF and systemic steroid treatment criteria, and 1 placebo patient met both PEF and additional albuterol/levalbuterol use.

With mAb1, the time to exacerbation was longer, and the risk of exacerbation was reduced relative to placebo (hazard ration 0,10; 95% Cl 0.03, 0.34; P< 0.001 ). An analysis of the time to asthma exacerbation by Kaplan-Meier Plot revealed that the effect of treatment with mAb1 is sustained over time, including after 8 weeks when patients are at higher risk of developing exacerbations due to steroid withdrawal.

Only 1 patient from the placebo group had a composite asthma event. A ite asthma event is defined as a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with 26 additional reliever puffs of rol or Ievalbuterol in a 24- hour period (compared to baseline) on 2 consecutive days. (ii) Other Efficacy Endpoints Lung function parameters (FEV1, AM PEF and PM PEF), asthma symptom-based endpoints (ACQ score, ime awakenings) and albuterol use were assessed for each patient at each visit. In addition, the SNOT-22 score was assessed at baseline and at the end of treatment. For all parameters, the baseline and Week 12 (LOCF) mean values along with the mean difference between ent groups (ANOVA model for 2) are summarized in Table 7. In Table 7, the column labeled "Difference vs. Placebo" reflects the placebo-corrected value from baseline which takes into account changes that are observed in the value of the parameter as compared to the changes that were observed for that ter in the placebo- treated group.

Table 7. ary Parameters of Lung on and Symptom Scores Least-Squared Baseline Mean Difference vs.

(SD) MeaI:SC[h)ange Placebo p value FEV1 (L) Placebo 52 2.54 (0.66) -0.22 (0.06) -- mAb1 52 2.47 (0.65) 0.05 (0.06) 0.27 (0.11, 0.42) 0.0009 AM PEF (L/min) Placebo 52 406.9 (110.7) -20.7 (9.1) -- mAb1 51 393.0 (101.1) 13.9 (8.8)f 34.6 (10.6, 58.5) 0.0051 PM PEF (L/min) Placebo 51 416.6 (116.8) -18.4 (8.9)1' -- mAb1 52 414.6 (102.3) 4.3 (8.5) 22.7 (-0.7, 46.0) 0.0567 Albuterol Use (Puffs/Day) Placebo 52 2.0 (1.8) 0 7 (0.3 -- mAb1 50 2.2 (2.4) -1 3 (0.3): -2.0 (-2.9, -1.2) <0.0001 ACQ Score Placebo 52 2.08 (0.52) -0.27 (0.16) -- mAb1 52 2.09 (0.46) -1.00 (0.16) -0.73 (-1.15, -0.30) 0.0011 Night-time Awakenings (No. of times/night) Placebo 52 0.2 (0.5) 0.1 (0.1) -- mAb1 52 0.4 (0.8) -0.2 (0.1) -0.2 (-0.5, -0.0) 0.0518 SNOT22 Average Score o 51 26.24 (15.62) 0.23 (2.15)‘I' -- mAb1 50 30.92 (14.77) -8.26 (2.20): -8.49 (-13.96, -3.03) 0.0027 T 51 patients with at least 1 post-baseline assessment. 1; 50 patients with at least 1 post-baseline assessment.

Treatment with mAb1 ed in a significant change from baseline in FEV1 at Week 1, which was maintained through Week 12 despite LABA and ICS withdrawal, with a small decrease in FEV1 at Week 5 coinciding with LABA withdrawal. Similar improvements were observed in morning PEF, but less so in g PEF. The least-squared (LS) mean change from ne to week 12 in FEV1 was -0.22 L for placebo and 0.05 L for the mAb1 group. (p=0.0009).

ACQ5 score improved in both treatment groups at Week 1. r, while ACQ5 ed r with mAb1 between Weeks 1 and 4, the placebo effect stabilized, maintaining the difference through Week 12.

[00145] Morning symptom scores increased from baseline to Week 12 with placebo. With mAb1, there was an initial decrease which ed below baseline through Week 12. A similar pattern (with greater variability) was observed for evening asthma symptom scores.

Nocturnal awakenings were stable from the placebo group through Week 6, then increased from Weeks 6 to 12. In st, nocturnal awakenings decreased in the mAb1 group by Week 1 and remained improved versus baseline through Week 12.

Changes in albuterol/levalbuterol use were similar to other secondary endpoints: an initial decrease followed by a return towards ne with placebo. With mAb1, the initial decrease was maintained over time.

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

Table 8. Secondary Endpoints e Placebo mAb1 Difference vs P Value (N = 52) ( N = 52) Placebo (95% Cl)** Kaplan-Meier estimate at 46.0 (31.8, 60.2) 5.8 0.10 (0.03 to 0.34) <0.001 12 weeks (0.0, 2.1) Change in morning 0.3 i 0.1 -0.4 i 0.1 -0.7 (-0.9 to -0.4) <0.001 asthma symptom scores, baseline to week 12 Change in evening 0.1 i 0.1 -0.6 i 0.1 -0.7 (-0.9 to -0.4) <0.001 asthma symptom scores, ne to week 12 Table 9. Change From Baseline at Week 12 in SNOT-22 Items Relevant to Upper Airway Disease.

SNOT-22 le Least-Squares Mean Difference vs Placebo P Value Change 1 Standard Error (95% Cl) Placebo mAb1 (N : 52) ( N : 52) Need to blow nose -0.70 (-1.13, -0.26) 0.002 Nasal blockage -0.20 i 0.19* -0.94 : 0.19T 0.75 (-1.22, -0.28) 0.002 Decreased sense of 0.04 i 0.18* -1.13 : 0.18T -1.16 (-1.62, -0.71) < 0.001 smell/taste *51 and f50 patients with at least 1 aseline assessment respectively For all secondary endpoints, Week 12 measurements favored mAb1 treatment and were significant except for evening PEF and nal awakenings (Table 7 and 8). Significant improvements with mAb1 were also observed for the three SNOT-22 items relevant to upper ainNay disease (Table 9) (iii) Safety mAb1 was generally safe and well tolerated. Treatment-emergent adverse events (TEAEs) were reported similarly by 40 (76.9%) of placebo-treated patients and by 42 (80.8%) of mAb1-treated patients (Table 10). TEAEs were ecific, generally mild to moderate in intensity and the ty recovered by the end of the study. An increased reporting of the following TEAEs was observed for mAb1 in comparison with placebo: injection site reactions were reported by 15 (28.8%) mAb1 patients and by 5 (9.6%) placebo patients; nasopharyngitis was reported by 7 (13.5%) mAb1 patients and 2 (3.8%) placebo patients; headache was reported by 6 (11.5%) mAb1 patients and 3 (5.85) placebo patients and nausea was ed by 4 (7.7%) mAb1 patients and 1 (1.9%) placebo patients.

