Methods for treating allergic fungal rhinosinusitis by administering an il-4r antagonist

Abstract

Methods for treating or preventing allergic fungal rhinosinusitis (AFRS) in a subject in need thereof are provided. Methods comprising administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof, are provided.

Description

Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NPMETHODS FOR TREATING ALLERGIC FUNGAL RHINOSINUSITIS BY ADMINISTERING AN IL-4R ANTAGONISTRELATED APPLICATIONS

[0001] This application claims the benefit of European Patent Application Nos. 26305247.4, filed February 23, 2026, 26305039.5, filed January 12, 2026, 25306823.3, filed October 31, 2025, and 25305420.9, filed March 24, 2025, which are incorporated by reference herein in their entireties.FIELD OF THE INVENTION

[0002] The disclosure relates to the treatment and / or prevention of allergic fungal rhinosinusitis (AFRS) in a subject in need thereof. The disclosure relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent AFRS in a subject in need thereof.BACKGROUND

[0003] Allergic fungal rhinosinusitis (AFRS) is a chronic disease of the sinuses characterized by a type 2 inflammatory response against fungus in the sinuses with accumulation of eosinophilic mucin containing fungal hyphae, which results in persistent sinus opacification and nasal polyp formation. The disease can be severe and often leads to bony erosion of the sinuses and even facial deformities.

[0004] The mainstay of treatment involves endoscopic sinus surgery and medical management that includes systemic and topical corticosteroids. AFRS is a unique and distinct type of chronic rhinosinusitis with nasal polyps that can be harder to treat because it does not respond well to available options. Patients require chronic suppression with topical corticosteroids and may need frequent oral steroid bursts. There is, however, a high recurrence rate after surgery even with systemic and topical nasal corticosteroids requiring frequent systemic steroid use and repeated surgeries. Delayed surgery can lead to increased risk for complications as bony erosions thin the sinus walls. The role of antifungals remains unclear, and they are currently not recommended. There are no approved targeted therapies for AFRS.

[0005] Thus, there is a need for targeted therapies that address the disease processes, minimize the need for systemic corticosteroids and their associated side effects, prevent recurrence, prevent complications and bony erosion, and achieve long-lasting disease control.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NPSUMMARY

[0006] In one aspect, a method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof is provided, comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

[0007] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0008] In certain exemplary embodiments, the subject does not have asthma.

[0009] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0010] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0011] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0012] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0013] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0014] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0015] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0016] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0017] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0018] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0019] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0020] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0021] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0022] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibodyAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0023] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0024] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0025] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0026] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0027] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0028] In certain exemplary embodiments, the anti-IL-4R antibody is administered to the subject as an initial dose followed by one or more secondary doses.

[0029] In certain exemplary embodiments, the initial dose is about 200 to about 300 mg and the one or more secondary doses are each about 200 to about 300 mg. In certain exemplary embodiments, the initial dose is about 300 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 200 mg and the one or more secondary doses are each about 200 mg. In certain exemplary embodiments, the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

[0030] In certain exemplary embodiments, the secondary doses are administered every other week (Q2W). In certain exemplary embodiments, the secondary doses are administered every four weeks (Q4W).

[0031] In certain exemplary embodiments, the subject is at least 6 years old.

[0032] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0033] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0034] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0035] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0036] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0037] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0038] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0039] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0040] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0041] In another aspect, a method is provided for treating severe allergic fungal rhinosinusitis (AFRS) in a subject in need thereof comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

[0042] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0043] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0044] In certain exemplary embodiments, the subject does not have asthma.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0045] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0046] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0047] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0048] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0049] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0050] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0051] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0052] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0053] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0054] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0055] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the groupAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0056] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0057] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0058] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0059] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0060] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0061] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0062] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0063] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0064] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0065] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0066] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0067] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0068] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0069] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0070] In certain exemplary embodiments, the anti-IL-4R antibody is administered to the subject as an initial dose followed by one or more secondary doses.

[0071] In certain exemplary embodiments, the initial dose is about 200 to about 300 mg and the one or more secondary doses are each about 200 to about 300 mg. In certain exemplary embodiments, the initial dose is about 300 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 200 mg and the one or more secondary doses are each about 200 mg. In certain exemplary embodiments, the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

[0072] In certain exemplary embodiments, the secondary doses are administered every other week (Q2W). In certain exemplary embodiments, the secondary doses are administered every four weeks (Q4W).

[0073] In certain exemplary embodiments, the subject is at least 6 years old.

[0074] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0075] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0076] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0077] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0078] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0079] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0080] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0081] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0082] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0083] In another aspect, a method is provided for treating allergic fungal rhinosinusitis (AFRS) with Type 2 inflammation in a subject in need thereof comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0084] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0085] In certain exemplary embodiments, the subject does not have asthma.

[0086] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0087] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0088] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0089] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0090] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0091] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0092] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0093] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0094] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0095] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0096] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0097] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0098] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0099] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0100] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0101] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0102] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0103] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0104] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0105] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0106] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0107] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0108] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0109] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatmentAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0110] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0111] In certain exemplary embodiments, the anti-IL-4R antibody is administered to the subject as an initial dose followed by one or more secondary doses.

[0112] In certain exemplary embodiments, the initial dose is about 200 to about 300 mg and the one or more secondary doses are each about 200 to about 300 mg. In certain exemplary embodiments, the initial dose is about 300 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 200 mg and the one or more secondary doses are each about 200 mg. In certain exemplary embodiments, the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

[0113] In certain exemplary embodiments, the secondary doses are administered every other week (Q2W). In certain exemplary embodiments, the secondary doses are administered every four weeks (Q4W).

[0114] In certain exemplary embodiments, the subject is at least 6 years old.

[0115] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0116] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone twoAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0117] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0118] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0119] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0120] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0121] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0122] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0123] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0124] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0125] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0126] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0127] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0128] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0129] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0130] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0131] In another aspect, a method is provided for treating allergic fungal rhinosinusitis (AFRS) not adequately controlled on background treatment in a subject in need thereof, comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

[0132] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0133] In certain exemplary embodiments, the subject does not have asthma.

[0134] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0135] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0136] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0137] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0138] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0139] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0140] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0141] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0142] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0143] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0144] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0145] In certain exemplary embodiments, the subject has comorbid asthma, and wherein an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0146] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0147] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0148] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0149] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0150] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the antibody is dupilumab.

[0151] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0152] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0153] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0154] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0155] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0156] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0157] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0158] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in riskAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0159] In certain exemplary embodiments, the background treatment comprises inhaled corticosteroid (ICS), oral corticosteroid (OCS) or a combination thereof.

[0160] In certain exemplary embodiments, the anti-IL-4R antibody is administered to the subject as an initial dose followed by one or more secondary doses.

[0161] In certain exemplary embodiments, the initial dose is about 200 to about 300 mg and the one or more secondary doses are each about 200 to about 300 mg. In certain exemplary embodiments, the initial dose is about 300 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 200 mg and the one or more secondary doses are each about 200 mg. In certain exemplary embodiments, the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

[0162] In certain exemplary embodiments, the secondary doses are administered every other week (Q2W). In certain exemplary embodiments, the secondary doses are administered every four weeks (Q4W).

[0163] In certain exemplary embodiments, the subject is at least 6 years old.

[0164] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0165] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0166] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0167] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0168] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0169] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0170] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0171] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0172] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0173] In another aspect, a method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof that remains symptomatic following sinonasal surgery is provided, comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

[0174] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0175] In certain exemplary embodiments, the subject does not have asthma.

[0176] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.1Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0177] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0178] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0179] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0180] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0181] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0182] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0183] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0184] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0185] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0186] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania SmellAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0187] In certain exemplary embodiments, the subject has comorbid asthma, and wherein an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0188] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0189] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0190] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0191] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0192] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the antibody is dupilumab.

[0193] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0194] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0195] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0196] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0197] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0198] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0199] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0200] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in riskAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0201] In certain exemplary embodiments, the background treatment comprises inhaled corticosteroid (ICS), oral corticosteroid (OCS) or a combination thereof.

[0202] In certain exemplary embodiments, the anti-IL-4R antibody is administered to the subject as an initial dose followed by one or more secondary doses.

[0203] In certain exemplary embodiments, the initial dose is about 200 to about 300 mg and the one or more secondary doses are each about 200 to about 300 mg. In certain exemplary embodiments, the initial dose is about 300 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 200 mg and the one or more secondary doses are each about 200 mg. In certain exemplary embodiments, the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg. In certain exemplary embodiments, the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

[0204] In certain exemplary embodiments, the secondary doses are administered every other week (Q2W). In certain exemplary embodiments, the secondary doses are administered every four weeks (Q4W).

[0205] In certain exemplary embodiments, the subject is at least 6 years old.

[0206] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0207] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0208] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0209] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0210] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0211] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0212] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0213] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0214] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0215] In another aspect, a method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof is provided comprising administering to the subject anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the anti-IL-4R antibody is administered to the subject at a dose of about 300 mg every two weeks (Q2W), and wherein the subject is an adult, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0216] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0217] In certain exemplary embodiments, the subject does not have asthma.

[0218] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0219] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0220] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0221] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0222] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0223] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0224] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0225] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0226] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0227] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0228] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0229] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0230] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0231] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0232] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0233] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0234] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0235] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0236] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0237] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0238] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0239] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0240] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0241] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatmentAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0242] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0243] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0244] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0245] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0246] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0247] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0248] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0249] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0250] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0251] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0252] In another aspect, a method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof is provided comprising administering to the subject anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the anti-IL-4R antibody is administered to the subject at a dose of about 200 mg every two weeks (Q2W), and wherein the subject is an adolescent or a child, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

[0253] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0254] In certain exemplary embodiments, the subject does not have asthma.

[0255] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0256] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0257] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0258] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0259] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0260] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0261] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0262] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0263] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0264] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0265] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0266] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0267] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0268] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0269] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0270] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0271] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0272] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0273] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody.

[0274] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0275] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0276] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0277] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0278] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0279] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in riskAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0280] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0281] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0282] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0283] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0284] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0285] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0286] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0287] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0288] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0289] In another aspect, a method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof comprising administering to the subject anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the anti-IL-4R antibody is administered to the subject at a dose of about 300 mg every four weeks (Q4W), and wherein the subject is an adolescent or a child, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

[0290] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0291] In certain exemplary embodiments, the subject does not have asthma.

[0292] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0293] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0294] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0295] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0296] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0297] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associatedAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0298] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0299] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0300] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0301] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0302] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0303] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0304] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0305] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0306] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasalAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0307] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0308] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0309] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0310] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0311] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0312] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0313] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0314] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopicAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0315] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0316] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0317] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0318] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0319] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0320] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0321] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0322] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0323] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0324] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0325] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0326] In another aspect, a method of improving one or more symptoms in a subject in need thereof selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain; or any combination thereof is provided, wherein the method comprises administering to the subject an anti -interleukin-4 receptor (IL-4R) antibody, and wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reductionAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby improving the one or more symptoms in the subject.

[0327] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0328] In certain exemplary embodiments, the subject does not have asthma.

[0329] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0330] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0331] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0332] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0333] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0334] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0335] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0336] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0337] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0338] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0339] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0340] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0341] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0342] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0343] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0344] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0345] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibodyAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0346] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0347] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0348] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0349] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0350] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0351] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0352] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85%Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0353] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0354] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0355] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0356] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0357] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0358] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0359] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0360] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0361] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0362] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0363] In another aspect, a method of improving health-related quality of life in a subject in a subject in need thereof selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, positive fungal stain, or any combination thereof is provided, wherein the method comprises administering to the subj ect anti -interleukin-4 receptor (IL-4R) antibody, and wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby improving the health-related quality of life in the subject.

[0364] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0365] In certain exemplary embodiments, the subject does not have asthma.

[0366] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0367] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0368] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0369] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0370] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0371] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0372] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0373] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0374] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0375] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0376] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania SmellAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0377] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0378] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0379] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0380] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0381] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0382] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0383] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0384] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0385] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0386] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0387] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0388] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0389] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0390] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in riskAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0391] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0392] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0393] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0394] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0395] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0396] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0397] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0398] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0399] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0400] In another aspect, method for reducing total volume of sinus occupied by diseased tissue in a subject in need thereof having allergic fungal rhinosinusitis (AFRS) is provided comprising administering to the subject anti-interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby reducing total volume of sinus occupied by diseased tissue in the subject.

[0401] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0402] In certain exemplary embodiments, the subject does not have asthma.

[0403] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0404] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0405] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0406] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0407] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0408] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0409] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0410] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0411] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0412] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0413] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0414] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0415] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0416] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured byAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0417] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0418] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

[0419] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0420] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0421] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0422] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0423] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0424] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibodyAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0425] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

[0426] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0427] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0428] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0429] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0430] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0431] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0432] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0433] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0434] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0435] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0436] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.

[0437] In another aspect, a method for reducing bone erosion or reducing bone erosion risk in a subject in need thereof having allergic fungal rhinosinusitis (AFRS) is provided comprising administering to the subject anti -interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, andAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, and wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby reducing bone erosion or reducing bone erosion risk in the subject.