Table 10. Adverse Events. e event Placebo mAb1 300 mg (N : 52) (N : 52) no. ofpatients (%) Any adverse event 40 (76.9) 42 (80.8) Any serious e event 3 (5.8) 1 (1.9) Study tinuation owing to adverse event 3 (5.8) 3 (5.8) Death 0 0 Most common AEs* Injection site reactionsf 5 (9.6) 15 (28.8) Nasopharyngitis 2 (3.8) 7 (13.5) Adverse event Placebo mAb1 300 mg (N : 52) (N : 52) no. ofpatients (%) Upper respiratory tract infection 9 (17.3) 7 (13.5) Headache 3 (5.8) 6 (11.5) Nausea 1 (1.9) 4 (7.7) Arthropod bite 0 3 (5.8) Muscle spasms 0 3 (5.8) Nasal congestion 1 (1.9) 3 (5.8) Rash 1 (1.9) 3 (5.8) Urticaria 0 3 (5.8) Viral upper respiratory tract infection 0 3 (5.8) *2 3 patients in any treatment group by Preferred Term tion site reaction includes events reported as: injection site pain, injection site reaction, injection site erythema, injection site rash, injection site haematoma, injection site urticaria, injection site dermatitis, ion sites inflammation, injection site nodule, injection site pruritus and injection site swelling.

] There were no deaths reported during the study period. Of the 4 treatment emergent serious adverse events (SAEs) reported: 1 mAb1 patient experienced bipolar disorder and 3 placebo ts experienced SAEs of asthma with pneumonia, gunshot wound with left pneumothorax, and right ankle fracture. None of these SAEs were considered as related to the mAb1 and all but the recent ankle fracture were recovered by the end of the study. There were no .

A total of 6 patients discontinued the study due to a TEAE: 3 patients in the mAb1 group (bipolar disorder, asthma with wheezing, and angioedema) and 3 patients in the placebo group (upper respiratory tract infection, psoriasis and asthma). The TEAE of angioedema ed in a 42-year old African-American female after the ninth study treatment dose as a pruritic, popular rash observed at, and distant to, the injection site. It persisted for one week, resolved after study treatment discontinuation, and some and diphenhydramine treatment. It was deemed treatment-related. This AE was subsequent to milder rashes at the injection site after the first and sixth study treatment doses.

Among the most common AEs occurring in 23 patients in any treatment group (Table ), injection site reactions, nasopharyngitis, nausea, and headache occurred more frequently with mAb1 than o. No ally significant changes in vital signs, physical examination, clinical laboratory or ECG findings were reported in either group.

G. Conclusion Significant improvements were observed for lung function and other asthma l parameters. Efficacy was observed early and sustained despite ound y withdrawal. A relative reduction of approximately 87% (p 1) in the primary endpoint of the incidence of asthma exacerbations in persistent, moderate-to-severe asthma patients with eosinophilia was observed after 12-week treatment with 300mg of mAb1 once weekly (5.8%) compared with placebo (44.2%). As shown in Table 7, clinically meaningful and statistically significant (without multiplicity adjustment) ements with treatment compared with placebo were observed in lung function parameters (FEV1, PEF AM), asthma m scores (A00) and albuterol use. Positive trends were obsen/ed for PEF PM (p=0.0567) and nocturnal awakenings (p=0.0518). A statistically significant (without multiplicity adjustment) improvement was also ed for the SNOT-22 score. Within the active treatment group, a sustained improvement versus baseline was observed during the course of study for all parameters, despite LABA and ICS withdrawal. mAb1 was generally safe and well tolerated. e 2: Biomarker studies Biomarker analysis was conducted on samples taken from ts who participated in clinical trials of mAb1 (see Example 1 above). In particular, plasma biomarkers associated with TH2 inflammation such as thymus and activation ine (TARC; CCL17), lmmunoglobulin E (lgE), eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and blood eosinophils were ed in samples from patients at baseline and at different time points following tion of study treatment(s). Baseline levels of these kers were assessed for potential predictive value for treatment response. In addition, the fraction of d NO (FeNO) and d sputum eosinophils and neutrophils were measured as biomarkers of bronchial inflammation. Exhaled nitric oxide assessment was conducted prior to spirometry and following a fast of at least 1 hour using a NIOX instrument (Aerocrine AB, Solna, Sweden). Biomarkers were analyzed using a mixed model and the least square mean derived from the model are reported below.

[00156] Asthma subjects (N=104) were administered either mAb1 (300 mg) or placebo subcutaneously, on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 of the study (i.e., 12 weekly doses) (see Example 1, above). Samples for biomarker analysis were ted from the antibody- and placebo-treated subjects at week 0, 1, 4, 8 and 12. Antigen-specific lgE was detected using the Phadiatop® test.

[00157] TARC, eotaxin-3 and lgE remained unchanged in response to placebo. In contrast, a rapid reduction in TARC (mean % change -22.7% vs +0.3%; p: 0.0003) and eotaxin-3 (mean % change -39.62% vs 12.69%; p<0.0001) was obsen/ed within one week in patients treated with mAb1 and persisted until week 12: TARC: -26.0% vs +7.6% o (p=0.0005); n-3: - 45.67% vs +5.13% placebo (p<0.0001).

[00158] TARC levels responded within a week following exposure to mAb1 at 300 mg administered subcutaneously. TARC levels u at approximately 50% of the baseline level in mAb1-treated ts, regardless of ICS withdrawal. The data suggest that TARC expression is more directly linked to lL-4R signaling, than FEV1 changes (which drop in parallel to ICS withdrawal [after Week 4]) and that lL-4R ge induces a shift towards a TH1 signature, as observed with, for example, lFNgamma stration. It might be le to titrate the mAb1 dose using TARC (and for example CXCL10) in ular in patients requiring long term treatment and at risk for TH1 type immune diseases.