[0438] In certain exemplary embodiments, the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

[0439] In certain exemplary embodiments, the subject does not have asthma.

[0440] In certain exemplary embodiments, the subject has undergone endoscopic nasal surgery for AFRS.

[0441] In certain exemplary embodiments, the subject has one or more AFRS-associated parameter(s) selected from the group consisting of: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; and positive fungal stain of sinus content, or any combination thereof.

[0442] In certain exemplary embodiments, the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content. In certain exemplary embodiments, the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

[0443] In certain exemplary embodiments, the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

[0444] In certain exemplary embodiments, the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

[0445] In certain exemplary embodiments, one or more AFRS-associated parameter(s) are improved in the subject. In certain exemplary embodiments, one or more AFRS-associated parameter(s) include: IgE mediated inflammatory response to fungal hyphae; nasal polyposis; characteristic CT findings; eosinophilic mucin without fungal invasions; positive fungal stain, or any combination thereof.

[0446] In certain exemplary embodiments, the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

[0447] In certain exemplary embodiments, the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count,Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

[0448] In certain exemplary embodiments, the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

[0449] In certain exemplary embodiments, an improvement in Lund Mackay (LMK) score is achieved after treatment.

[0450] In certain exemplary embodiments, an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

[0451] In certain exemplary embodiments, the subject has comorbid asthma, and an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

[0452] In certain exemplary embodiments, treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.

[0453] In certain exemplary embodiments, the treatment reduces bone erosion or reduces bone erosion risk in patients. In certain exemplary embodiments, bone erosion is measured by a radiologic staging system. In certain exemplary embodiments, the radiologic staging system comprises a CT scan.

[0454] In certain exemplary embodiments, the subject has one or more of the following: a baseline serum IgE of >500; an IgE mediated inflammatory response to fungal hyphae; nasal polyposis; hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT); eosinophilic mucin / mucus identified with or without positive fungal stain; an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps; a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

[0455] In certain exemplary embodiments, the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0456] In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL-4R antibody is dupilumab.

[0457] In certain exemplary embodiments, the anti-IL-4R antibody is administered subcutaneously.

[0458] In certain exemplary embodiments, the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the anti-IL-4R antibody is administered using a prefilled device.

[0459] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

[0460] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

[0461] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

[0462] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0463] In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids. In certain exemplary embodiments, treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

[0464] In certain exemplary embodiments, the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment. In certain exemplary embodiments, the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

[0465] In certain exemplary embodiments, an improvement in LMK score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus. In some embodiments, improvements are observed in all individual sinus areas and the osteomeatal complex.

[0466] In certain exemplary embodiments, the subject has a history of sinonasal surgery. In certain exemplary embodiments, the subject had previously undergone one sinonasal surgery prior to the treatment. In certain exemplary embodiments, the subject had previously undergone two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject had previously undergone more than two sinonasal surgeries prior to the treatment. In certain exemplary embodiments, the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

[0467] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who have a history of sinonasal surgery.

[0468] In certain exemplary embodiments, dupilumab is indicated for the treatment of adult and pediatric patients aged 6 years and older with AFRS who had evidence of sinusAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP opacification on the Lund Mackay (LMK) sinus CT scan with a LMK score of >9 for subjects with unilateral polyps and >12 for subjects with bilateral polyps.

[0469] In certain exemplary embodiments, the subject has a nasal polyps score (NPS) of >2 for unilateral polyps or >3 for bilateral polyps.

[0470] In certain exemplary embodiments, adults and pediatric subjects who weigh >60 kg receive 300 mg dupilumab every 2 weeks, while pediatric subjects who weigh >30 kg to <60 kg receive 200 mg dupilumab every 2 weeks.

[0471] In certain exemplary embodiments, dupilumab reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

[0472] In certain exemplary embodiments, dupilumab reduces the risk of systemic corticosteroids use in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% compared to baseline after a 52-week treatment.

[0473] In certain exemplary embodiments, dupilumab reduces the risk of undergoing sinonasal surgery in the subject to less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2.0%, less than 1.0%, or 0% compared to baseline after a 52-week treatment.BRIEF DESCRIPTION OF THE DRAWINGS

[0474] The foregoing and other features and advantages of the disclosure will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings.

[0475] FIG. 1 schematically depicts the overview of the study design of the LIBERTY-AIMS AFRS study of Example 1. The study is a multinational, randomized, double-blind, placebo-controlled, 52-week phase 3 study to assess the efficacy, safety, and tolerability of dupilumab in patients with allergic fungal rhinosinusitis (AFRS).

[0476] FIG.2 depicts a table showing the schedule of activities for the randomized, placebo-controlled study to assess the efficacy, safety and tolerability of dupilumab in patients with AFRS (Example 1). ACQ-6: asthma control questionnaire 6-question version; ADA: anti-drug antibody; AE: adverse event; CT: computerized tomography; D: day; DNA: deoxyribonucleic acid; ECG: electrocardiogram; eCRF: electronic case report form; EOS: end of study; EOT: end of treatment; FEF: forced expiratory flow; FEV1: forced expiratory volume; FVC: forced vital capacity; HBcAb: hepatitis B core antibody; HBsAb: hepatitis B surface antibody;Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HCVAb: hepatitis C virus antibody; HIV: human immunodeficiency virus; IEC: Independent Ethics Committee; Ig: immunoglobulin; IMP: investigational medicinal product; IRB: Institutional Review Board; INCS: intranasal corticosteroids; IRT: Interactive response technology; NPS: Nasal Polyp Score; PK: pharmacokinetics; PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PRO: Patient-Reported outcome; RNA: ribonucleic acid; SAE: serious adverse event; SC: subcutaneous; SNOT-22: 22-item sino-nasal outcome; TB: tuberculosis; TSS: total symptom score; UPSIT: University of Pennsylvania smell identification test; VAS: visual analog scale; V: Visit; Wk: Week; WOCBP: women of childbearing potential.aAll assessments at visit 2, (day 1) were conducted pre-IMP dose with the exception of the assessment of local tolerability of SC injections.bParti cipants who discontinued the study treatment prematurely (prior to completing the 52-week treatment period) performed the EOT assessments at the time of discontinuation to assure a complete clinical assessment in close temporal proximity to the premature termination of study treatment. In addition, to allow assessment of participant outcomes over the stipulated study period, participants will be asked and encouraged to complete all remaining study visits and participate in all assessments according to the visit schedule.cIf a participant discontinued treatment period prematurely before week 40 but completed 12-week follow-up at week 52, he / she was considered to have completed the study.dConsent was obtained for optional procedures (whole blood DNA and whole blood RNA sampling and serum / plasma sampling for archival; HIV test if specific consent locally required).ePast medical history including allergic comorbidities (asthma, aspirin sensitivity, allergic rhinitis etc.). Surgeries were assessed including type and dates of sinonasal surgeries, in the past. Systemic corticosteroids (SCS) use (number of courses, doses, way of administration and duration) in the past 2 years before VI and / or contraindication / intolerance to SCS, as well as long-term antibiotics use (>2 weeks) in the previous year was entered in the eCRF.fDetails on actual or planned date for surgery type and outcome (whenever possible) of surgery were recorded in a specific eCRF page. If surgery was performed during the study treatment period or follow-up, an AE or SAE page will be completed. Participants were discontinued from study treatment and assessed as soon as possible using the procedures normally planned for the EOT visit. If surgery was scheduled after the planned end of study, a follow-up contact(s) was potentially required to document the surgery date and outcome.gIn case of emergency (e.g., natural disaster, pandemic) remote visit (except for baseline, week 24 and week 52) could be considered (e.g., Home nursing, Telehealth) and was documented in the participant’s study file. ArrangementsAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP could also be made for qualified site personnel and / or health care professionals (e.g., visiting nurse service) to collect study samples, administer IMP at participant’s home or perform study examinations as needed. “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on the conduct of clinical trials, some lab tests and clinical assessment procedures can be considered to be conducted locally per local regulation requirement.hRefer to Section 4 Study Design for details on treatment arms. IMP will be administered after completion of all scheduled clinical assessments and sample collections at the visit or at home. ‘Nasal endoscopy (including use of decongestants before the procedure): The participant will be considered eligible based on a VI central reading followed by a V2 local reading of NPS score of 3 or more. 'Assessments / procedures should be conducted in the following order: Patient-Reported outcome (PRO), Investigator assessments, safety and laboratory assessments (including sample collection for ADA, PK, biomarker, and optional archival serum / plasma, DNA and RNA), and administration of IMP.kCT scan should be performed during screening period before first administration of IMP, at V5 (Week 24 if accepted per local EC requirement) and at V7 (Week 52), and central reading will be used for comparison baseline (BL) to week 52 for the primary analysis and at EOT. In countries for which a specific approval procedure for the CT scan is required by a different committee than the lEC / IRB, these countries will be exempted from all the planned study CT scans until approval from these committees is received. It was recommended if a patient must use SCS during week 36 to week 52 per the Investigator’s decision, the site should make every effort to arrange the patient to complete last CT scan prior to starting SCS unless not possible in which case a CT should be performed within 48 hours of SCS use. In any case no more than 3 CT scans during the study. If patient needed to have CT scan around the time of surgery the next scheduled CT scans per protocol did not need to occur after a surgery for AFRS. 'Electronic diary was used for daily recording of nasal symptoms: 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 symptoms and 3 = severe symptoms). This device is dispensed at VI and information is downloaded from this device on the other indicated days. “During the study the PROs should be completed by the participants in the e-diary before seeing the physician, in the following order: daily symptoms of nasal congestion, loss of smell and rhinorrhea; SNOT-22; VAS rhinosinusitis; PGIS; PGIC; ACQ-6 (in patients with asthma). “Spirometry (FEV1, FVC and FEF25-75): should be performed for asthma patients, locally after withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for at least 6 hours, and long-acting β2-adrenergic receptorAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP agonists (LABA), and long-acting muscarinic acetylcholine receptor antagonists (LAMA) for 12 to 24 hours. All participants with asthma should have the result of FEV1 (% of predicted normal), FVC and FEF25-75 will be recorded in eCRF at the study scheduled visits. The test can be considered as optional per local regions’ restriction due to COVID-19 pandemic. “Vital signs, including blood pressure (mm Hg), pulse (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius), body weight (kg), and height (cm) were measured at the screening and randomization visits (VI and V2) and subsequent visit pre-specified in the flow-chart. Vital signs will be measured prior to receiving IMP at the clinic visits in the semisupine or sitting position using preferably the same arm at each visit.pRefer to central lab manual for collection details.qClinical laboratory testing at VI included hepatitis screen covering HBsAg, HBsAb, HBcAb including HBcAb IgM, IgG and total, HCVAb and HIV screen (anti-HIV-1 and HIV-2 antibodies). In case of results showing HBsAg (negative), HBsAb (negative), and HBcAb IgG / total (positive), an HBV DNA testing may be performed prior to randomization to rule out a false positivity if the Investigator believed the patient is a false positive, or to clarify the serological status if the Investigator found it unclear to interpret in absence of known HBV infection. In case of results showing HCV Ab (positive), an HCV RNA testing may be performed to rule out a false positivity, if the Investigator believes the patient is a false positive.rSerum pregnancy test at VI and urine pregnancy tests at V2 and every 4 weeks thereafter. A negative result must be obtained between V 1 and V2 prior to randomization visits. Urinary test could be performed at home with or without the assistance of a home care provider after appropriate training. In case of positive urine test, the study treatment will be withheld and a serum pregnancy test to confirm the pregnancy should be performed as soon as possible. Pregnancy will lead to definitive treatment discontinuation in all cases.sAt indicated time points, serum dupilumab concentration and ADA samples were collected and archived prior to administration of investigational product. Blood samples for PK and ADA assessment may be collected in case a suspected SAE. In response to AEs of special interest like anaphylaxis or hypersensitivity additional ADA samples may be collected at or near the event based on the judgment of the medical Investigator and / or Sponsor representative. Pharmacokinetic and ADA samples will be collected unless restricted due to local regulation. However, the PK and ADA samples will be collected for safety assessment in the event of an SAE. Samples for ADA will only be collected for analysis in the event of any SAE for participants from China sites.lFor sites that cannot send fungal specific IgE to central lab to test timely, additional local fungal specific IgE tests or skin test may be needed to meet patient’s eligibility.uAt selected sites patients required informed consent for optionalAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP nasal biomarker sampling which was stored for future analysis. The nasal brushing was performed after the nasal secretion collection. Both nasal brushing and nasal secretion were an exemption for China.vOptional sampling for exploratory analysis of biomarkers or use in bioanalytical method validation, requiring agreement with future use of samples in informed consent. " Optional blood for DNA could be collected any time during the study; optional blood for RNA (RNA for adults only) had to be collected prior to any IMP administration. Pharmacogenetics informed consent was required before sampling.

[0477] FIG. 3 is a table depicting endpoint definitions.

[0478] FIG. 4 is a table depicting Lund Mackay (LMK) scoring.