Total serum lgE also decreased following mAb1 treatment. Total serum lgE response was more heterogeneous and delayed compared to TARC response. Mean (SD) baseline lgE levels were 694.68 lU/L (1837.82) for the placebo group (n=52) and 657.66 (1482.25) for the mAb1 group (n=52), whereas median was 169.95 for the placebo group and 206.15 for the mAb1 group. Despite this heterogeneity, a trend towards lgE se in mAb1-exposed patients compared with placebo was obsen/ed — however, starting at week 4 only. Serum lgE was significantly reduced in the mAb1 group ed with o (mean % change, -10.1% vs +13.5%; p=0.0325) starting from week 4 and continued to decrease until week 12 (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 lgE all favored mAb1 (all P< 0.001) (Table 11). No differences from baseline or between treatments were observed in YKL-40 or CEA.

Table 11. Percent Change From Baseline at Week 12 in Pharmacodynamic Endpoints.

Squares Mean Percent Change 1 Standard Error Outcome P Value Placebo mAb1 (N : 52) (N : 52) FeNO 35.0 i 10.8 28.7 i 11.2 < 0.001 TARC 7.6 i 6.9 -26.0 i 6.9 < 0.001 Eotaxin-3 5.1 i 4.7 -45.7 i 4.7 < 0.001 lgE 5.5 i 3.6 -36.8 i 3.6 < 0.001 Blood eosinophils 2.7 i 15.8 41.6 i 15.7 0.078 There was a ent decrease in periostin levels, followed by an increase with CS withdrawal. Administration of mAb1 delayed the increase, but did not prevent the increase above baseline. No consistent treatment effect was observed with CEA and YKL-40.

The number of blood eosinophils ed unchanged through Week 6, but then increased at Weeks 8 and 12. Peripheral blood eosinophil numbers were unchanged on placebo throughout treatment. The difference n the treatments was not significant, with the borderline increase driven by larger blood eosinophil elevations in only a few patients treated with mAb1.

Little or no increases were obsen/ed in the majority of patients.

Table 12. Proportions of Patients Achieving Thresholds of Change in Blood Eosinophil Levels.

Change in eosinophils Number (%) of patients Placebo (n = 52) mAb1 (n = 52) > 15% Decrease 13 (30.2) 21 (47.7) % se — 0% change 7 (16.3) 6 (13.6) 0%-15% se 8 (18.6) 4 (9.1) % - 100% Increase 13 (30.2) 6 (13.6) 100% - 200% increase 2 (4.7) 3 (6.8) > 200% increase 0 4 (9.1) ] Since only 3 mAb1 ts experienced asthma exacerbation during the study, no conclusion could be drawn regarding the association between baseline biomarker levels and asthma exacerbations. mAb1 treatment was also associated with a significant decrease from baseline in FeNO at Week 4, and FeNo remained below ne through Week 12, regardless of lCS withdrawal (mean % change at week 12: -28.7 for mAb1 vs 35.0 for placebo; p<0.0001). In contrast, placebo FeNo values remained stable through Week 8, followed by an increase at Week 12 coincident with lCS withdrawal.

Forced expiratory volume in 1 second (FEV1) improvement significantly correlated with FeNO reduction ( 8, p=0.009) at week 12. Similarly, improvements in AM-PEF and PM- PEF correlated with FeNO reduction. Other correlations with FeNO were not significant. See Table 13.

Table 13. Correlation between FEV1 and PD Endpoints.

Outcome Correlation P Value FeNO -0.408 <0.009 TARC -0.248 0.10 Eotaxin-3 -0.146 0.34 lgE -0.279 0.06 Blood phils 0.165 0.28 r plot analysis of baseline eosinophils versus change from baseline in FEV1 at week 12 did not seem to suggest association of baseline eosinophils and treatment effect, as measured by change from baseline in FEV1 at week 12 in the study population (baseline eosinophils 2 0.3 ). Baseline phils correlated with decreased ACQ and decreased albuterol/levalbuterol use. Periostin and YKL-40 at baseline correlated with decreased ACQ.

The FEV1 change from baseline at week 12 was compounded by the withdrawal of lCS (starting at week 4). Similar analyses did not suggest association between baseline TARC or lgE and change from baseline in FEV1 at week 12 in the study population (baseline eosinophils 2 0.3 Giga/L).

H. Summary These results show that mAb1 significantly reduced serum biomarkers associated with Th2 inflammation (TARC, eotaxin-3 and lgE) and ial inflammation (FeNO) in adult asthma patients. The correlation between FeNO reduction and FEV1 improvement suggests a relationship between lL-4/lL-13 mediated anti-inflammatory activity and improvement in pulmonary function in moderate-to-severe, uncontrolled asthma.

Example 3. al Trial of Subcutaneously stered Anti-lL-4R Antibody (mAb1) In Patients with Bilateral Nasal sis and Chronic Symptoms of Sinusitis A. Study Objectives and Overview

[00168] The positive effect of mAb1 on the SNOT-22 test described in Example 1 suggested that the anti-lL-4R dy might also be ive for treating nasal polyposis. Further, nasal polyps are most commonly eosinophilic/TH2 driven, and mAb1 significantly d biomarkers associated with Th2 inflammation (see Example 2). A clinical trial was ore designed to test the therapeutic effect of mAb1 on nasal sis.

] A randomized, double-blind, phase 2, placebo lled, 2 arm study will be performed to evaluate mAb1 administered once a week (QW) subcutaneously (SC) for 16 weeks in patients with bilateral nasal polyposis and chronic symptoms of sinusitis. The primary objective of the study will be to te the cy of mAb1 in the treatment of ral nasal polyposis (NP) by assessment of the endoscopic nasal polyp score in comparison to placebo. Secondary objectives of the study include evaluation of mAb1 in patients with bilateral nasal polyps with regards to symptoms of sinusitis, Computed Tomography (CT) scan changes, Nasal polyp score in the sub-group of patients with co-morbid asthma, safety and tolerability, pharmacodynamic responses based on suppression of TH2 biomarkers, concentrations of mAb1 in serum, immune response to mAb1 (Anti-drug antibodies (ADA)), and effect of mAb1 in patient reported outcomes and Quality of Life (QoL) scales. mAb1 will be administered concomitantly with Mometasone furoate nasal spray (MFNS). Also, there is high co-morbidity of NP with asthma, aspirin/ nonsteroidal anti- inflammatory drug (NSAID) hypersensitivity and previous ies, and therefore patients will be allowed to enter the study unless they present any of the exclusion criteria described below.

Approximately 56 patients will be ized into 2 treatment groups of 28 patients per group.

To ensure at least 28 patients with co-morbid asthma are included in the study, recruitment of NP patients without co-morbid asthma will stop when approximately 28 patients without asthma are randomized. Both the patient and the investigator will be blinded to the assigned treatment group.

[00171] The study will t of three periods: 1) a four week screening run in period on MFNS (Visit 1); (2) a 16 week ized mAb1 or placebo treatment period (Visits 2-18); and (3) a 16 week post-treatment period to assay pharmacokinetics, immunogenicity, safety and efficacy (Visits 19-22). The total duration of the study is up to 36 weeks.

The primary endpoint will be the change from baseline at Week 16 in bilateral nasal polyp score (NPS).

Numerous secondary efficacy endpoints will be measured to more comprehensively te the efficacy of mAb1. The study will explore improvement of nasal polyposis and associated sinus inflammation in CT scan, improvement in condition specific and general medical questionnaires in order to obtain a better understanding of the impact of severe nasal polyposis on the subject's y of life (QOL).

These endpoints, together with exploratory sub-group analysis and biomarkers will provide the information on the therapeutic value of mAb1 to reduce nasal polyp score and to improve ms in NP and its subsets. The sustainability of the effect will be also explored through the 4-month post-treatment evaluation period.

The 300 mg QW dose regimen is anticipated to te apparent target mediated clearance level (10-15 mg/L). This regimen has been tested and provided statistically significant and clinically relevant response in two previous proof of concept studies performed with mAb1 in asthma and atopic dermatitis (see, e.g., Example 1 above, USSN 61/805797 and USSN 61/816191). The first dose will employ a loading dose of 600 mg in order to e faster steady-state tration. This loading dose range is supported by the acceptable safety profile of the highest loading dose (600 mg) demonstrated in a prior study conducted in Japanese healthy subjects.

[00176] In addition, given that the Cmax after 600 mg loading dose is around 70 mg/L and that the steady state Ctrough of 300 mg QW is around 150 mg/L, the Cmax after the proposed dosing regimen (ie, 600 mg g dose followed by 300 mg QW) will be below the mean Cmax of 12 mg/kg lV dose (421 mg/L), the highest single dose tested in y subjects that was well tolerated, providing additional confidence that this dose regimen should have an acceptable safety profile.

Patient inclusion criteria include (i) a physician endoscopic diagnosis of bilateral nasal polyposis (ie, a minimum bilateral nasal polyp score of 5 out of a maximum score of 8 for both nostrils, with at least a score of 2 for each nostril, despite completion of a prior INCS nasal corticosteroid) treatment) for at least 8 weeks before screening, and (ii) c ms of sinusitis, which are the presence of at least two of the following symptoms prior to screening: nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); facial pain/pressure; and reduction or loss of smell.

] Patients who have met these criteria will be screened for the following exclusion criteria: age <18 or >65 years; any technical/administrative reason that makes it impossible to randomize the patient in the study; previous participation in any clinical trial of mAb1 ; a SNOT22 score <7; receipt of any other igational drug or prohibited therapy for this study within 2 months before screening or 5 half-lives, ver is ; receipt of oral corticosteroids (008) or asal corticosteroid drops within 2 months or 1 month before screening or scheduled to receive OCS during the study period for another ion; treatment with mAB or immunosuppressive therapy; treatment with an anti-immunoglobulin E (IgE) therapy (e.g., omalizumab) within 130 days of Visit 1; treatment with a leukotriene antagonist / er for patients who were not on a continuous treatment for 230 days prior to Visit 1; initiation of allergen therapy within 3 months prior to Visit 1 or a plan to begin therapy during the Screening Period or the Randomized Treatment Period; any nasal surgery within six months before screening or have had more than five sinonasal ies in the past of which maximal two were surgeries changing the lateral wall ure of the nose; or a condition/concomitant disease that makes a patient aluable for the primary efficacy endpoint (e.g., antrochoanal polyps; nasal septal deviation that would occlude at least one nostril; acute sinusitis, nasal infection or upper respiratory infection at ing or in the 2 weeks before screening; ongoing rhinitis mentosa; Churg-Strauss syndrome, Young’s syndrome, Kartagener’s syndrome or dyskinetic ciliary mes, Cystic fibrosis; signs or a CT scan tive of Allergic fungal rhinosinusitis). Patients with co-morbid asthma are excluded if: the patient has a forced expiratory volume (FEV1) of 60% or less; an exacerbation requiring ic (oral and/or parenteral) steroid treatment or Hospitalization (>24h) for treatment of asthma, has occurred within 3 months prior screening; or the patient is receiving a dose higher than 1000 pg fluticasone or the equivalent of inhaled corticosteroids. Other exclusion criteria include patients with short life expectancy (less than 6 months); patients receiving concomitant treatment prohibited in the study; women who are pregnant or intend to become pregnant during the study, or breast-feeding women. Other exclusion criteria include concomitant severe diseases (e.g., active and inactive pulmonary tuberculosis, Diabetes mellitus etc.); sed active parasitic infection; suspected or high risk of parasitic infection; history of human immunodeficiency virus (HIV) infection or positive HlV screen at Visit 1 ; evidence of acute or chronic infection; known or suspected suppression, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), despite infection tion; live vaccinations within 12 weeks prior to Visit 1 or planned ations during the study; patients with active autoimmune e or patients using immunosuppressive therapy for autoimmune disease (eg, Hashimoto’s thyroiditis, Graves’ disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematous, multiple sis, psoriasis vulgaris, rheumatoid arthritis); patients with positive or indeterminate hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at Visit 1; patients with liver injury related criteria ( e.g., underlying hepatobiliary disease, or ALT>3 ULN).

B. Study Treatments ] lnvestigational Product: Sterile mAb1 of various concentrations will be provided in 5 mL glass vials. Each vial will contain a withdrawable volume of 2 mL: 150 mg/mL solution (300 mg dose/ 2 mL). Sterile placebo will be ed in identically matched glass 5 mL vials, where each vial contains a deliverable volume of 2 mL. ] mAb1 will be administered every 7 :r 2 days (QW). The doses of mAb1 will be separated by 25 days to avoid an overdose. At Visit 2 (V2), 2 injections will be performed. After V2 one injection of mAb1 will be performed weekly at the investigational site throughout the randomized treatment . The mAb1 will be stered following clinic procedures and blood collection. Patients will be monitored for at least 1 hour after each administration for any signs or symptoms of a local site injection or hypersensitivity reaction. Subcutaneous injection sites will be alternated between the 4 quadrants of the abdomen (avoiding navel and waist areas) or upper thighs so that the same site is not injected for two consecutive times/weeks.