[0479] FIG.5 is a table depicting baseline demographics and disease characteristics from the LIBERTY-AIMS AFRS study. NPS (nasal polyp score): 0-8, higher is worse. NCS (nasal congestion score): 0-3, higher is worse. TSS (total symptom score, composite of rhinorrhea, loss of smell, nasal congestion): 0-9, higher is worse. SNOT-22 (impact on quality of life (QoL)): 0-110, higher is worse.1Among adult patients only, mean (SD) age is 42.6 (14.2), n=56.2Bilateral polyps were inclusion criterion for SINUS studies, assumed all patients for comparison.3FEV1 and ACQ-6 measurements only for participants with asthma, n=29 (15 dupilumab, 14 placebo).

[0480] FIG. 6 is a table depicting multiplicity-controlled endpoints.

[0481] FIG. 7 is a table showing efficacy compared to the SINUS studies (SINUS-24 and SINUS-52) for week 24 endpoints. Subjects with AFRS were excluded from the SINUS studies. 3D-volumetric was not performed in the SINUS studies.

[0482] FIG. 8 is a table showing efficacy compared to the SINUS studies for week 52 endpoints.1SINUS-52 had two dosing schedules for dupilumab; these data are for 300 mg Q2W dose.2AIMS: Number and RD; SINUS: proportion and HR; pooled 300 mg Q2W and 300 mg Q2W to Q4W (dupilumab N=295).

[0483] FIG. 9 graphically depicts that dupilumab improved Lund Mackay (LMK) scores. LMK score measures radiographic measure of opacification in each sinus (anterior ethmoid, posterior ethmoid, maxillary, frontal, sphenoid) and the osteomeatal complex using scale of 0-24, with a higher score being worse, indicating radiographically more opacified. The minimal clinically important difference (MCID) was -4.

[0484] FIG. 10 graphically depicts that dupilumab improved nasal congestion scores. NCS (nasal congestion score) is monthly average of daily symptom score with a range of 0-3. A higher score indicates more severe symptoms.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0485] FIG. 11 graphically depicts that dupilumab improved nasal polyp scores. NPS: endoscopic score assessing presence, size, and location of polyps in each nostril with a scale of 0-4 on each side. A higher score is worse. The total score was bilateral NPS.

[0486] FIG. 12 graphically depicts that dupilumab improved total symptom score (TSS). TSS: monthly average of daily clinical composite score assessing nasal congestion, anterior / posterior rhinorrhea, loss of sense of smell, with a scale of 0-9. A higher score indicates more severe symptoms.

[0487] FIG. 13 graphically depicts that dupilumab improved University of Pennsylvania Smell Identification Test (UPSIT) scores. UPSIT is a clinical measure based on a test of 40 odorants with 4 multiple choice answers to assess sense of smell having a scale of 0-40. A higher score is better and indicates stronger olfactory smell. The MCID was 4.

[0488] FIG. 14 graphically depicts that dupilumab improved decreased / loss sense of smell. Decreased / loss of sense of smell was determined by eDiary entries using a scale of 0-3 with higher scores indicating more severe symptoms. The MCID was -0.88 to -1.00.

[0489] FIG. 15 graphically depicts that dupilumab improved 22-item Sino Nasal Outcome Test (SNOT-22) scores. SNOT-22 is a measure of health-related quality of life (HRQoL). SNOT-22 scores range from 0-110, with a higher score indicating a greater disease burden. The MCID was -8.9.

[0490] FIG. 16 graphically depicts that dupilumab decreased the total volume of disease as determined by CT. The CT parameters were the 3D volumetric measurement of volume occupied by disease in all sinuses with a scale of 0-100%, with a higher score being worse, indicating greater disease involvement in the sinus cavities.

[0491] FIG. 17 depicts that dupilumab reduced the need for systemic corticosteroid (SCS) use, and reduced the need for surgery. Rescue therapy was defined as a need for surgery or SCS use for any reason.

[0492] FIG. 18 graphically depicts that dupilumab decreased the biomarker total IgE, showing a progressive decline in total IgE over time to a -79% change from baseline by week 52 in the dupilumab group.

[0493] FIG. 19 graphically depicts that dupilumab use resulted in blood eosinophils remaining at or below baseline. There were no cases of clinically symptomatic eosinophilia, eosinophilic granulomatosis with polyangiitis (EGPA), or eosinophilic pneumonia (EP).

[0494] FIG. 20 is a table showing the safety overview summary of the LIBERTY-AIMS AFRS study. TEAE, treatment emergent adverse event; SAE, serious adverse event; AESI, adverse event of special interest; AE, adverse event.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0495] FIG. 21 graphically depicts that dupilumab improved forced expiratory volume in 1 second (FEV1) scores in patients with comorbid asthma.

[0496] FIG.22 graphically depicts that dupilumab improved Asthma Control Questionnaire-6 (ACQ-6) scores in patients with comorbid asthma.

[0497] FIG. 23 depicts the change from baseline in Lund Mackay (LMK) score at week 52 by subgroup in the intent-to-treat (ITT) population.

[0498] FIG. 24 graphically depicts the pharmacokinetic profile (PK) of dupilumab to week 64.

[0499] FIG. 25 depicts the change from baseline in proportion (%) of patients having bone erosion receiving either placebo treatment or dupilumab treatment.

[0500] FIGs. 26A-26B graphically depict the mean LMK computed tomography score at baseline at week 52 by individual sinus region in (A) dupilumab and (B) placebo groups.

[0501] FIG. 27 is a table showing the proportion of patients with bone erosion in sinuses on CT scan by visit. CT, computed tomography; n, number of patients with bone erosion in sinuses on CT scan (after intercurrent events handling and multiple imputation); N / A, not available.

[0502] FIG. 28 schematically depicts the patient disposition of the study described further herein. IgE, immunoglobulin E; ITT, intention to treat; LMK-CT, Lund-Mackay computed tomography; NPS, nasal polyp score.

[0503] FIG. 29 is a table summarizing primary and secondary efficacy endpoints in the intention-to-treat population. *The following secondary end points were included in the multiplicity adjustment scheme and tested in the following order: change from baseline to week 24 in 1) NC, 2) NPS, 3) LMK-CT, 4) TSS, 5) UPSIT, 6) LoS, change from baseline to week 52 in 7) NPS, 8) NC, 9) SNOT-22, 10) 3D volumetric scan, 11) the proportion of patients who receive SCS and / or undergo / plan to undergo surgery for AFRS during the planned study treatment period, 12) change from baseline to week 24 in SNOT-22, and 13) percent change from baseline in serum total IgE at week 52. Results for continuous variables were based on analysis of covariance model with the corresponding baseline value, intervention group, time from last surgery (<2 years, >2 years), and region (the Americas and Asia) as covariates. Results for binary variable were based on Mantel-Haenszel estimate and confidence limits, with Mantel-Haenszel stratum weights for time from last surgery (<2 years, >2 years) and region (the Americas and Asia) and the Sato variance estimator, fthree-dimensional computed total volume occupied by disease in all sinuses. A reduction in score indicates improvement, except UPSIT, where an increase indicates improvement. AFRS, allergic fungal rhinosinusitis;Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP CI, confidence interval; IgE, immunoglobulin E; LoS, loss of smell; LMK-CT, Lund-Mackay computed tomography score; NC, nasal congestion score; NPS, nasal polyp score; SCS, systemic corticosteroids; SD, standard deviation; SE, standard error; SNOT-22, 22-item Sinonasal Outcome Test; TSS, total symptom score; UPSIT, University of Pennsylvania Smell Identification Test.

[0504] FIG. 30 is a table summarizing the testing hierarchy used for the study described herein. All comparisons were dupilumab versus placebo. 3D, 3 dimensional; AFRS, allergic fungal rhinosinusitis; CT, computed tomography; Ig, immunoglobulin; LMK, Lund-MacKay; NPS, nasal polyp score; SCS, systemic corticosteroid; SNOT-22, 22-item Sinonasal Outcome Test; TSS, total symptom score; UPSIT, University of Pennsylvania Smell Identification Test.DETAILED DESCRIPTION

[0505] Before the disclosure is described, it is to be understood that this disclosure is not limited to 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 embodiments only, and is not intended to be limiting, because the scope of the disclosure will be limited only by the appended claims.

[0506] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0507] As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0508] As used herein, the terms “treat,” “treating,” or the like, mean to alleviate symptoms, eliminate the causation of symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition (e.g., to prevent exacerbation of one or more symptoms of AFRS).

[0509] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the disclosure, the typical methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP Methods for Treating Allergic Fungal Rhinosinusitis

[0510] In certain aspects, the present disclosure provides methods for treating allergic fungal rhinosinusitis (AFRS).

[0511] AFRS is a chronic disease characterized by a type 2 inflammatory response directed against colonizing fungi in the sinuses with accumulation of eosinophilic mucin containing fungal hyphae, which results in persistent sinus opacification and nasal polyp formation. This disease accounts for a small (<10%) portion of patients with chronic rhinosinusitis. In some embodiments, a subject has nasal polyps. Although AFRS and chronic rhinosinusitis can present with nasal polyps and the shared type 2 driven inflammatory pathways underlying the two conditions, AFRS is distinct from chronic rhinosinusitis with nasal polyposis (CRSwNP) in its diagnosis, presentation, clinical course, pathophysiology, and management. (See Tyler et al. (2018) World J. Otorhinolaryngol. Head Neck. Surg. 4(3): 179-85; Fokkens et al. (2020) Rhinology 58(suppl. S29)l-464.) Unlike CRSwNP, diagnosis of AFRS requires evidence of immunoglobulin IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test), nasal polyps, characteristic computed tomography (CT) findings, eosinophilic mucin without fungal invasion into sinus tissue, and a positive fungal stain of sinus contents (referred to as “AFRS -associated parameters”). (See Bent and Kuhn (1994) Otorhinolaryngol. Head Neck. Surg. 111 (5): 580-8.) In some embodiments, subjects with AFRS have an indolent disease course, with slow growing opacification of sinuses due to mucin production. In other embodiments, the disease can be severe, and unlike CRSwNP, it often leads to bony erosion of the sinuses and even facial deformities. The disease typically occurs in a younger population with a mean age in the 20s to 30s. (See Tyler et al; Alobid et al. (2011) J. Investig. Allergol. Clin. Immunol. 21(Suppl.1): 1-58.) In some embodiments, subjects with AFRS are more likely to have concomitant asthma than the general population, but the overall incidence is lower at approximately 25%. (See Promsopa et al. (2016) Int. Forum Allergy Rhinol. 6(4):373-7.) In some embodiments, AFRS presents in young adults in their late teens and twenties, however there are rare case reports of AFRS in children between 6 to 12 years of age. (See Tyler et al. (2018) Otolaryngol. Head Neck Surg. 159(1): 185-93.)

[0512] Molecular endotyping has also identified pathways that are distinct to AFRS, which differentiate AFRS from CRSwNP as a subtype of CRS demonstrating an extreme of type 2 inflammations, such as the ICOS, CD28, and PKC6 pathways, which play pivotal roles in type 2 inflammatory effector function. Although there are rare cases of AFRS in children >6 to <12 years of age, in these children the disease commonly leads to facial dysmorphism. The growing facial skeleton of younger children may account for the higher degree of dysmorphismAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP seen as compared to adults. In some embodiments, asymmetric disease and unilateral sinus disease are more frequent in children (above 6 years of age) compared with adults while incidence of bony erosion is comparable with adults.

[0513] Bent-Kuhn Criteria can be used to diagnoses AFRS. The major criteria are: type I hypersensitivity to fungi (e.g., by history, skin prick test, IgE levels); nasal polyposis; characteristic CT signs; eosinophilic mucus without fungal invasion into sinus tissue; and a positive fungal stain of sinus contents removed from surgery, and five of these criteria must be met. The minor criteria are: radiographic bone erosion; positive fungal cultures; unilateral disease predominance; Charcot Leyden crystals; peripheral eosinophilia; and asthma.

[0514] In certain embodiments, an IL-4R antagonist described herein is indicated for the treatment of subjects with AFRS, who have persistent signs and symptoms despite endoscopic nasal surgery, topical or oral corticosteroids or a combination thereof.

[0515] In some embodiments, a subject has immunoglobulin IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test), nasal polyps, characteristic computed tomography (CT) findings, eosinophilic mucin without fungal invasion into sinus tissue, and a positive fungal stain of sinus contents. (See Singh (2019) J. Maxillofac. Oral Surg.18(2): 164-79; Ento Key website: entokey.com / the-diagnosis-of-allergic-fungal-sinusitis / )

[0516] As used herein, a “nasal polyp” is an overgrowth of tissue in one or more of the nasal cavities. The condition of having 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 polyps are typically teardrop-shaped growths that form in the nose and / r sinuses, obstructing the sinuses and nasal passages. NP is a clinical condition characterized by the presence of multiple polyps in the upper nasal cavity, originating from the osteomeatal complex. 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; promotes eosinophil survival and differentiation), ECP, and eotaxin (eosinophil chemoattractant), factors that attract and activate eosinophils, are typically found in nasal polyps. Eosinophils are the predominant inflammatory cell found in the sinuses and nasal polyps, and nasal polyps are also associated with elevated levels of IgE. The presence or absence of nasal polyps can be confirmed 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. As used herein, “bilateral NP” refers to the presence of one or more NPs at each side of the nasal cavity.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0517] An IL-4R antagonist can be used to treat AFRS associated with IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test), nasal polyps, characteristic computed tomography (CT) findings, eosinophilic mucin without fungal invasion into sinus tissue, and a positive fungal stain of sinus contents. In some embodiments, AFRS can be associated with rhinosinusitis (e.g., allergic and non-allergic rhinosinusitis), and / or asthma (e.g., moderate-to-severe asthma).

[0518] Fungal infections include, for example, infections from Aspergillus species, Bipolaris species, or Curvularia species.

[0519] The term “rhinitis” refers to an allergic response, such as to a common allergen (“allergic rhinitis,” e.g., perennial allergic 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.

[0520] As used herein, “allergic rhinitis” refers to rhinitis that occurs when the body’s immune system responds to specific, non-infectious irritants.

[0521] As used herein, “non-allergic rhinitis” refers to rhinitis that is not due to an allergic reaction, that can be triggered by factors such as, e.g., cigarette smoke and other pollutants, strong odors, strong chemical environments, alcoholic beverages, cold, blockages in the nose, a deviated septum, infections and over-use of medications such as decongestants and / or nasal sprays. Symptoms of non-allergic rhinitis include constriction or inflammation in the nasal passages which leads to many of the same symptoms of allergic rhinitis.

[0522] 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 rhinosinusitis (CRS), which is characterized by mucosal inflammation of the nasal cavity and paranasal sinuses with symptoms lasting more than 8 weeks. Chronic eosinophilic rhinosinusitis with nasal polyps is a condition that lasts longer than 8 weeks.Methods for Improving Allergic Fungal Rhinosinusitis-Associated Parameters

[0523] Described are methods for improving one or more AFRS-associated parameters in a subject in need thereof, wherein the methods include administering a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist to the subject. SomeAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP embodiments include a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist for use in improving one or more AFRS-associated parameters in a subject in need thereof. For example, an IL-4R receptor antagonist can reduce endoscopic Nasal Polyp Score (NPS) in a patient.Nasal Polyp Score (NPS)

[0524] A nasal polyp score of 0 indicates the presence of no polyps. An NPS of 1 indicates the presence of small polyps in the middle meatus not reaching below the inferior border of the middle turbinate. An NPS of 3 indicates large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate. An NPS of 4 indicates large polyps causing complete obstruction of the inferior nasal cavity. The maximum score is 8 (4 points per nasal cavity). In some embodiments, a patient to be treated has a baseline NPS of about 5. Treatment with an IL-4R antagonist can decrease NPS by about 1 to about 8 points. For example, treatment with an IL-4R antagonist can decrease NPS 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 IL-4R antagonist can decrease NPS 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 points, or a fraction thereof; by 6 points, or a fraction thereof; by 7 points, or a fraction thereof; or by 8 points or a fraction thereof. In some embodiments, a patient to be treated has a baseline NPS score of about 5.

[0525] Treatment with an IL-4R antagonist can decrease NPS in a patient relative to NPS prior to treatment. In certain aspects, NPS is decreased after treatments with an IL-4R antagonist by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30, about 31%, about 32%, about 33%, about 34%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%, or any ranges between these numbers. Thus, in certain aspects, NPS is decreased after treatments with an IL-4R antagonist by from about 1% to about 99%, or from about 2% to about 98%, or from about 3% to about 97%, or from about 4% to about 96%, or from about 5% to about 95%, or from about 6% to about 90%, or from about 7% to about 85%, or from about 8% to about 80%, or from about 9% to about 75%, or from about 10% to about 70%, or from about 11% to about 65%, or from about 12% to about 60%, or from about 13% to about 55%, or from about 14% to about 50%, or from about 15%Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP to about 45%, or from about 16% to about 40%, or from about 17% to about 35%, or from about 18% to about 34%, or from about 19% to about 33%, or from about 20% to about 32%, or from about 21% to about 31%, or from about 22% to about 30%, or from about 23% to about 29%, or from about 24% to about 28%, or from about 25% to about 27%, or from about 25% to about 26%.

[0526] A reduction in NPS may correlate with an improvement in one or more other AFRS-associated parameters. Such a correlation, however, is not necessarily observed in all cases.

[0527] In other embodiments, administering a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist to the subject with AFRS improves or reduces the subject’s use of systemic or inhaled corticosteroids, need to have surgery for AFRS, and / or sinus opacification as determined by computer tomography (CT) scans. In other embodiments, administering a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist to the subject with AFRS improves or reduces the subject’s AFRS-associated parameters.

[0528] Other examples of “AFRS-associated parameters” include, but are not limited to: (a) 22-item Sino Nasal 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 (ACQ5) score, such as in patients with asthma; (f) Nasal Peak Inspiratory 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; (j) Three Dimensional volumetric measurement of the maxillary sinus; (h) bone erosion.22-Item Sinonasal Outcome Test (SNOT-22) Score

[0529] According to certain embodiments, administration of an IL-4R antagonist to a patient 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 quality 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 CRS on Health Related Quality of Life (HRQoL) (Hopkins et al 2009, Clin. Otolaryngol. 34: 447-454). In some embodiments, a patient to be treated has a baseline SNOT-22 score of about 50.

[0530] In some embodiments, the therapeutic methods 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 IL-4R antagonist. In other embodiments, the therapeutic methods described herein include an IL-4RAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP antagonist for use in decreasing a SNOT-22 score from baseline of at least 1 point at week 4 to week 52. For example, administration of an IL-4R antagonist will result in a decrease in SNOT-22 score at week 4, week 6, week 8, week 12, or week 16, week 24, week 36, or week 52 following initiation of treatment. In some embodiments, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 4, week 6, week 8, week 12, week 16, week 24, week 36, or week 52. Thus, in one embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 4. In another embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 6. In a further embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 8. In yet another embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 12. In yet another embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 24. In yet another embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 36. In still another embodiment, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 52.Individual and Total Nasal Symptom Score

[0531] Subject-assessed symptoms are assayed by responding to morning and evening individual rhinosinusitis symptom questions using a 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), and including the symptoms of congestion and / or obstruction, anterior rhinorrhea, posterior rhinorrhea, and loss of sense of smell. Nasal symptoms can be assayed in the day (AM), at night (PM) or both AM and PM.

[0532] A loss of sense of smell can be tracked. Administration of an IL-4R antagonist can result, for example, in a decrease in loss of sense of smell (i.e., achieving a lower number on the scale) from baseline compared to week 4 to week 16 following initiation of treatment withAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a decrease in loss of sense of smell from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4, week 6, week 8, week 12, week 16, week 24, week 36, or week 52 following initiation of treatment. Thus, in an example, a decrease in loss of sense of smell from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4 following initiation of treatment. In a further example, a decrease in loss of sense of smell from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 6 following initiation of treatment. In a further example, a decrease in loss of sense of smell from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 8 following initiation of treatment. In a further example, a decrease in loss of sense of smell from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 12 following initiation of treatment. In a further example, a decrease in loss of sense of smell from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 16 following initiation of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in a decrease in loss of sense of smell symptom score from baseline by about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at week 4, week 8, week 12, or week 16, for example. Administration of an IL-4R antagonist to a subject in need thereof can result in a decrease in loss of sense of smell symptom score from baseline by about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at week 52.

[0533] A decrease in congestion and / or obstruction can be tracked. Administration of an IL-4R antagonist can result, for example, in a decrease in congestion and / or obstruction (i.e., achieving a lower number on the scale) from baseline compared to week 4 to week 16 following initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a decrease in congestion and / or obstruction from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment. Thus, in an example, a decrease in congestion and / or obstruction from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4 following initiation of treatment. In a further example, a decrease in congestion and / or obstruction from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 6 following initiation of treatment. In a further example, a decrease in congestion and / or obstruction from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can beAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP detected at week 8 following initiation of treatment. In a further example, a decrease in congestion and / or obstruction from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 12 following initiation of treatment. In a further example, a decrease in congestion and / or obstruction from baseline (e.g., from about 0.5, about 1.0, about 1.5, about2.0, about 2.5 or about 3.0) can be detected at week 16 following initiation of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in a decrease in congestion and / or obstruction symptom score from baseline by about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at week 4, week 8, week 12, or week 16, for example.

[0534] A decrease in runny nose can be tracked. Administration of an IL-4R antagonist can result, for example, in a decrease in runny nose (i.e., achieving a lower number on the scale) from baseline compared to week 4 to week 16 following initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a decrease in runny nose from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment. Thus, in an example, a decrease in runny nose from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4 following initiation of treatment. In a further example, a decrease in runny nose from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 6 following initiation of treatment. In a further example, a decrease in runny nose from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 8 following initiation of treatment. In a further example, a decrease in runny nose from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 12 following initiation of treatment. In a further example, a decrease in runny nose from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 16 following initiation of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in a decrease in runny nose symptom score from baseline by about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at week 4, week 8, week 12, or week 16, for example.

[0535] A decrease in post nasal drip can be tracked. Administration of an IL-4R antagonist can result, for example, in a decrease in runny nose (i.e., achieving a lower number on the scale) from baseline compared to week 4 to week 16 following initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, a decrease in post nasal drip from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 orAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP about 3.0) can be detected at week 4, week 6, week 8, week 12, or week 16 following initiation of treatment. Thus, in an example, a decrease in post nasal drip from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 4 following initiation of treatment. In a further example, a decrease in post nasal drip from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 6 following initiation of treatment. In a further example, a decrease in post nasal drip from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 8 following initiation of treatment. In a further example, a decrease in post nasal drip from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 12 following initiation of treatment. In a further example, a decrease in post nasal drip from baseline (e.g., from about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0) can be detected at week 16 following initiation of treatment. Administration of an IL-4R antagonist to a subject in need thereof can result in a decrease in post nasal drip symptom score from baseline by about 0.5, about 1.0, about 1.5, about 2.0, about 2.5 or about 3.0 or more at week 4, week 8, week 12, or week 16, for example.

[0536] A measure of night-time awakenings can also be tracked. For example, a measure of night-time awakenings can be assessed according to the following scores based on subject selfassessment: 0 = no symptoms, slept through the night; 1 = slept well, but some complaints 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 IL-4R antagonist can result, for example, in a decrease in average number of nighttime awakenings per night from baseline 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-IL-4R antagonist. For example, a decrease 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. Administration of an IL-4R antagonist to a subject in need thereof can result in 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. Thus, in one example, administration of an IL-4R antagonist toAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP a subject in need thereof can result in 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. In a further example, administration of an IL-4R antagonist to a subject in need thereof can result in 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 8. In a further example, administration of an IL-4R antagonist to a subject in need thereof can result in 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 12. In a further example, administration of an IL-4R antagonist to a subject in need thereof can result in 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 16.Visual Analog Score (VAS)

[0537] 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 IL-4R antagonist to a subject in need thereof results in 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. Thus, in one example,Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP administration of an IL-4R antagonist to a subject in need thereof results in 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. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 6. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 12. The decrease in VAS score can be detected as early as week 4, and as late as week 52.5-Item Asthma Control Questionnaire (ACQ) Score

[0538] The ACQ5 measures both the adequacy of asthma control and change in asthma control, which occurs either spontaneously or as a result of treatment. The five questions on the ACQ5 reflect the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Patients respond to the symptom questions on a 7-point scale (0 = no impairment, totally controlled; 6 = maximum impairment, severely uncontrolled).