On a daily basis throughout the study, the subject will use an electronic diary to record daily use of MFNS. Mometasone furoate (NASONEX ®) 50 micrograms/actuation Nasal Spray, is contained in a , that contains 18 g (140 actuations) of t formulation.

[00182] Screening Period: Prior to screening, subjects must be on a stable dose of intranasal corticosteroids (INCS) for 22 month prior to Visit 1. If the patient is using an ative INCS product other than MFNS prior to the screening visit, at V1, the patient will be switched to MFNS. After V1 all patients will enter a run-in period of 4 weeks where they will receive MFNS: 2 actuations (50 ug/actuation) in each l twice daily (BID) (total daily dose of 400 pg), unless they are intolerant to BID INCS in which case, they can stay on the lower dose (QD) regimen. To be ed for the study, patients must also have presence of at least two of the following symptoms prior to screening: Nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); +/- facial pain/pressure or +/- reduction or loss of smell

[00183] Treatment Period: The treatment period will proceed as ted in the Study Flow- chart at Table 14.

Table 14.

Screenin Randomized treatment period Post-treatment 9 period period Inclusion Criteria X X including Informed Consent s Exclusion Criteria in Randomized treatment period Post-treatment g period penod RDN E VISIT 1 2 15 16 17 18 19 20 21 Week (DAY) W-4(D- W0 14 4 28) (D1) Medical/Surgical X History Prior Medication X Historyb Physical X X Examination Spirometryc X X Treatment: mAb1 weekly SC administrationd Call IVRS Dispense or x x download electronic diary/NPIFe NIMP (MFNS) Record concomitant medication Efficacy CT scan9 Smell test (UPSIT) SNOT- 22 Visual ue scale (VAS) QoL (SF-36, EQ- Nasal polyp related resource use questionnaire ACQ-5h Safet AE /SAE recording (if any) Vital Si 0 ns Laboratory Testing Screenin ized treatment period reatment g period period VISIT 1 l\) oo 4> \l 15 16 17 18 19 20 l\) _\ Week (DAY) w-4( UI Eo l\) coo-I 4; O) 13-1614 20 l\)4; l\) 00 28) (D1) Clinical laboratory x >< >< testingi Urinalysis X diostick Pregnancy test (for X x >< PK/Anti-drug >< >< >< antibody sampling PKk .->< Serum Biomarker >< >< >< sampling Archival nasal X >< samplingm -I---E— -uuuuumm Polyp biopsyn - Stored DNA sampling I- Stored whole blood X >< X RNA sampling0 E The Screening Period is 28 days in duration to run in any patient on MFNS, and to collect baseline data. V2 will take place 28days+/-2 day window after V1 3 No mAb1 administration during this visit. Patients who discontinue ent early will be assessed as soon as possible using the procedures normally planned for the End-of-treatment Visit and the 4 Post- treatment Period Visits. b Prior to screening, patients must be on a stable dose of INCS for more than 8 weeks 0 Spirometry: all patients should have FEV1 anytime during Screening Period (before V2) and at the other scheduled visits during the Randomized treatment period d Weekly mAb1 administrations starting from V2 at the site investigational site must be separated by at least 5 days. 9 Electronic diary/NPIF meter is used for daily recording of MFNS use, nocturnal ings, g and evening NPIF and rhinosinusitis symptom scores 1) nasal congestion/obstruction 2) anterior rhinorrhea (runny nose), 3) posterior rhinorrhea (post nasal drip), and 4) loss of sense of smell, scored using a 0-3 categorical scale where 0 = no symptoms, 1 = mild symptoms, 2 = moderate ms and 3 = severe symptoms); This device is dispensed at Visit 1 and information is downloaded from this device on the other indicated days. The average of the last 7 days before V2 is needed to determine the baseline value f Nasal endoscopy: endoscopy (including use of decongestants before the procedure) will be performed after all other efficacy assessments have been completed for each visit; Standard video ces will be downloaded by the investigator to the central reader’s secured Internet site. For eligibility l g of V1 will be used. At V2 investigator review V1 results from central reader to confirm entry criteria and reconfirm eligibility based on review of Inclusion/Exclusion Criteria and the V2 endoscopy local reading g CT scan should be med anytime during ing Period before a first stration of mAb1 and at EOT. Central reading will be used for comparison baseline (BL) to EOT h Only for patients with bid asthma, ACQ-5 is completed in the patient’s electronic diary during clinic visits. i Hematology: hemoglobin, hematocrit, platelet count, total white blood cell count with five-part differential count, differential count, and total red blood cell count. Serum chemistry (Obtain fasting at planned visits but V2): creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, ate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), onate, and creatine phosphokinase. Clinical laboratory testing at Visit 1 includes hepatitis screen itis B surface antigen (HBsAg), Hepatitis B lgM core antibody (HBcAb-lgM), hepatitis C antibodies (HC Ab), HIV screen (Anti-HlV-1 and HIV-2 antibodies), anti-nuclear antibody (ANA). Clinical laboratory testing at Visit 2 is limited to hematology and a separate logy sample obtained for local analysis. Note: Anti-ds DNA antibody will be tested if ANA is ve (21:160 titer). al lab testing at Visit 2 consists of hematology only j Serum pregnancy test at Visit 1 and urine pregnancy tests at other visits. A ve result must be obtained at Visits 1 and 2 prior to randomization visits k Serum pharmacokinetic s, immune response assessment (ADA) s and optional whole blood RNA samples will be collected prior to administration of investigational product during the Randomized ent . During the post-treatment period PK samples will be collected at all visits and ADA samples only at EOS visit. Patients with titers >1000 of the ADA at last visit may be followed after the study. Blood samples for PK and ADA assessment will be collected at any time iln case an SAE occurs. m Nasal ion s will be collected and stored for potential future discovery s to identify predictors of treatment response n Optional polyp biopsies will be collected in selected clinical centers 0 Samples will be collected prior to administration of investigational t during the Randomized Treatment Period

[00184] During the Treatment Period, patients will continue the stable dose of mometasone furoate: two actuations of MFNS in each nostril BID or QD (in case patient cannot tolerate the high dose). At Visit 2, patients will be administered the SNOT-22 test, VAS and QoL questionnaires (SF-36, EQ-5D, Nasal polyp related resource use questionnaire), the smell test, and the ACQ-5 in patients with asthma.