[0539] Embodiments of the disclosure include therapeutic methods which result in a decrease in ACQ5 score from baseline of at least 0.10 point at week 12 following initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, according to the present disclosure, administration of an IL-4R antagonist to a subject in need thereof results in 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 points, 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. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof results in 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 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more at week 4. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more at week 6. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 points,Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more at week 12. The decrease in ACQ score can be detected as early as week 4, and as late as week 12 or later following administration of the IL-4R antagonist.Nasal Peak Inspiratory Flow (NPIF)

[0540] The Nasal Peak Inspiratory Flow (NPIF) represents a physiologic measure of air flow through both nasal cavities during forced inspiration 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 IL-4R antagonist to a subject in need thereof results in 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 minute, 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. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof results in 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 minute, 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. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 minute, 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 6. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 minute, 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 12. The increase in NPIF score can be detected as early as week 4, and as late as week 52 following administration of the IL-4R antagonist.Bone ErosionAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0541] As a result of the chronic inflammation and pressure exerted by the accumulated mucin and polyps, remodeling of the sinus walls may happen, and in severe cases, this leads to erosion of the bone. Symptoms associated with bone erosion may include facial pressure, proptosis, and visual disturbances. A radiologic staging system involving a review of computed tomography (CT) images may be used to determine existence of bone remodeling. The system can also be used to quantify bone erosion severity. For example, scoring might be distributed as follows: up to 3 points per frontal sinus wall, 2 points per ethmoid complex, 3 points for each sphenoid and maxillary sinus, with additional points for septal involvement. The aggregate score (with a maximum of 24 points) reflects the overall degree of bony changes, see Wise et al. (Otolaryngology-Head and Neck Surgery (2009) 140, 735-740). An alternative system is the Bone Erosion Score (BES), which quantifies the extent of bony erosion by evaluating the CT images of paranasal sinuses. Each eroded wall is given a score based on the severity and extent of the erosion. The total BES is then used to monitor changes over time, including post-treatment bone regeneration, see Alarifi et al. (Cureus et al. 2019 Dec 29;1 11(12):e6502) and Al-Dousary et al. (Cureus 2019 11(12): e6395).Background Treatments

[0542] Background treatments for AFRS include: (1) daily saline irrigation; (2) inhaled corticosteroids (ICS), e.g., intranasal corticosteroids (INCS); (3) systemic corticosteroids (SCS), e.g., oral corticosteroids (OCS) or injected corticosteroids; and (4) surgery. In certain embodiments, a subject with AFRS remains symptomatic despite using one or more of these background treatments. In certain embodiments, the pharmaceutical composition comprising an IL-4R antibody or antigen-binding fragment thereof reduces or eliminates the need for a subject to use one or more of these background treatments.Nasal Saline Irrigation

[0543] In certain embodiments, the pharmaceutical composition comprising an IL-4R antagonist is administered with nasal saline irrigation. Nasal saline irrigation is low risk and well tolerated by most patients. Multiple devices are known in the art for nasal irrigation, including squeeze bottles and neti pots. Patients can make their own saline solution or purchase commercially prepared solutions. High-volume (>200 mL per nostril) saline irrigations are more effective than low-volume nasal saline sprays. In certain exemplary embodiments, treatment with a pharmaceutical composition comprising an IL-4R antibody or antigen-binding fragment thereof reduces or eliminates the need for nasal saline irrigation.Inhaled Corticosteroid (ICS)Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0544] In certain embodiments, the pharmaceutical composition comprising an IL-4R antagonist is administered with a high dose ICS. In some embodiments, the high dose ICS is beclometasone dipropionate (CFC) and the dose is greater than 1000 mcg. In some embodiments, the high dose ICS is beclometasone dipropionate (HF A) and the dose is greater than 400 pg. In some embodiments, the high dose ICS is budesonide (DPI) and the dose is greater than 800 mcg. In some embodiments, the high dose ICS is ciclesonide (HF A) and the dose is greater than 320 mcg. In some embodiments, the high dose ICS is fluticasone propionate (DPI or HF A) and the dose is greater than 500 pg. In some embodiments, the high dose ICS is mometasone furoate and the dose is greater than 440 pg. In some embodiments, the high dose ICS is triamcinolone acetonide and the dose is greater than 2000 pg.

[0545] In certain embodiments, the pharmaceutical composition comprising an IL-4R antagonist is administered with a non-high dose ICS. In some embodiments, the non-high dose ICS is beclometasone dipropionate (CFC) and the dose is equal or less than 1000 mcg. In some embodiments, the non-high dose ICS is beclometasone dipropionate (HF A) and the dose is equal or below 400 pg. In some embodiments, the non-high dose ICS is budesonide (DPI) and the dose is equal or below 800 mcg. In some embodiments, the non-high dose ICS is ciclesonide (HF A) and the dose is equal or below 320 mcg. In some embodiments, the non-high dose ICS is fluticasone propionate (DPI or HF A) and the dose is equal or below 500 pg. In some embodiments, the non-high dose ICS is mometasone furoate and the dose is equal or below 440 pg. In some embodiments, the non-high dose ICS is triamcinolone acetonide and the dose is equal or below 2000 pg.

[0546] In certain exemplary embodiments, methods for reducing or eliminating the dependency of the subject on ICS use are provided. The reduction or elimination of steroid dependency is highly advantageous and desirable. In certain embodiments, a reduction of 50% or greater (e.g., 50%, 60%, 70%, 80%, 90% or more) in the ICS dose is achieved after administration of IL-4R antibody therapy for a period of time (e.g., 24 weeks or 52 weeks). In certain embodiments, ICS use is substantially eliminated after 24 weeks, 30 weeks, 35 weeks, 40 weeks, 45 weeks, 50 weeks, 52 weeks, or greater after first dose following administration of the loading dose. In other embodiments, the dependency on ICS use is substantially eliminated after 3 months, 6 months, 9 months or 1 year following treatment with IL4R antibody or fragment thereof.Oral Corticosteroid (PCS) Use

[0547] According to certain embodiments, administration of an IL-4R antagonist to a patient can be used in conjunction with an PCS such as, e.g., oral prednisone. In other aspects,Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP prednisone is used concurrent with or as a substitution for ICS. Oral prednisone may be administered in dosages of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg. OCS can optionally be administered once a day or multiple times a day (e.g., twice a day, three times a day, four times a day, etc.)

[0548] In certain exemplary embodiments, methods for reducing or eliminating the dependency of the subject on OCS use are provided. The reduction or elimination of steroid dependency is highly advantageous and desirable. In certain embodiments, a reduction of 50% or greater (e.g., 50%, 60%, 70%, 80%, 90% or more) in the OCS dose is achieved after administration of IL-4R antibody therapy for a period of time (e.g., at week 24 or week 52). In certain embodiments, the OCS is substantially eliminated after 24 weeks, 30 week, 35 weeks, 40 weeks, 45 weeks, 50 weeks, 52 weeks, or greater after first dose following administration of the loading dose. In other embodiments, the level of OCS use is reduced to less than 5 mg per day (e.g., less than 5 mg, 4 mg, 3 mg, 2 mg or less per day). In other embodiments, the dependency on OCS use is substantially eliminated after 3 months, 6 months, 9 months or 1 year following treatment with IL4R antibody or fragment thereof.

[0549] In certain embodiments, a subject having AFRS has a lower risk of needing systemic corticosteroids (e.g., OCS) following treatment with IL4R antibody or fragment thereof. In certain embodiments, a subject having AFRS has a risk of needing systemic corticosteroids (e.g., OCS) that is reduced about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to baseline risk.Surgery

[0550] In certain embodiments, the pharmaceutical composition comprising an IL-4R antagonist is administered to a subject that has undergone one or more previous surgeries for AFRS. Surgery for AFRS is not curative, but can improve symptoms and facilitate topical corticosteroid therapy. 29% of patients with AFRS will need revision surgery. The primary surgical approach for AFRS is functional endoscopic sinus surgery (FESS). In certain exemplary embodiments, treatment with a pharmaceutical composition comprising an IL-4R antibody or antigen-binding fragment thereof reduces the frequency of or eliminates the need for AFRS surgery.University of Pennsylvania Smell Identification Test (UPSIT)

[0551] The UPSIT is a method to quantitatively assess human olfactory function. The test consists of samples of odorants, and the subject must describe the odor. The score is based on the number of correct answers. This test can distinguish patients with a normal sense of smellAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP (“normosmia”) from those with different levels of reduction (“mild, moderate and severe microsmia”) or loss (“anosmia”). Administration of an IL-4R antagonist to a subject in need thereof results in 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, week 12, week 16, week 24, week 36, or week 52. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof results in 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. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 6. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 12. The increase in UPSIT score can be detected as early as week 4, and as late as week 52 or later following administration of the IL-4R antagonist.Lund-Mackay Score

[0552] The Lund-Mackay scoring system is based on localization with points given for degree of opacification: 0 = normal, 1 = partial opacification, 2 = total opacification. 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 (OC) is missing (because of a previous surgery) the location of the former OC is considered, and a score is provided, as if the OC was there. In some embodiments, a patient to be treated has a baseline Lund-Mackay score of about 18. Administration of an IL-4R antagonist to a subject in need thereof results in 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 points, 0.80 points, 0.85 points, or more at week 4, week 6, week 12, week 16, week 24, week 36, or week 52. Thus, in one example, administration of an IL-4R antagonist to a subject in need thereof results in 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 points, 0.80 points, 0.85 points, or more at week 4. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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, 0.55Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or more at week 6. In a further example, administration of an IL-4R antagonist to a subject in need thereof results in 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 points, 0.80 points, 0.85 points, or more at week 12. The decrease in Lund-Mackay score can be detected as early as week 4, and as late as week 52 or later following administration of the IL-4R antagonist.Physiological parameters

[0553] The efficacy of an IL-4R antagonist can be assayed by measuring the effect of physiological parameters, such as within the nasal cavities, such as by nasal endoscopy or computed tomography (CT) scan.Three-Dimensional (3D) Volumetric Measurement of Maxillary Sinus

[0554] 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 as a three-dimensional volume value that can be visualized by CT. The scale is 0-100%. A higher percentage is worse, and indicates a greater disease involvement in the sinus. In exemplary embodiments, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in the 3D-volumetric measurement.

[0555] In certain exemplary embodiments, administration of an IL-4R antagonist to a subject in need thereof reduces the total volume of the sinuses occupied by diseased tissue (e.g., eosinophilic mucus without fungal invasion, fungal-laden mucin, polyps, eosinophils, Charcot Leyden crystals, abnormal cells and the like) in a subject having AFRS. In exemplary embodiments, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in the 3D-volumetric measurement by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70% or more.Quality of Life (OoL) Questionnaires

[0556] Various QoL questionnaires can be used to monitor efficacy of an IL-4R antagonist, including Short-Form-36 (SF-36) questionnaire, the Euroqol-5D (EQ-5D), nasal polyp related resource use questionnaire, and the patient qualitative self-assessment.

[0557] 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 limitations due to emotional problems (3 items), mental healthAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP (5 items), energy / 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 possible 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 (MCS).

[0558] The EQ-5D is a standardized health-related quality of life questionnaire developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic 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 ‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top and 0 (Worst imaginable health state) at the bottom.

[0559] 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.AFRS-Associated Biomarkers

[0560] Examples of AFRS-associated biomarkers include, but are not limited to, one or more of serum immunoglobulin E (IgE) level, eotaxin (e.g., eotaxin-3) level, periostin level, thymus and activation-regulated chemokine (TARC) level, IL-5 level, secreted P-glycoprotein level, and any combinations thereof.

[0561] In certain embodiments, one or more AFRS-associated biomarkers may be detected from a biological sample derived from a subject. A biological sample includes, but is not limited to, one or any combination of materials taken from a patient including cultures, cells, tissues, blood, saliva, nasal secretions, cerebrospinal fluid, pleural fluid, milk, lymph, sputum, semen, needle aspirates, and the like. Biological samples may be obtained using any methods known in the art. For example, nasal secretion samples may be obtained from smears, blown secretions, imprints, lavage, swabs, brushes and the like.

[0562] A normal IgE level in healthy subjects is less than about 100 kU / L (e.g., as measured using the IMMUNOCAP® assay [Phadia, Inc. Portage, MI]). Thus, embodiments include methods for decreasing an elevated serum IgE level, which is a serum IgE level greater than about 100 kU / L, greater than about 150 kU / L, greater than about 500 kU / L, greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than aboutAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or greater than about 5000 kU / L, by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0563] TARC levels in healthy subjects are in the range of 106 ng / L to 431 ng / L, with a mean of about 239 ng / L. (An exemplary assay system for measuring TARC level is the TARC quantitative ELISA kit offered as Cat. No. DDN00 by R& D Systems, Minneapolis, MN.) Thus, embodiments include methods for decreasing an elevated serum TARC level, which is a serum TARC (e.g., serum TARC) level greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L, by administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0564] Improvement of an AFRS-associated parameter, such as a nasal polyp-associated parameter 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.

[0565] Biomarker expression, as discussed above, can be assayed by detection of protein or RNA in serum. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., RNA levels of biomarkers, and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0566] An “improvement in an AFRS-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 IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test), nasal polyps, characteristic computed tomography (CT) findings, eosinophilic mucin without fungal invasion into sinus tissue, and a positive fungal stain of sinus contents. In other embodiments, improvement in an AFRS-associated parameter is a decrease from baseline of one or more of a SNOT-22 score, subject-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 asthma. As used herein, the term “baseline,” e.g., of an AFRS-associated parameter, means the numerical value of the nasal polyp-associated parameter for a patientAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP prior to or at the time of administration of a pharmaceutical composition of the present disclosure.

[0567] To determine whether an AFRS-associated parameter has “improved,” the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition of the present disclosure. For example, an AFRS-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 disclosure. 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.

[0568] The difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an “improvement” in the nasal associated parameter (e.g., an increase or decrease depending on the specific parameter being measured).

[0569] In certain embodiments, an improvement in LMK score is observed in a subject having AFRS relative to a baseline LMK score, mean (SD) of about 17.9 (3.6).

[0570] In certain embodiments, an improvement in NPS score is observed in a subject having AFRS relative to a baseline NPS score, mean (SD) of about 5.2 (1.9).

[0571] In certain embodiments, an improvement in TSS score is observed in a subject having AFRS relative to a baseline TSS score, mean (SD) of about 5.5 (2.4).

[0572] In certain embodiments, an improvement in NCS symptom severity score is observed in a subject having AFRS relative to a baseline NCS symptom severity score, mean (SD) of about 1.9 (0.9).

[0573] In certain embodiments, an improvement in SNOT-22 score is observed in a subject having AFRS relative to a baseline SNOT-22 score, mean (SD) of about 44.7 (22.1).

[0574] In certain embodiments, an improvement in UPSIT score is observed in a subject having AFRS relative to a baseline UPSIT score, mean (SD) of about 16.4 (10.1).

[0575] In certain embodiments, an improvement in blood eosinophil (Eos) count for a subject having AFRS and a blood Eos count <300 cells pl prior to treatment is observed relative to a baseline blood Eos count for <300 cells pl (%) of about 20 (32.3).Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0576] In certain embodiments, an improvement in blood Eos count for a subject having AFRS and a blood Eos count >300 cells pl prior to treatment is observed relative to a baseline blood Eos count for >300 cells pl (%) of about 40 (64.5).

[0577] In certain embodiments, an improvement in blood Eos is observed in a subject having AFRS and a blood Eos count of 10A9 / L prior to treatment relative to a baseline Eos count, mean (SD) of about 0.5 (0.3).

[0578] In certain embodiments, an improvement in blood Eos is observed in a subject having AFRS and a blood Eos count of 10A9 / L prior to treatment relative to a baseline Eos count, median (Q1; Q3) of about 0.4 (0.3;0.7).

[0579] In certain embodiments, an improvement serum total IgE level is observed in a subject having AFRS relative to a baseline serum total IgE level, mean (SD) of about 1356.4 (1535.0).

[0580] In certain embodiments, an improvement serum total IgE level is observed in a subject having AFRS relative to a baseline serum total IgE level, median (Q1; Q3) of about 953.0 (285.0;1928.0).

[0581] In certain embodiments, an improvement in FEV1 score is observed in a subject having AFRS relative to a baseline FEV1 score PP (%), mean (SD) of about 80.3 (14.4).

[0582] In certain embodiments, an improvement in ACQ-6 score is observed in a subject having AFRS relative to a baseline ACQ-6 score, mean (SD) of about 1.40 (1.1).

[0583] In certain embodiments, an improvement in FEV1 score is observed in a subject having AFRS and comorbid asthma relative to a baseline FEV1 score PP (%), mean (SD) of about 80.3 (14.4).

[0584] In certain embodiments, an improvement in ACQ-6 score is observed in a subject having AFRS and comorbid asthma relative to a baseline ACQ-6 score, mean (SD) of about 1.40 (1.1).Interleukin-4 Receptor Antagonists

[0585] The methods featured herein comprise administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, an “IL-4R antagonist” is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on a cell in vitro or in vivo. Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., “peptibody” molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind human IL-4R. According to certain embodiments, the IL-4R antagonist comprises an anti-IL-4R antibody that can be usedAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP in the context of the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to an IL-4R and comprises the heavy chain and light chain (complementarity determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID Nos: 1 and 2, respectively.

[0586] The term “human IL4R” (hIL-4R) refers to a human cytokine receptor that specifically binds to interleukin-4 (IL-4), such as IL-4Ra.

[0587] In some embodiments, an antibody (such as an anti-IL-4R antibody as disclosed herein) does not have a C-terminal lysine in the heavy chain. For example, a C-terminal lysine that is present at the end of a heavy chain sequence may be removed as a post-translational modification during manufacture, e.g., during protein expression. Alternatively, a C-terminal lysine may be removed by recombinant technology (e.g., the coding sequence of the heavy chain does not include a codon for a C-terminal lysine). Thus, contemplated within the present disclosure are antibodies comprising a heavy chain in which a C-terminal lysine, if included in the amino acid sequence (e.g., as in SEQ ID NO: 11), is absent (e.g., as in SEQ ID NO:9).

[0588] The term “antibody” refers 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 thereof e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, Cnl, 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 (CLI). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the anti-IL-4R antibody (or antigenbinding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs. In some embodiments, the antibody is a human IgG antibody. In some embodiments, the antibody is a human IgG4 antibody.

[0589] The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymaticallyAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to 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 recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily 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.

[0590] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab’)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable 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 nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment.”

[0591] An antigen-binding fragment of an antibody will typically comprise 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 that is adj acent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains 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 contain a monomeric VH or VL domain.

[0592] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody described herein include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3;Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly 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 that result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule, typically the hinge region may consist of between 2 to 60 amino acids, typically between 5 to 50, or typically between 10 to 40 amino acids. Moreover, an antigen-binding fragment of an antibody described herein may comprise a homo-dimer 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 monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0593] 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 antibody format, may be adapted for use in the context of an antigen-binding fragment of an antibody described herein using routine techniques available in the art.

[0594] The constant 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 whether it is desirable for the antibody to mediate cytotoxicity.

[0595] The term “human antibody” includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies described herein 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 CDR3. However, the term “human antibody” does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0596] The term “recombinant human antibody” includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for humanAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 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 splicing 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 embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig 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.

[0597] 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 together 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 (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.

[0598] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 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 IgGl hinge. Antibodies having one or more mutations in the hinge, CH2, or CH3 region, which may be desirable, for example, in production, to improve the yield of the desired antibody form, are provided.

[0599] An “isolated antibody” means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally 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 purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0600] The term “specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologicAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 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” IL-4R includes antibodies that bind IL-4R or portion thereof with a KD 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 plasmon resonance assay. An isolated antibody that specifically binds human IL-4R may, however, have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0601] The anti-IL-4R antibodies useful for the methods may comprise one or more amino acid substitutions, insertions, and / or deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deletions) in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. Methods involving the use of antibodies, and antigen-binding fragments thereof, that are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) within one or more framework and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 with respect to the tetrameric antibody or 1, 2, 3, 4, 5 or 6 with respect to the HCVR and LCVR of an antibody) 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 sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”), are provided. A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments that comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all 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 certain residues are mutated back to the original germline sequence,Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. 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 sequence 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 sequence while certain other residues that differ from the original germline sequence are maintained or are mutated 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 disclosure.

[0602] Methods involving the use of anti-IL-4R antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the use of anti-IL-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. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein, are provided.

[0603] The term “surface plasmon resonance” 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 BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0604] The term “KD” refers to the equilibrium dissociation constant of a particular antibodyantigen interaction.

[0605] The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies 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 produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitopeAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0606] The term “substantial identity” or “substantially identical,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, or at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed below.

[0607] As applied to polypeptides, the term “substantial similarity” or “substantially similar” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, or at least 98% or 99% sequence identity. In exemplary embodiments, residue positions which are not identical differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. (See, e.g, Pearson (1994) Methods Mol. Biol. 24: 307-331, herein incorporated by reference). Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine. Exemplary conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamateaspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45, herein incorporated by reference. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0608] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions andAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. (See, e.g., GCG Version 6.1.) Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another exemplary algorithm when comparing a sequence of the disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. (See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res.25:3389-402, each of which is herein incorporated by reference.)Preparation of Human Antibodies

[0609] Methods for generating human antibodies in transgenic mice are known in the art. Any such known methods can be used to make human antibodies that specifically bind to human IL-4R.

[0610] Using VELOCIMMUNE® technology (see, for example, US 6,596,541, Regenerome Pharmaceuticals) or any other known method for generating monoclonal antibodies, high affinity chimeric antibodies to IL-4R are initially isolated having a human variable region and a mouse constant region. The VELOCIMMUNE® technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing the fully human antibody.

[0611] Generally, a VELOCIMMUNE® mouse is challenged with the antigen of interest, and lymphatic cells (such as B-cells) are recovered from the mice that express antibodies. The lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regionsAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigenspecific lymphocytes.

[0612] Initially, high affinity chimeric antibodies are isolated having a human variable region and a mouse constant region. The antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant regions are replaced with a desired human constant region to generate a fully human antibody described herein, for example wild-type or modified IgGl or IgG4. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.

[0613] In general, the antibodies that can be used in the methods described herein possess high affinities, as described above, when measured by binding to antigen either immobilized on solid phase or in solution phase. The mouse constant regions are replaced with desired human constant regions to generate the fully-human antibodies described herein. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.

[0614] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds IL-4R that can be used in the context of the methods described herein comprises the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment may comprise the three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of the structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273'.921-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86.9263-9272 (1989). PublicAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP databases are also available for identifying CDR sequences within an antibody.

[0615] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy and light chain variable region amino acid sequence pairs (HCVR / LCVR) of SEQ ID Nos: 1 and 2.

[0616] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID Nos: 3 / 4 / 5 / 6 / 7Z8.

[0617] In certain embodiments, the antibody or antigen-binding fragment thereof comprises HCVR / LCVR amino acid sequence pair of SEQ ID Nos: 1 and 2.

[0618] In certain embodiments, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID Nos: 1 and 2.

[0619] In certain embodiments, the antibody sequence is dupilumab, which comprises the heavy chain / light chain amino acid sequence pair of SEQ ID Nos: 9 and 10.Dupilumab HCVR amino acid sequence:

[0620] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSI SGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPR YYGLDVWGQGTTVTVS (SEQ ID NO: 1).Dupilumab LCVR amino acid sequence:

[0621] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIY LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 2).Dupilumab HCDR1 amino acid sequence:

[0622] GFTFRDYA (SEQ ID NO: 3).Dupilumab HCDR2 amino acid sequence:

[0623] ISGSGGNT (SEQ ID NO: 4).Dupilumab HCDR3 amino acid sequence:

[0624] AKDRLSITIRPRYYGL (SEQ ID NO: 5).Dupilumab LCDR1 amino acid sequence:

[0625] QSLLYSIGYNY (SEQ ID NO: 6).Dupilumab LCDR2 amino acid sequence:Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP

[0626] LGS (SEQ ID NO: 7).Dupilumab LCDR3 amino acid sequence:

[0627] MQALQTPYT (SEQ ID NO: 8).Dupilumab HC amino acid sequence:

[0628] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSI SGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPR YYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSS IEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQE. G. NVFSCSVMHEALHNHYTQKSLSLSL G (SEQ ID NO: 9) (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant).Dupilumab HC amino acid sequence with a C-terminal lysine:

[0629] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSI SGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPR YYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSS IEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 11) (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant). Dupilumab LC amino acid sequence:

[0630] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIY LGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10) (amino acids 1-112 = LCVR; amino acids 112-219 = LC constant).

[0631] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises light chain variable region (LCVR) and heavy chain variable regionAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP (HCVR) sequence pairs (LCVR / HCVR) selected from the group consisting of SCB-VL-39 / SCB-VH-92; SCB-VL-40 / SCB-VH-92; SCB-VL-41 / SCB-VH-92; SCB-VL-42 / SCB-VH-92; SCB-VL-43 / SCB-VH-92; SCB-VL-44 / SCB-VH-92; SCB-VL-44 / SCB-VH-62; SCB-VL-44 / SCB-VH-68; SCB-VL-44 / SCB-VH-72; SCB-VL-44 / SCB-VH-82; SCB-VL-44 / SCB-VH-85; SCB-VL-44 / SCB-VH-91; SCB-VL-44 / SCB-VH-93; SCB-VL-45 / SCB-VH-92; SCB-VL-46 / SCB-VH-92; SCB-VL-47 / SCB-VH-92; SCB-VL-48 / SCB-VH-92; SCB-VL-49 / SCB-VH-92; SCB-VL-50 / SCB-VH-92; SCB-VL-51 / SCB-VH-92; SCB-VL-51 / SCB-VH-93; SCB-VL-52 / SCB-VH-92; SCB-VL-52 / SCB-VH-62; SCB-VL-52 / SCB-VH-91; SCB-VL-53 / SCB-VH-92; SCB-VL-54 / SCB-VH-92; SCB-VL-54 / SCB-VH-62; SCB-VL-54 / SCB-VH-68; SCB-VL-54 / SCB-VH-72; SCB-VL-54 / SCB-VH-82; SCB-VL-54 / SCB-VH-85; SCB-VL-54 / SCB-VH-91; SCB-VL-55 / SCB-VH-92; SCB-VL-55 / SCB-VH-62; SCB-VL-55 / SCB-VH-68; SCB-VL-55 / SCB-VH-72; SCB-VL-55 / SCB-VH-82; SCB-VL-55 / SCB-VH-85; SCB-VL-55 / SCB-VH-91; SCB-VL-56 / SCB-VH-92; SCB-VL-57 / SCB-VH-92; SCB-VL-57 / SCB-VH-93; SCB-VL-57 / SCB-VH-59; SCB-VL-57 / SCB-VH-60; SCB-VL-57 / SCB-VH-61; SCB-VL-57 / SCB-VH-62; SCB-VL-57 / SCB-VH-63; SCB-VL-57 / SCB-VH-64; SCB-VL-57 / SCB-VH-65; SCB-VL-57 / SCB-VH-66; SCB-VL-57 / SCB-VH-67; SCB-VL-57 / SCB-VH-68; SCB-VL-57 / SCB-VH-69; SCB-VL-57 / SCB-VH-70; SCB-VL-57 / SCB-VH-71; SCB-VL-57 / SCB-VH-72; SCB-VL-57 / SCB-VH-73; SCB-VL-57 / SCB-VH-74; SCB-VL-57 / SCB-VH-75; SCB-VL-57 / SCB-VH-76; SCB-VL-57 / SCB-VH-77; SCB-VL-57 / SCB-VH-78; SCB-VL-57 / SCB-VH-79; SCB-VL-57 / SCB-VH-80; SCB-VL-57 / SCB-VH-81; SCB-VL-57 / SCB-VH-82; SCB-VL-57 / SCB-VH-83; SCB-VL-57 / SCB-VH-84; SCB-VL-57 / SCB-VH-85; SCB-VL-57 / SCB-VH-86; SCB-VL-57 / SCB-VH-87; SCB-VL-57 / SCB-VH-88; SCB-VL-57 / SCB-VH-89; SCB-VL-57 / SCB-VH-90; SCB-VL-57 / SCB-VH-91; SCB-VL-58 / SCB-VH-91; SCB-VL-58 / SCB-VH-92; and SCB-VL-58 / SCB-VH-93.