[00185] Clinical laboratory testing at Visit 2 is limited to hematology, pharmacokinetics, anti- drug antibodies, biomarkers in serum and plasma, allergen-specific lgE panel sampling. Blood samples are taken prior to administration of mAb1. Nasal secretion sampling for biomarkers.

For those patients who have signed a specific informed consent form, collect blood sample for DNA and RNA sampling (prior to administration of investigational product during the 40 Randomized Treatment Period).

Temporary treatment discontinuation may be considered by the Investigator because of suspected AEs. Reinitiation of treatment with mAb1 will be done under close and riate clinical/and or laboratory monitoring once the Investigator will have considered according to his/her best medical judgment that the responsibility of mAb1 in the occurrence of the concerned 45 event was unlikely and if the selection criteria for the study are still met.

An e event (AE) is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

A serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death, or is life-threatening, (the term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe); requires inpatient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect; is a medically ant event l and scientific judgment should be exercised in deciding whether ted ing is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require inten/ention (ie, ic measures or corrective ent) to prevent one of the other outcomes listed in the definition above (he following list of lly important events is intended to sen/e as a guideline for determining which condition has to be ered as a medically important event. The list is not intended to be exhaustive: intensive treatment in an emergency room or at home for: Allergic bronchospasm, anaphylaxis, blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, myelodysplasia, pancytopenia, etc), convulsions (seizures, sy, epileptic fit, absence, etc), development of drug dependency or drug abuse); ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN; Suicide attempt or any event suggestive of suicidality; e, loss of consciousness (except if documented as a consequence of blood sampling); bullous cutaneous eruptions; Cancers sed during the study or ated during the study; chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study (only if judged unusual/significant by the Investigators in s assessing specifically the effect of a study drug on these diseases).

Post-treatment Period: Upon completing the Randomized Treatment Period (or following early tinuation of mAb1), patients will continue treatment with the stable dose of MFNS maintained over the randomized treatment period, or modify treatment based on medical judgment.

The following concomitant treatments are not permitted during the Screening Period and the ized ent period: use of intranasal medication that would interfere with the symptoms of diseases (antihistamines, nasal atropine, ipratropium bromide, nasal cromolyn), except nasal saline; INCS drops; systemic corticosteroid; estion (topical or systemic), except before opy; long term use of systemic antibiotics (for 2 weeks or more); genase inhibitors; any supressive treatment ing but not limited to methotrexate, cyclosporine, mycophenolate, tacrilomus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, cyclophosphamide; anti-immunoglobulin E (lg E) therapy (omalizumab); and aspirin or NSAID in patients with hypersensitivity to aspirin.

[00191] The following concomitant treatments are allowed: MFNS during the screening and hout the whole study; Nasal normal saline; Topical decongestants (e.g., Oxymetazoline hydrochloride to reduce the swelling and widen the path for the endoscope), as well as a topical anesthetic e.g. ine are allowed before endoscopy; short term use of Antibiotics (<2weeks); and for patients with asthma, SABA, LABA, and Methylxanthines (e.g., theophylline, aminophyllines). The following inhaled osteroids are allowed for patients on a stable dose $1000 pg Fluticasone (or the equivalent dose of another inhaled CS; see Table 16) and only for patients that were on a stable dose 230 days prior to Visit 1 : Leukotriene antagonists / modifiers are permitted during the study, only for patients that were on a continuous treatment for 230 days prior to Visit 1; Systemic antihistamines; and Initiation of allergen immunotherapy (allergen immunotherapy in place for 23 months prior to Visit 1 is permitted).

C. Efficacy of treatment The primary endpoint of this study is the change from baseline at week 16 in bilateral endoscopic Nasal Polyp Score.

Table 15.

Pol score Polyp size 0 No polyps 1 Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate 2 Polyps reaching below the lower border of the middle turbinate 3 Large polyps reaching the lower border of the or turbinate or polyps medial to the middle ate 4 Large polyps causing complete obstruction of the inferior nasal cavity Nasal endoscopy will be performed at the end of the scheduled visits and preceded by local administration of hetic drugs in combination with a decongestant. Standard video sequences will be downloaded or sent to a centralized reader. Centralized imaging data assessments and scoring by an independent physician reviewer for the imaging data will be performed for all endoscopies. To confirm eligibility at V2, only the V1 central reading will be made available to the site. The final results of central reading will be made ble after the study.

For the analysis of the primary endpoint, central reading of V2 will be used for comparison with EOT reading. The sites will remove subject-identifying information from the imaging data header prior to sending the imaging data to the central reader.

Secondary endpoints of the study will include change from baseline at Week 16 in: patient ed symptoms (including 22-item Sinonasal Outcome Test (SNOT-22)); subject- assessed nasal congestion/obstruction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post nasal drip), and loss of sense of smell, (daily AM and PM e-diary) month average; number of nal awakenings; patient-rated rhinosinusitis symptoms severity using a visual analog scale (VAS); 5-item Asthma control questionnaire (ACQ-5) in asthma sub-group); nasal peak atory flow (NPIF); smell test (UPSIT); NPS in patients with co-morbid asthma; CT scan assessments; etry (overall and in oup with asthma); time to first response (21 point improvement) in NPS; time to study treatment discontinuation; and incidence of treatment discontinuation due to need for OCS or nasal surgery.

Quality of life (QoL) end points will include change from baseline at Week 16 in: 36- item short form health sun/ey ; European quality of life scale (EQ-5D); and Nasal polyp related resource use questionnaire.

Disease-specific efficacy measures include: Computed tomography (CT). CT of the sinuses should be performed before V2 and at EOT. For both Lund-Mackay scores and 3D volumetric measurement of the maxillary sinus, the same itions (sequences) will be used for lized imaging data assessments and g by an independent physician reviewer for the g data. Central reading of V2 will be used for comparison with EDT. The final results of central g will be made available after the study.

[00220] For Three-Dimensional tric measurement of the maxillary sinus, central reading before V2 will be used for comparison with EOT reading. The sites will remove subject- identifying information from the imaging data header prior to sending the imaging data to the central reader. The % change in opacification from BL to EOT will be calculated.

At screening (Visit 1), patients will be issued an NPIF meter for recording morning (AM) and evening (PM) NPIF. The patients will be instructed to record the following variables in the e-diary on a daily basis: AM NPIF performed within 15 s after arising (between 6 am and am) prior to taking MFNS; and PM NPIF med in the evening (between 6 pm and 10 pm) prior to taking MFNS.

Three NPIF efforts will be performed by the patient; all 3 values will be recorded by the patient in the e-diary, and the highest value will be used for evaluation. The baseline AM NPIF will be the mean AM measurement recorded for the 28 days prior to the first dose of investigational product, and baseline PM NPIF will be the mean PM measurement recorded for the 28 days prior to the first dose of investigational product.

To assess disease-specific, daily symptoms, the patient will use an electronic diary to: d to the morning and evening individual rhinosinusitis m questions using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate ms and 3 = severe symptoms), and including the symptoms of congestion and/or ction, anterior rhinorrhea (runny nose), posterior rhinorrhea (post-nasal drip), and loss of sense of smell. The number of nocturnal awakenings will also be recorded.

The same safety assessments will be applied across all arms. Adverse , including serious e events (SAEs) and adverse events of special interest (AESI), will be collected at every visit.

[00225] e blood samples will be collected for determination of serum functional mAb1 and anti-mAb1 antibodies as designated in Table 14.

Optional sampling for exploratory analysis of DNA and RNA, requiring separate pharmacogenetics informed consent.

[00227] Pharmacokinetics. Functional mAb1 and anti-mAb1 antibodies in serum will be d by ELISA. Predose functional mAb1 concentrations in serum at Visit 2 (Day 1), mAb1 trough concentrations at Week 2, Week 4, Week 8, Week 12, Week 16, and follow-up serum mAb1 at Week 20, Week 24, Week 28 and Week 32 will be ed. Anti-mAb1 antibody status (negative or titer value) at Visit 2 (Day 1), Week 2, Week 4, Week 8, Week 12, Week 16, and Week 32 will also be provided. Patients with ADA titers 21000 at the end of study visit will be scheduled to return approximately 6 months later for an additional ment of ADA titer.

Further follow-up will be considered based on the overall assessment of antibody titers and clinical presentation.

[00228] Pharmacodynamics. Since the secretion of certain proteins is dependent, at least in part, on Th2 cytokines and is associated with chronic inflammation of the ainNay , including sinus tissue, expression of certain biomarkers will be assayed to monitor a therapeutic effect of mAb1. These biomarkers also will be assessed for their value in predicting ty and/or in documenting the time course of drug response. The values to be used as baselines will be those collected on Day 1 (predose assessments).

Nasal secretions will be obtained by inserting nasal swabs rally into the nasal cavity for five minutes. The nasal secretions will be presen/ed for possible is of onal biomarkers related to nasal polyposis and responses to mAb1 treatment.

At selected clinical site (s) and with specific informed consent, nasal polyp tissue will be optionally obtained by biopsy. A baseline biopsy will be obtained at V2 of the study. After randomization, another biopsy of nasal polyp tissue will be obtained at the end of treatment visit (Week 16).

The biopsied nasal polyp tissue will be assessed for various biomarkers of inflammation and disease process or response. For example, RNA will be extracted and used for expression profiling (e.g., microarray, riptome sequencing or quantitative RT-PCR).

DNA and RNA samples may be used to determine a le relationship between genes and response to treatment with mAb1 and possible side effects to mAb1.

] Analysis of proportion of patients with binary events. Proportion of patients with binary events will be assessed for : 21 point improvement (reduction) in NPS at week 16 (as read centrally); 10% or more improvement in CT opacification from baseline at week 16; drop-out due to oral CS or surgery; or INCS increase after 8 weeks will be analyzed using a logistic model with the above ses, respectively, as the response variable, and treatment group, pooled countries ns and the stratification factor(s) prior to the study as ates.

Analysis of time to event variables. Time to event (e.g., the first se with 21 point improvement (reduction) in NPS, study treatment discontinuation, etc) will be analyzed suing a Cox regression model with time to event as the dependent variable, and treatment, pooled countries/regions, asthma idity prior to the study as covariates. The Kaplan-Meier method will be used to derive the proportion of patients with an event at Week 4, 8, 12 and 16 specific to each treatment group. For analysis during the treatment period, if a patient has no event before treatment tinuation/completion, then the patient will be considered as free of event till the end of treatment period (last dose date + 7 days).

Analysis of change from baseline for uous variables. The change from baseline at week 16 in: NPS for patients with co-morbid asthma; Lund Mackay score; 22-item Sinonasal Outcome Test (SNOT-22); Subject-assessed congestion and/or ction score; nasal peak inspiratory flow (NPIF); ACQ-5 in patients with co-morbid asthma; QoL measures (SF36, EQ- 5D), and VAS will be analyzed using MMRM same as the primary endpoints. Descriptive statistics including number of patients, mean, standard error and LS means will be provided. In addition, differences in LS means, the corresponding 95% Cl and the p-value will be provided for comparisons of each dose t placebo.

Analysis of efficacy in ne biomarker of characteristics defined subsets. To examine baseline biomarkers for their potential value to t treatment response, es of change in NPS will also be performed for the following subsets and the entire lTT population by each dose group and selected pooled dose group.

Subgroup analysis. To assess the consistency treatment effects across the subgroup levels and to examine baseline biomarkers for their potential value to predict treatment se, exploratory subgroup analyses will be conducted for the change from baseline in NPS with respect to age group, gender, region, race, INCS dose level, ne NPS, baseline CT scan score, asthma comorbidity, and ed biomarkers prior to the study.

Listings of anti-mAb1 antibody results (Negative or titer value) will be presented by t, time point and treatment groups. ADA titer levels will be classified into categories: Low, moderate and high. Low levels of ADA titers are defined as titers below 1000; moderate levels of ADA titers are defined as titers between 1000 and 10,000; high levels of ADA titers are d as titers >10,000.

Anti-mAb1 antibody assay s will be described categorically. The following summary will be provided for: Patients with any positive ADA assay response during the TEAE period; Patients with treatment d positive ADA assay response during the TEAE period; Patients with treatment induced ve ADA assay response during the TEAE period will be further described as patients with transient positive response and patients with persistent positive response. Patients with any ve ADA assay response during the TEAE period is defined as those having at least one sample positive in the ADA assay.