[0632] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a LCVR / HCVR sequence pair of SCB-VL-44 / SCB-VH-92.

[0633] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a LCVR / HCVR sequence pair of SCB-VL-54 / SCB-VH-92.

[0634] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a LCVR / HCVR sequence pair of SCB-VL-55 / SCB-VH-92.

[0635] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises an HCVR comprising an HCDR1 sequence of SCB-92-HCDR1, an HCDR2 sequence of SCB-92-HCDR2, and an HCDR3 sequence of SCB-92-HCDR3, and anAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP LCVR comprising an LCDR1 of SCB-55-LCDR1, and LCDR2 of SCB-55-LCDR2, and an LCDR3 of SCB-55-LCDR3.

[0636] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises an HCVR comprising an HCDR1 sequence of SCB-92-HCDR1, an HCDR2 sequence of SCB-92-HCDR2, and an HCDR3 sequence of SCB-92-HCDR3, and an LCVR comprising an LCDR1 of SCB-55-LCDR1, and LCDR2 of SCB-54-LCDR2, and an LCDR3 of SCB-55-LCDR3.

[0637] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises an HCVR comprising an HCDR1 sequence of SCB-92-HCDR1, an HCDR2 sequence of SCB-92-HCDR2, and an HCDR3 sequence of SCB-92-HCDR3, and an LCVR comprising an LCDR1 of SCB-55-LCDR1, and LCDR2 of SCB-54-LCDR2, and an LCDR3 of SCB-44-LCDR3.

[0638] The antibodies recited below in Table 1 are described in more detail in U. S.10,774,141, incorporated herein by reference in its entirety for all purposes.Table 1.Sequence ID SequenceSCB-VL-39 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQ YGS SPP WTFGQGTKVEIK SCB-VL-40 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPP WTFGQGTKVEIK SCB-VL-41 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRAPGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQ YGS SPP WTFGQGTKVEIK SCB-VL-42 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPP WTFGQGTKVEIK SCB-VL-43 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IFGAS SRAPGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQ YGS SPP WTFGQGTKVEIK SCB-VL-44 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPP WTFGQGTKVEIK SCB-VL-45 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHSPP WTFGQGTKVEIK SCB-VL-46 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQ YGS SAGWTFGQGTKVEIKAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP SCB-VL-47 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHS AG WTFGQGTKVEIK SCB-VL-48 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHSPP WTFGQGTKVEIK SCB-VL-49 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQQYDHSPP WTFGQGTKVEIK SCB-VL-50 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRAPGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHSPP WTFGQGTKVEIK SCB-VL-51 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDHSA GWTFGQGTKVEIK SCB-VL-52 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IFGAS SRAPGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHS AG WTFGQGTKVEIK SCB-VL-53 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDHSA GWTFGQGTKVEIK SCB-VL-54 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRAPGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHS AG WTFGQGTKVEIK SCB-VL-55 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDHSA GWTFGQGTKVEIK SCB-VL-56 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYDHS AG WTFGQGTKVEIK SCB-VL-57 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL IFGAS SRATGIPDRF SGSGSGTDFTLTISRLEPEDF AVYYCQQYGS SPP WTFGQGTKVEIK SCB-VL-58 EIVLTQSPGTLSLSPGERATLSCRASQSVSNSYLAWYQQKPGQAPRLL IYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDHSA GWTFGQGTKVEIK SCB-VH-59 EVQLVESGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-60 EVQLVQSGGGLVQPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-61 EVQLVQSGGGLVHPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-62 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLEWVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMAVYYC ARGRYYFD YWGQGTL VT VS SAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP SCB-VH-63 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-64 EVQLVESGGGLVQPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-65 EVQLVESGGGLVHPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-66 EVQLVQSGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-67 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-68 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-69 EVQLVESGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-70 EVQLVQSGGGLVQPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-71 EVQLVQSGGGLVHPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-72 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-73 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-74 EVQLVQSGGGLVHPGRSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-75 EVQLVQSGGGLVHPGGSLRLTCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-76 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMHWVRQAPGKGL EWVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-77 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGE. G. L EWVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTLVT VS S SCB-VH-78 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLEWVSGIGTGGATNYADSVKGRFTISRDEAKNSLYLQMNSLRAEDMAVYYC ARGRYYFD YWGQGTLVT VS SAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP SCB-VH-79 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAGDMA V YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-80 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFDDYAMFWVRQAPGKGL EWVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-81 EVQLVQSGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV Y YC ARGRYYFPWWGQGTL VT VS S SCB-VH-82 EVQLVESGGGLVHPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-83 EVQLVESGGGLVQPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-84 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-85 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-86 EVQLVQSGGGLVHPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-87 EVQLVQSGGGLVQPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-88 EVQLVESGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-89 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-90 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFPWWGQGTL VT VS S SCB-VH-91 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-92 EVQLVQSGGGLVHPGGSLRLSCAGSGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDMA V YYC ARGRYYFD YWGQGTL VT VS S SCB-VH-93 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNAMFWVRQAPGKGLE WVSGIGTGGATSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYC ARGRYYFPWWGQGTL VT VS S SCB-92- RNAMFHCDR1SCB-92- GIGTGGATSYADSVKGHCDR3Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP SCB-92- GRYYFDYHCDR3SCB-55- RASQSVSSSYLALCDR1SCB-55- GASSRATLCDR2SCB-55- QQYDHSAGWTLCDR3SCB-54- GASSRAPLCDR2SCB-44- QQYGSSPPWTLCDR3

[0639] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises light chain variable region (LCVR) and heavy chain variable region (HCVR) sequence pairs (LCVR / HCVR) selected from the group consisting of MEDI-l-VL / MEDI-l-VH through MEDI-42-VL / MEDI-42-VH.

[0640] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises a LCVR / HCVR sequence pair of MEDI-37GL-VL / MEDI-37GL-VH.

[0641] In certain embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises an HCVR comprising an HCDR1 sequence of MEDI-37GL-HCDR1, an HCDR2 sequence of MEDI-37GL-HCDR2, and an HCDR3 sequence of MEDL37GL-HCDR3, and an LCVR comprising an LCDR1 of MEDI-37GL-LCDR1, and LCDR2 of MEDI-37GL-LCDR2, and anLCDR3 of MEDI-37GL-LCDR3.

[0642] The antibodies recited below in Table 2 are described in more detail in U. S. 8,877,189, incorporated herein by reference in its entirety for all purposes.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP Table 2.Sequence ID SequenceMEDI-l-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWLD YWGKGTL VT VS S MEDI-l-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SLSANYVFGTGTKLTVL MEDI-2-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YNWGKGTL VT VS S MEDI-2-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SQPPNPLFGTGTKLTVL MEDI-3-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKLLKNPWGKGTL VT VS S MED 1-3 -VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWFG TPASNYVFGTGTKLTVL MEDI-4-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YNWGKGTL VT VS S MEDI-4-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT S SPPQPIFGTGTKLTVL MEDI-5-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YDWGKGTLVT VS S MEDI-5-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT S SPPQPIFGTGTKLTVL MEDI-6-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MEDI-6-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTYHPIFGTGTKLTVL MEDI-7-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWWQYWGKGTLVT VS S MEDI-7-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT S SPPQPIFGTGTKLTVL MEDI-8-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT AVYYC ARGKWWWQYWGKGTLVT VS SAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP MEDI-8-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTYHPIFGTGTKLTVL MEDI-9-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YNWGKGTL VT VS S MEDI-9-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTMYPLFGTGTKLTVL MEDI-10-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YDWGKGTLVT VS S MEDI-10-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STVLTPIFGTGTKLTVL MEDI-ll-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWF YDWGKGTLVT VS S MEDI-ll-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SPSMIPLFGTGTKLTVL MEDI-12-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWF YDWGKGTLVT VS S MEDI-12-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTMYPLFGTGTKLTVL MEDI-13-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YDWGKGTLVT VS S MEDI-13-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTLQPLFGTGTKLTVL MEDI-14-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YNWGKGTL VT VS S MEDI-14-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SPPTKPLFGTGTKLTVL MEDI-15-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWL YNWGKGTL VT VS S MEDI-15-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STHRHPLFGTGTKLTVL MEDI-16-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT AVYYC ARGKWWL YNWGKGTL VT VS SAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP MEDI-16-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTYHPIFGTGTKLTVL MEDI-17-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWWQHWGKGTLVT VS S MEDI-17-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SPVDRPIFGTGTKLTVL MEDI-18-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWWQHWGKGTLVT VS S MEDI-18-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTPMPVFGTGTKLTVL MEDI-19-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKWWWQHWGKGTLVT VS S MEDI-19-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STTYHPIFGTGTKLTVL MEDI-20-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MEDI-20-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STVWEWPFGTGTKLTVL MEDI-21-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSASYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MEDI-21-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEAVYFCGTWDT STVWEWPFGTGTKLTVL MEDI-22-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MEDI-22-VL QPVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYFCGTWDT STVWEWPFGTGTKLTVL MEDI-23-VH QVQLVQSGAEVRKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MED 1-23 -VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNNYVSWYQQLPGTAPKL LIYDNNKRPPGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STVWEWPFGTGTKLTVL MEDI-24-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQGLEWMGIINPRGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT AVYYC ARGKYWMYDWGKGTLVT VS SAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP MEDI-24-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYFCGTWDT STVWEWPFGTGTKLTVL MEDI-25-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPRGGSASYAQKFQGRVSMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWM YDWGKGTL VT VS S MEDI-25-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTTATLAITGLQTGDEADYYCGTWVT STVWEWPFGTGTKLTVL MEDI-26-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWM YDWGKGTL VT VS S MEDI-26-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYFCGTWDT STVWEWPFGTGTKLTVL MEDI-27-VH QVQLVQSGAEVRKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRPED T AVYYC ARGKYWMYDWGKGTQVT VS S MEDI-27-VL QSVLTQPPLVSAAPGQKVTISCSGGSSNIGNSYVSWYQRLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STVWEWPFGTGTKLTVL MEDI-28-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGNGTLVT VS S MEDI-28-VL LPVLTQPPSVSAAPGQKVTISCSGGSSSIGNSYVSWYQQLPGAAPKL LIYDNNKRPSGIPDRFSGFRSGTSATLAITGLQTGDEADYYCGTWDT SPVWEWPFGTGTKLTVL MEDI-29-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTRVT VS S MEDI-29-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SPVWEWPFGTGTKLTVL MEDI-30-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MEDI-30-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQRLPGAAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT STVWEWPFGTGTKLTVL MEDI-31-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTLVT VS S MEDI-31-VL QSVLTQPPSVSAAPGQKVTISCSGGSSSIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWAT SPVWEWPFGTGTKLTVL MEDI-32-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDT AVYYC ARGKYWMYDWGKGTLVT VS SAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP MEDI-32-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYFCGTWDT STAWEWPFGTGTKLTVL MEDI-33-VH QVQLVQSGAEEKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTL VT VS S MED 1-33 -VL QSALTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYFCGTWDT STVWEWPFGTGTKLTVL MEDI-34-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVSMTRDTSTSTVYMELSSLRSEDT AVY YC ARGKYWMYDWGKGTL VT VS S MEDI-34-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYFCGTWDT STVWEWPFGTGTKLTVL MEDI-35-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTL VT VS S MEDI-35-VL QSVLTQPPSVSAAPGQKVTISCSGGSSNIGNSYVSWYQQLPGTAPKL LIYDNNKRPSGIPDRFSGSKSGTSATLAITGLQTGDEADYYCGTWDT SPVWEWPFGTGTKLTVL MEDI-36-VH QVQLVQSGAEVKKPGASVKVSCKASGYAFTSYYMHWARQAPGQG LEWMGIINPSGGSASYAQKFQGRVTMTRDTSTSTVYMELSSLRSED T AVYYC ARGKYWMYDWGKGTL VT VS S MED 1-36- VL QSVLTQPPSVSAAPGQKVTISC...

Claims

Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP CLAIMSWhat is claimed is:

1. A method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof, comprising administering to the subject an anti -interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

2. A method for treating severe allergic fungal rhinosinusitis (AFRS) in a subject in need thereof, comprising administering to the subject an anti -interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

3. A method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof with Type 2 inflammation, comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP4. A method for treating allergic fungal rhinosinusitis (AFRS) not adequately controlled on background treatment in a subject in need thereof, comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

5. A method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof that remains symptomatic following sinonasal surgery, comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

6. A method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof, comprising administering to the subject an anti -interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively,wherein the anti-IL-4R antibody is administered to the subject at a dose of about 300 mg every two weeks (Q2W), andwherein the subject is an adult, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery,Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP thereby treating AFRS in the subject.

7. A method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof, comprising administering to the subject an anti -interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively,wherein the anti-IL-4R antibody is administered to the subject at a dose of about 200 mg every two weeks (Q2W), andwherein the subject is an adolescent or a child, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

8. A method for treating allergic fungal rhinosinusitis (AFRS) in a subject in need thereof, comprising administering to the subject an anti -interleukin-4 receptor (IL-4R) antibody, wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively,wherein the anti-IL-4R antibody is administered to the subject at a dose of about 300 mg every four weeks (Q4W), andwherein the subject is an adolescent or a child, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby treating AFRS in the subject.

9. The method of any one of the preceding claims, wherein the subject further has asthma, chronic rhinosinusitis, or a combination thereof.

10. The method of any one of claims 1-8, wherein the subject does not have asthma.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 11. The method of any one of the preceding claims, wherein the subject has undergone endoscopic nasal surgery for AFRS.

12. The method of any one of claims 4 or 9-11, wherein the background treatment comprises inhaled corticosteroid (ICS), oral corticosteroid (OCS) or a combination thereof.

13. The method of any one of the preceding claims, wherein the subject has one or more AFRS-associated parameter(s) selected from the group consisting of:IgE mediated inflammatory response to fungal hyphae;nasal polyposis;characteristic CT findings;eosinophilic mucin without fungal invasions; andpositive fungal stain of sinus content, or any combination thereof.

14. The method of claim 13, wherein the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content.

15. The method of claim 13 or 14, wherein the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

16. The method of any one of the preceding claims, wherein the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

17. The method of any one of the preceding claims, wherein the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

18. The method of any one of claims 1-17, wherein the anti-IL-4R antibody is administered to the subject as an initial dose followed by one or more secondary doses.

19. The method of claim 18, wherein the initial dose is about 200 mg to about 300 mg and the one or more secondary doses are each about 200 mg to about 300 mg.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 20. The method of claim 18, wherein the initial dose is about 300 mg and the one or more secondary doses are each about 300 mg.

21. The method of claim 18, wherein the initial dose is about 200 mg and the one or more secondary doses are each about 200 mg.

22. The method of claim 18, wherein the initial dose is about 600 mg and the one or more secondary doses are each about 300 mg.

23. The method of claim 18, wherein the initial dose is about 400 mg and the one or more secondary doses are each about 200 mg.

24. The method of any one of the claims 18-23, wherein the secondary doses are administered every other week (Q2W).

25. The method of any one of the claims 18-23, wherein the secondary doses are administered every four weeks (Q4W).

26. The method any one of the preceding claims, wherein one or more AFRS-associated param eter(s) are improved in the subject.

27. The method of claim 26, wherein one or more AFRS-associated parameter(s) include:IgE mediated inflammatory response to fungal hyphae;nasal polyposis;characteristic CT findings;eosinophilic mucin without fungal invasions;positive fungal stain, or any combination thereof.

28. The method of claim 27, wherein the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content.

29. The method of claim 27 or 28, wherein the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP30. The method of any one of claims 27-29, wherein the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

31. The method of any one of claims 27-30, wherein the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

32. The method of any one of the preceding claims, wherein the treatment reduces one or more of asthma, chronic rhinosinusitis with nasal polyposis, bone erosion, fungal cultures or any combination thereof.

33. The method of any one of the preceding claims, wherein the treatment reduces the level of one or more biomarkers in the subject selected from the group consisting of blood eosinophil (Eos) count, serum immunoglobulin E level (IgE), eotaxin level, periostin, and thymus and activation-regulated chemokine (TARC), IL-5, secreted P-glycoprotein, and combinations thereof.

34. The method of any one of the preceding claims, wherein the method comprises the step of determining the baseline level of a biomarker selected from the group consisting of TARC, eotaxin-3, FeNO (post-bronchodilator), total IgE, fibrinogen, and any mixture thereof in the subject.

35. A method of improving in a subject one or more symptoms selected from the group consisting of:IgE mediated inflammatory response to fungal hyphae;nasal polyposis;characteristic CT findings;eosinophilic mucin without fungal invasions;positive fungal stain; or any combination thereof,wherein the method comprises administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andAttorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP wherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby improving the one or more symptoms in the subject.

36. The method of claim 35, wherein the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content.

37. The method of claim 35 or 36, wherein the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

38. The method of any one of claims 35-37, wherein the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

39. The method of any one of claims 35-37, wherein the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

40. A method of improving health-related quality of life in a subject selected from the group consisting of:IgE mediated inflammatory response to fungal hyphae,nasal polyposis,characteristic CT findings,eosinophilic mucin without fungal invasions,positive fungal stain, or any combination thereof,wherein the method comprises administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody, andwherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby improving the health-related quality of life in the subject.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP41. The method of claim 40, wherein the subject has each of IgE mediated inflammatory response to fungal hyphae, nasal polyposis, characteristic CT findings, eosinophilic mucin without fungal invasions, and positive fungal stain of sinus content.

42. The method of claim 40 or 41, wherein the characteristic CT findings are hyperdensity, bony demineralization, bone erosion of sinus, or a combination thereof.

43. The method of any one of claims 35-42, wherein the subject has an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps.

44. The method of any one of claims 35-43, wherein the subject has a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps.

45. The method of any one of claims 35-44, wherein an improvement in Lund Mackay (LMK) score is achieved after treatment.

46. The method of any one of claims 35-45, wherein an improvement in one or more symptoms of AFRS is achieved after treatment, wherein the improvement is selected from the group consisting of: a reduction in nasal congestion; a reduction in number of nasal polyps; a decreased total symptom (TSS) score; an increased University of Pennsylvania Smell Identification Test (UPSIT) score; a decreased decreased / loss of sense of smell score; a decreased 22-item Sino Nasal Outcome Test (SNOT-22) score; a decreased total volume of sinus occupied by diseased tissue; a reduced need for systemic corticosteroid (SCS) treatment; and a decreased need for AFRS surgery.

47. The method of any one of claims 35-46, wherein the subject has comorbid asthma, and wherein an improvement in one or both of forced expiratory volume in 1 second (FEV1) score and Asthma Control Questionnaire (ACQ) score are achieved after treatment.

48. The method of any one of claims 35-47, wherein treatment reduces the need for rescue therapy with systemic corticosteroids (SCS) or surgery for AFRS.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 49. A method for reducing total volume of sinus occupied by diseased tissue in a subject having allergic fungal rhinosinusitis (AFRS) comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby reducing total volume of sinus occupied by disease in the subject.

50. The method of claim 49, wherein the treatment reduces bone erosion or reduces bone erosion risk in patients.

51. The method of claim 50, wherein bone erosion is measured by a radiologic staging system.

52. The method of claim 51, wherein the radiologic staging system comprises a CT scan.

53. A method for reducing bone erosion or reducing bone erosion risk in a subject having allergic fungal rhinosinusitis (AFRS) comprising administering to the subject an anti-interleukin-4 receptor (IL-4R) antibody,wherein the anti-IL-4R antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, andwherein the treatment results in one or more of: a reduction in sinus opacification; a reduction in patient-reported nasal congestion / obstruction; a reduction in nasal polyp size; a lowered risk of systemic corticosteroid use; and a lowered risk for endoscopic nasal surgery, thereby reducing bone erosion or reducing bone erosion risk in the subject.

54. The method of claim 53, wherein bone erosion is measured by a radiologic staging system.

55. The method of claim 54, wherein the radiologic staging system comprises a CT scan.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 56. The method of any one of the preceding claims, wherein the subject has one or more of the following:a baseline serum IgE of >500;an IgE mediated inflammatory response to fungal hyphae;nasal polyposis;hyperdensities, bony demineralization and / or bone erosion of sinus observed by computed tomography (CT);eosinophilic mucin / mucus identified with or without positive fungal stain;an endoscopic nasal polyps score (NPS) of >2 out of 4 for unilateral polyps or >3 out of 8 for bilateral polyps;a Lund Mackay (LMK) score of >9 with unilateral polyps or >12 with bilateral polyps; or a previous sinonasal surgery.

57. The method of any one of the preceding claims, wherein the subject receives a background therapy of intranasal corticosteroid (INCS) treatment.

58. The method of any one of the preceding claims, wherein the subject is at least 6 years old.

59. The method of any one of the preceding claims, wherein the anti-IL-4R antibody comprises a heavy chain variable region (HCVR) sequence comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence comprising the amino acid sequence of SEQ ID NO: 2.

60. The method of any one of the preceding claims, wherein the anti-IL-4R antibody comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 9 and a light chain sequence consisting of the amino acid sequence of SEQ ID NO: 10.

61. The method any one of the preceding claims, wherein the anti-IL-4R antibody is dupilumab.

62. The method of any one of the preceding claims, wherein the anti-IL-4R antibody is administered subcutaneously.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 63. The method of any of the preceding claims, wherein the anti-IL-4R antibody is administered using an autoinjector, a needle and syringe, or a pen.

64. The method any one of the preceding claims, wherein the anti-IL-4R antibody is administered using a prefilled device.

65. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 5 points at week 24 of treatment in sinus opacification score.

66. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 7 points at week 52 of treatment in sinus opacification score.

67. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 0.8 points at week 24 of treatment in patient reported nasal congestion / obstruction score.

68. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 1.4 points at week 52 of treatment in patient reported nasal congestion / obstruction score.

69. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.3 points at week 24 of treatment in patient reported nasal polyp size score.

70. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in a reduction from baseline of at least 2.7 points at week 52 of treatment in patient reported nasal polyp size score.

71. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least a 29% reduction of risk from baseline at week 52 of treatment of a need for endoscopic nasal surgery.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 72. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids.

73. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of undergoing or planning to under sinonasal surgery.

74. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline at week 52 of treatment of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery.

75. The method of any one of claims 1-64, wherein the subject achieves an improvement of at least 29% in risk that endoscopic nasal surgery is needed from baseline at week 52 of treatment.

76. The method of any one of claims 1-64, wherein the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids from baseline at week 52 of treatment.

77. The method of any one of claims 1-64, wherein the subject achieves an improvement of at least 90% in risk of undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

78. The method of any one of claims 1-64, wherein the subject achieves an improvement of at least 90% in risk of receiving systemic corticosteroids and / or undergoing or planning to under sinonasal surgery from baseline at week 52 of treatment.

79. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least an 80% lower risk from baseline of receiving systemic corticosteroids.

80. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least an 85% lower risk from baseline of receiving systemic corticosteroids.

81. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least a 90% lower risk from baseline of receiving systemic corticosteroids.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP82. The method of any one of claims 1-64, wherein treatment with the anti-IL-4R antibody results in at least a 95% lower risk from baseline of receiving systemic corticosteroids.

83. The method of any one of the preceding claims, wherein an improvement in Lund Mackay (LMK) score is achieved from baseline at week 52 of treatment in one or more of the osteomeatal complex, the maxillary sinus, the anterior ethmoid sinus, the posterior ethmoid sinus, the sphenoid sinus, and the frontal sinus.

84. The method of claim 83, wherein improvements are observed in all individual sinus areas and the osteomeatal complex at week 52 of treatment.

85. The method of any one of the previous claims, wherein the subject had previously undergone one sinonasal surgery prior to the treatment.

86. The method of any one of claims 1-84, wherein the subject had previously undergone two sinonasal surgeries prior to the treatment.

87. The method of any one of claims 1-84, wherein the subject had previously undergone more than two sinonasal surgeries prior to the treatment.

88. The method of any one of claims 85-87, wherein the subject remained symptomatic after the one, the two, or the more than two sinonasal surgeries but prior to the treatment.

89. The method of any one of claims 1-84, wherein the subject has a history of sinonasal surgery.

90. The method of claim 89, wherein the treatment reduces the proportion of subjects receiving systemic corticosteroids, undergoing sinonasal surgery, and / or having bone erosion in sinuses on CT scan compared to placebo after a 52-week treatment.

91. The method of claim 90, wherein the treatment reduces the risk of systemic corticosteroids use in the subject to about 3.0% after the 52-week treatment.Attorney Docket No. 774329: SA9-364PC Client Ref. No. PAT20247-WO1-NP 92. The method of claim 91, wherein the treatment reduces the risk of undergoing sinonasal surgery in the subject to about 0% after the 52-week treatment.

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