[00243] The treatment induced positive ADA assay response is defined as: Patients with no positive assay response at baseline but with a positive assay response during the TEAE period or patients with a positive ADA assay response at baseline and also have at least a 4-fold increase in titer during the TEAE .

A persistent positive response is a treatment d positive ADA assay response in which at least 2 consecutive post-baseline samples from a patient are positive in the ADA assay or the last post-baseline sample collected is positive in the ADA assay. A transient positive response is defined as any treatment induced ve ADA assay response that is not considered persistent.

Table 16. Allowable lnhaled Glucocorticosteroid / Long-Acting Beta2 Agonist Combination Products and Acceptable Dosage Form, th and Dosage Schedule Generic Name Brand Name Acceptable Acceptable Dosage Form, Strength Product and Dosage Schedule Fluticasone propionate and Advair®/ DPI 0 or DPI: 1 puff twice daily 0) salmeterol Seretide® 500/50) DPI: 1 puffs twice daily (250/50) |V|D|(115/210r MDI: 2 puffs twice daily (115/21) 230/21) MDI: 2 puffs twice daily (230/21) Budesonide and formoterol Symbicort® DPI (200/6 or DPI: 1 puff twice daily (400/12) 400/12 DPI: 2 puffs twice daily (200/6) MDI (160/4-5) MDI: 2 puffs twice daily 5) Mometasone furoate and Dulera® MDI ( 100/5 or MDI: 2 puffs twice daily (200/5) formoterol 200/5) MDI: 2 puffs twice daily (100/5) The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications in addition to those described herein will become nt to those skilled in the art from the foregoing description and the accompanying . Such modifications are intended to fall within the scope of the appended claims.

Claims (30)

What is claimed 1. is:

1. Use of an antibody, or antigen binding fragment f, that specifically binds an interleukin-4 receptor (IL-4R) for the preparation of a pharmaceutical composition for treating chronic rhinosinusitis with nasal polyposis P) in a subject, and wherein the dy, or antigen-binding fragment thereof, comprises: three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3, the HCDR2 comprises the amino acid sequence of SEQ ID NO:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence of SEQ ID NO:7, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

2. The use of claim 1, n the subject has chronic rhinosinusitis with bilateral nasal polyposis.

3. The use of claims 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1; and a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2.

4. The use of any one of claims 1-3, wherein the subject has one or more of asthma, aspirin hypersensitivity, or hypersensitivity to a non-steroidal anti-inflammatory drug (NSAID).

5. The use of any one of claims 1-4, wherein the t has severe nasal polyposis.

6. The use of any one of claims 1-5, n the ition is formulated for administration as a single initial dose and one or more secondary doses.

7. The use of claim 6, wherein the initial dose and one or more secondary doses are each about 300 mg. 17032506_1 (GHMatters) P39476NZ01

8. The use of claim 6 or78, wherein the pharmaceutical composition is formulated for administration every two weeks.

9. The use of any one of claims 1-8, wherein the ceutical composition is formulated for subcutaneous, intravenous or intranasal administration to the subject.

10. The use of any one of claims 1-9, wherein the subject has nasal polyposis which persists after a treatment regimen with inhaled corticosteroids (INCS) or after the subject stops receiving INCS.

11. The use of any one of claims 1-10, wherein the subject is selected based on one or more of the following criteria: i) a minimum bilateral nasal polyp score of 5; ii) an elevated level of one or more genes selected from the group consisting of thymus and tion-regulated ine (TARC), eotaxin-3, periostin, carcinoembryonic antigen (CEA), and YKL-40; and iii) an elevated level of blood eosinophils or sputum eosinophils.

12. The use of any one of claims 1-11, for improving one or more of: a) m sinonasal outcome test (SNOT-22) score; b) nasal symptom score; c) number of nocturnal awakenings; d) visual analog score (VAS); e) five-item asthma control questionnaire (ACQ5) score; f) nasal peak inspiratory flow (NPIF); g) University of Pennsylvania Smell fication test (UPSIT); h) Lund-McKay Score; and 17032506_1 ters) P39476NZ01 i) three-dimensional volumetric measurement of the maxillary sinus, in particular an increase in one or both of NPIF and UPSIT and/or a se in in one or more of SNOT-22 score, nasal symptom score, VAS, Lund-McKay Score and 3DVolumetric Score.

13. The use of any one of claims 1-12, for decreasing a nasal polyp score.

14. The use of any one of claims 1-13, for increasing one or both of NPIF and UPSIT.

15. The use of any one of claims 9-14, wherein the ceutical composition is formulated for subcutaneous administration to the subject with a pen delivery device or an autoinjector, or formulated for subcutaneous or enous administration with a standard syringe and .

16. The use of any one of claims 1-15, wherein the antibody is dupilumab.

17. The use of any one of claims 1-16, wherein the pharmaceutical composition is formulated for administration with a second therapeutic agent before, after or concurrently with the second therapeutic agent.

18. The use of claim 17, wherein the second therapeutic agent is selected from the group consisting of an IgE inhibitor, an antibiotic agent, and an anti-fungal agent.

19. The use of claim 17, wherein the second therapeutic agent comprises an intranasal corticosteroid, optionally wherein the intranasal corticosteroid is sone furoate nasal spray (MFNS).

20. The use of claim 19, wherein the second therapeutic agent comprises an inhaled corticosteroid, optionally wherein the inhaled corticosteroid is fluticasone or budesonide.

21. The use of claim 17, wherein the second eutic agent comprises a long-acting beta2 agonist, ally wherein the long-acting beta2 agonist is salmeterol or formoterol. 06_1 (GHMatters) P39476NZ01

22. The use of any one of claims 1-16, wherein the t has been prescribed or is tly taking a ound therapy for nasal polyposis.

23. The use of claim 22, wherein the background therapy is an asal corticosteroid.

24. The use of claim 23, wherein the intranasal corticosteroid is sone furoate nasal spray (MFNS).

25. The use of claim 22, wherein the background therapy is an intranasal corticosteroid and a long-acting beta2 agonist.

26. The use of claim 25, wherein the background therapy is asone/salmeterol combination therapy.

27. The use of claim 25, wherein the background therapy is budesonide/formoterol combination therapy.

28. The use of claim 22, wherein the background therapy is selected from the group consisting of a nasal saline, a topical decongestant, a topical anesthetic, a leukotriene antagonist, and a systemic antihistamine.

29. The use of any one of claims 6-28, wherein the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

30. The use of any one of claims 6-28, wherein the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg.