IL-13 antibody for treating perennial allergic rhinitis

Abstract

Provided herein are methods and uses of antibodies that specifically bind human IL-13 ("anti-IL-13 antibodies") for the treatment of perennial allergic rhinitis.

Description

[0001] sequence list

[0002] This application is submitted together with a sequence list in ST.26 XML format. This sequence list is provided as a file named “30944_WO_000Sequence Listing ST26”, created on December 11, 2024, and is 20 kilobytes in size. The sequence list information in ST.26 XML format is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to methods and uses of antibodies that specifically bind to human interleukin (IL)-13 (“anti-IL-13 antibody”) for the treatment of perennial allergic rhinitis (PAR). Background Technology

[0004] Perennial allergic rhinitis (PAR) is a type 2 inflammatory mediated disease (Giavina-Bianchi P et al., United airway disease: current perspectives. J Asthma Allergy. 2016;9:93-100). Studies using samples collected from patients with allergic rhinitis (AR) have shown that IL-13 levels in the nasal mucosa and nasal secretions increase after allergen provocation (Baumann, R. et al., The release of IL-31 and IL-13 after nasal allergen challenge and their relation to nasal symptoms. Clin Transl Allergy. 2012;2(1):13). Another study found that serum Th2 cytokine transcript levels, especially IL-13 and IL13RA1, were higher in AR patients than in non-allergic controls (Nur Husna SM et al., IL-4 / IL-13 axis inallergic rhinitis: elevated serum cytokines levels and inverse association with tight junction molecules expression. Front Mol Biosci. (2022); 9:819772).

[0005] Symptoms of PAR include nasal congestion, nasal itching, and sleep disturbances. Diagnosis is usually made based on characteristic symptoms of perennial allergic rhinitis, risk factors, and physical examination findings, and can be confirmed by a skin test for airborne allergen-specific IgE (Dykewicz, MS et al., Rhinitis 2020: a practice parameter update. J AllergyClin Immunol. (2020); 146(4):721-67).

[0006] The primary treatment option for PAR is intranasal corticosteroids (INCS), along with other options including antihistamines (oral and intranasal), mast cell stabilizers, leukotriene modifiers, and allergen immunotherapy (AIT) (Dykewicz et al., 2020). However, these therapies have limitations and may not adequately address the daily symptoms in some patients. Although INCSs are the most effective treatment option for most patients with allergic rhinitis, they often cause bothersome local side effects such as nosebleeds; there are concerns about potential growth inhibition when used in children; in addition, they can cause unpleasant aftertaste and throat irritation, all of which can affect patient preference and treatment adherence (Seidman, MD et al., Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg. (2015); 152(1 Supplement): S1-43; Mener, DJ et al., Topical intranasal corticosteroids and growth velocity in children: a meta-analysis. Int Forum Allergy Rhinol. (2015); 5(2):95-103; Meltzer, EO, Formulation considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. (2007); 98(1):12-21). Although AIT is a treatment option for patients with symptomatic refractory disease, it is not suitable for all patients, and the non-adherence rate has been reported to be as high as 90%, with most patients only adhering for one year, while the recommended course of treatment to achieve long-term efficacy is three to five years (Roberts, G. et al., EAACI guidelines on allergen immunotherapy: allergic rhinoconjunctivitis. Allergy. (2018); 73(4):765-98; Mao J et al., Cost of subcutaneous immunotherapy in a large insured population in the United States. Curr Med Res Opin. (2019); 35(2):351-8.).Despite the availability of treatment options, many patients with PAR still experience poor control with standard therapy, resulting in a significant residual economic burden (Hellings, PW et al., A common language to assess allergic rhinitis control: results from a survey conducted during EAACI 2013 Congress. Clin Transl Allergy. (2015); 5:36; Dykewicz et al., 2020).

[0007] There is still a need for effective alternative therapies for PAR. Furthermore, there is a need to provide treatment and dosing regimens that are more tolerable, convenient, and less risky for patients, thereby improving patient adherence and satisfaction. Summary of the Invention

[0008] This article provides a method and use of an anti-IL-13 antibody (i.e., an antibody that specifically binds to human IL-13) such as lebrikizumab or a pharmaceutical composition containing an anti-IL-13 antibody for the treatment of perennial allergic rhinitis.

[0009] In one aspect, this article provides a method for treating perennial allergic rhinitis in patients in need, the method comprising administering a therapeutically effective amount of anti-IL-13 antibody to the patient. In some embodiments, this article provides a method for treating perennial allergic rhinitis, the method comprising: selecting a patient suffering from perennial allergic rhinitis and administering a therapeutically effective amount of anti-IL-13 antibody to the patient.

[0010] On the other hand, this invention provides anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for the treatment of perennial allergic rhinitis. The invention also provides the use of anti-IL-13 antibodies in the preparation of medicaments for the treatment of perennial allergic rhinitis.

[0011] In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 11 and VL as shown in SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 13 and a light chain as shown in SEQ ID NO: 14. In some embodiments, the anti-IL-13 antibody is lerechizumab. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, and a human IgG sequence as shown in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, a human IgG sequence as shown in SEQ ID NO: 15, and a constant light chain sequence as shown in SEQ ID NO: 16.

[0012] In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient. In some embodiments, the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg. In some embodiments, the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks. In some embodiments, the patient further receives a 500 mg loading dose of the anti-IL-13 antibody. In some embodiments, the loading dose is administered to the patient once or twice. In some embodiments, the loading dose is administered to the patient at week 0 (baseline) and week 2. In some embodiments, the patient receives anti-IL-13 antibody treatment for approximately 16 weeks.

[0013] In some implementations, patients further receive maintenance therapy for approximately 40 weeks. In some implementations, during the maintenance period, patients receive a maintenance dose of 250 mg of anti-IL-13 antibody every 4 weeks. In some implementations, during the maintenance period, patients receive a maintenance dose of 250 mg of anti-IL-13 antibody every 8 weeks.

[0014] In some implementations, patients receive a loading dose of 500 mg anti-IL-13 antibody at week 0 (baseline) and week 2; followed by a 250 mg dose every two weeks for 16 weeks; and then a 250 mg maintenance dose every four weeks for 40 weeks.

[0015] In some embodiments, the methods and uses described herein also include determining a patient's Total Nasal Symptom Score (TNSS) before, during, and after treatment. In some embodiments, the methods and uses described herein also include determining a patient's Rhinoconjunctivitis Quality of Life Questionnaire Standardized Version (RQLQ(S)) score before, during, and after treatment. In some embodiments, the methods and uses described herein also include determining a patient's postnasal drip score before, during, and after treatment.

[0016] In some embodiments, the methods and uses described herein also include administration of an intranasal corticosteroid to a patient. In some embodiments, the intranasal corticosteroid is mometasone furoate. In some embodiments, the intranasal corticosteroid is administered concurrently, in parallel, or sequentially with an anti-IL-13 antibody.

[0017] In some implementations, the patient has a history of inadequate response to intranasal corticosteroids prior to treatment. In some implementations, the patient has moderate to severe nasal symptoms and a TNSS score ≥8 prior to treatment. In some implementations, the patient is 18 years of age or older. In some implementations, the patient is 12–18 years of age and weighs at least 40 kg. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the phase 3 study design described in Example 1. Abbreviations: TBSS = Total Nasal Symptom Score; CFBL = Change from Baseline; INCS = Intranasal Corticosteroid; Lebri = Leprizumab; PBO = Placebo; Q2W = Every 2 weeks; Q4W = Every 4 weeks; Q8W = Every 8 weeks. Detailed Implementation

[0019] This article provides a method and use of an anti-IL-13 antibody (e.g., lerechizumab) or a pharmaceutical composition containing an anti-IL-13 antibody (e.g., lerechizumab) for the treatment of perennial allergic rhinitis.

[0020] In one aspect, this article provides a method for treating perennial allergic rhinitis in patients in need, the method comprising administering a therapeutically effective amount of anti-IL-13 antibody to the patient. In some embodiments, this article provides a method for treating perennial allergic rhinitis, the method comprising: selecting a patient suffering from perennial allergic rhinitis and administering a therapeutically effective amount of anti-IL-13 antibody to the patient.

[0021] On the other hand, this invention provides anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for the treatment of perennial allergic rhinitis. The invention also provides the use of anti-IL-13 antibodies in the preparation of medicaments for the treatment of perennial allergic rhinitis.

[0022] In some embodiments, the methods and uses described herein also include determining a patient's Total Nasal Symptom Score (TNSS) before, during, and after treatment. In some embodiments, the methods and uses described herein also include determining a patient's Rhinoconjunctivitis Quality of Life Questionnaire Standardized Version (RQLQ(S)) score before, during, and after treatment. In some embodiments, the methods and uses described herein also include determining a patient's postnasal drip score before, during, and after treatment.

[0023] In some embodiments, the methods and uses described herein also include administration of an intranasal corticosteroid to a patient. In some embodiments, the intranasal corticosteroid is mometasone furoate. In some embodiments, the intranasal corticosteroid is administered simultaneously, concurrently, or sequentially with an anti-IL-13 antibody.

[0024] In some implementations, the patient has a history of inadequate response to intranasal corticosteroids prior to treatment. In some implementations, the patient has moderate to severe nasal symptoms and a TNSS score ≥8 prior to treatment. In some implementations, the patient is 18 years of age or older. In some implementations, the patient is 12–18 years of age and weighs at least 40 kg.

[0025] Anti-IL-13 antibodies suitable for the methods and uses provided herein have been previously described, for example, WO2005 / 062967. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO: 8. In some embodiments, the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 11 and VL as shown in SEQ ID NO: 12. In some embodiments, the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, and a human IgG sequence as shown in SEQ ID NO: 15. In some embodiments, the anti-IL-13 antibody comprises a VH sequence as shown in SEQ ID NO: 11, a VL sequence as shown in SEQ ID NO: 12, a human Fc region comprising a human IgG sequence as shown in SEQ ID NO: 15, and a constant light chain sequence as shown in SEQ ID NO: 16. In some embodiments, the anti-IL-13 antibody is lerechizumab (CAS No. 953400-68-5). Lerechizumab is a humanized monoclonal IgG4 antibody that specifically binds to IL-13 with high affinity and blocks signal transduction through an active IL-4Rα / IL-13Rα1 heterodimer. The amino acid sequence of lerechizumab is shown in Table 1. C-terminal clipping of the IgG antibody can occur when one or two C-terminal amino acids are removed from the heavy chain. For example, if a C-terminal lysine (K) is present, this amino acid may be truncated or shortened from the heavy chain. The penultimate glycine (G) may also be truncated or shortened from the heavy chain. Modifications to the N-terminal amino acids of IgG can also be made. For example, N-terminal glutamine (Q) or glutamate (E) can spontaneously cyclize to pyroglutamic acid (pE). SEQ ID NO: 9 reflects these potential modifications to the heavy chain of lerechizumab.Similarly, SEQ ID NO: 11, 13 and 15 reflect these potential modifications to the lerechizumab variant VH, lerechizumab variant HC and the human IgG1 Fc region, respectively.

[0026] Table 1. Anti-IL-13 antibody sequences

[0027] In some embodiments, the anti-IL-13 antibody is a lerechizumab variant containing the same HCDR and LCDR sequences as lerechizumab. In some embodiments, the anti-IL-13 antibody is a lerechizumab variant described in WO2023245187, such as constructs 133, 134, 136, and 141. In some embodiments, the anti-IL-13 antibody is APG777. The amino acid sequences of the lerechizumab variants are also shown in Table 1.

[0028] Other exemplary anti-IL-13 antibodies include, but are not limited to, IMA-026, IMA-638 (also known as anrukinzumab, QAX-576, CAS No. 910649-32-0), tralokinumab (also known as CAT-354, CAS No. 1044515-88-9), cendakimab (also known as CC-93538, RPC4046, ABT-308, CAS No. 2151032-62-9), AER-001, and ABT-308 (also known as humanized 13C5.5 antibody). Examples of such anti-IL-13 antibodies and other inhibitors of IL-13 are disclosed in WO2008 / 086395, WO2006 / 085938, US 7,615,213, US 7,501,121, US 7,935,343, US 7,829,090, US7,947,273, WO2007 / 036745, WO2010 / 073119, WO2007 / 045477, and WO 2014 / 165771. In some embodiments, the anti-IL-13 antibody is trorocalumab. In some embodiments, the anti-IL-13 antibody is cedazine.

[0029] Anti-IL-13 antibodies can be formulated with suitable carriers or excipients into pharmaceutical compositions suitable for administration to patients. For example, anti-IL-13 antibodies, such as lerechizumab, can be formulated in pharmaceutical compositions as described in WO 2013 / 066866. The pharmaceutical composition may contain 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-IL-13 antibody. In some embodiments, the pharmaceutical composition contains 250 mg to 500 mg of anti-IL-13 antibody. In some embodiments, the pharmaceutical composition contains 250 mg or 500 mg of anti-IL-13 antibody. In some embodiments, the concentration of anti-IL-13 antibody in the pharmaceutical composition is 100 mg / mL to 150 mg / mL, for example, 125 mg / mL. The pharmaceutical composition may also contain a buffer, such as 5 mM-40 mM histidine acetate buffer, pH 5.4 to 6.0. In some embodiments, the pharmaceutical composition further comprises a polyol (e.g., a sugar) at a concentration of 100 mM to 200 mM, and / or a surfactant (e.g., polysorbate 20) at a concentration of 0.01% to 0.1%. In one embodiment, the pharmaceutical composition comprises 125 mg / mL of an anti-IL-13 antibody (e.g., lerechizumab), 20 mM histidine acetate buffer (pH 5.7), 175 mM sucrose, and 0.03% polysorbate 20. In some embodiments, this document provides pharmaceutical compositions comprising an IL-13 inhibitor and a pharmaceutically acceptable carrier or excipient.

[0030] In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient. The anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody may be administered to the patient at a frequency of approximately once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every two weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every four weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every eight weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient every 8 weeks, every 12 weeks, every 24 weeks, every 36 weeks, or every 52 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered to the patient about every 8 weeks, about every 12 weeks, about every 24 weeks, about every 36 weeks, or about every 52 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 8 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 12 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 24 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 36 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg every 52 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 8 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 12 weeks. In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 24 weeks.In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 36 weeks. In some embodiments, the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 360 mg approximately every 52 weeks.

[0031] In some implementations, patients receive treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 16 weeks or longer. In some implementations, patients further receive maintenance therapy for approximately 40 weeks or longer. In some implementations, patients receive treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 54 weeks, 56 weeks, 58 weeks, or 60 weeks. In some implementations, patients receive treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 16 weeks. In some implementations, patients receive treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 40 weeks of maintenance. In some implementations, patients receive treatment with an anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody for approximately 56 weeks.

[0032] In some implementations, patients receive a loading dose of anti-IL-13 antibody, such as a 500 mg loading dose. The loading dose may be administered to the patient several times at the start of treatment. For example, a 500 mg loading dose of anti-IL-13 antibody may be administered at week 0 (baseline) and week 2. After the loading dose, the anti-IL-13 antibody may be administered to the patient at the following doses: 250 mg every two weeks, 250 mg every four weeks, and 250 mg every eight weeks.

[0033] In some implementations, patients receive a loading dose of 500 mg anti-IL-13 antibody at week 0 (baseline) and week 2; followed by a 250 mg dose every two weeks for 16 weeks; and then a 250 mg maintenance dose every four weeks for 40 weeks.

[0034] In some implementations, patients receive a loading dose of 500 mg anti-IL-13 antibody at week 0 (baseline) and week 2; followed by a 250 mg dose every two weeks for 16 weeks; and then a 250 mg maintenance dose every eight weeks for 40 weeks.

[0035] In some implementations, patients receive a loading dose of 720 mg anti-IL-13 antibody at weeks 0 and 2; followed by a 360 mg dose of anti-IL-13 antibody at weeks 4 and 12; and then a maintenance dose of 360 mg anti-IL-13 antibody every 12 weeks for 40 weeks.

[0036] In some implementations, patients receive a loading dose of 720 mg anti-IL-13 antibody at weeks 0 and 2; followed by a 360 mg dose of anti-IL-13 antibody at weeks 4 and 12; and then a maintenance dose of 360 mg anti-IL-13 antibody every 24 weeks for 40 weeks.

[0037] In some embodiments, anti-IL-13 antibodies or pharmaceutical compositions containing anti-IL-13 antibodies are administered to a patient using a subcutaneous administration device. The subcutaneous administration device may be selected from pre-filled syringes, disposable pen-type injection devices, microneedle devices, microinfusion devices, needle-free injection devices, or auto-injector devices. Various subcutaneous administration devices, including auto-injector devices, are known in the art and are commercially available. Exemplary devices include, but are not limited to, pre-filled syringes (e.g., BD HYPAK SCF® from Becton Dickinson, READYFILL). TM and STERIFILL SCF TM ;Clearshot from Baxter TM Copolymer prefilled syringes; and DaikyoSeiko CRYSTAL ZENITH® prefilled syringes available from West Pharmaceutical Services; disposable pen-type injection devices, such as the BD pen from Becton Dickinson; ultra-tipped and microneedle devices (e.g., the INJECT-EASE from Becton Dickinson). TM and micro-infusion devices; and H-PATCH purchased from Valeritas. TM This includes needle-free injection devices (e.g., BIOJECTOR® and IJECT® available from Bioject; and SOF-SERTER® and patch devices available from Medtronic). In some embodiments, the subcutaneous administration device is an autoinjector device described in WO 2008 / 112472, WO 2011 / 109205, WO 2014 / 062488, or WO 2016 / 089864.

[0038] Before, during, and after treatment, one or more characteristics of the patient can be assessed, identifying certain signs, symptoms, features, or parameters associated with perennial allergic rhinitis, and can be evaluated quantitatively or qualitatively. These characteristics include, but are not limited to, TNSS, RQLQ(S), postnasal drip score, VAS for allergic rhinitis control, NPIF, FEV1, TOSS, SNOT-22, ACQ-6, EQ-5D-5L, WPAI+CIQ:AS, PROMIS Short Form Anxiety Scale v1.0 - Anxiety Disorder 8a, PROMIS Short Form Depression Scale v1.0 - Depression 8a, PGI-S, and PGI-C.

[0039] The Total Nasal Symptom Score (TNSS) is a clinical outcome assessment used to measure the severity of four symptoms reported by subjects (Downie, SR et al., Symptoms of persistent allergic rhinitis during a full calendar year in house dust mite-sensitive subjects. Allergy. (2004); 59(4):406-14): nasal discharge (runny nose), nasal congestion (nasal obstruction), nasal itching (nasal itching), and sneezing. Subjects assessed the severity of each symptom daily (for the past 24 hours) using a 0-3 rating scale (0 = no symptoms, 3 = severe symptoms), and the results were recorded in an eDiary outside the research center. The individual scores for the four symptoms were then summed to obtain a total score from 0 to 12.

[0040] The subjective impact of PAR on participants' health-related quality of life could be assessed using the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)) (Juniper, EF et al., Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol. (1996); 98(4):843-5). The RQLQ(S) contains 28 items divided into 7 domains: nasal symptoms (4 items); ocular symptoms (4 items); activity limitation (3 items); sleep disturbances (3 items); non-nasal / ocular symptoms (7 items); practical problems (3 items); and emotional functioning (4 items). Participants were asked to recall experiences of impairment in health-related quality of life in the past week, answer each question using a 7-point scale (0 to 6), and record their answers using a tablet computer at the research center. The overall mean score of the RQLQ(S) was calculated, with a maximum severity score of 6. A change of at least 0.5 points in the total RQLQ(S) score is considered a minimally clinically significant change, while a change of at least 1.0 point is considered a moderately significant change (Juniper et al., 1996). The three-item sleep disorder domain of the RQLQ(S) is used to assess the degree of distress experienced by the subject over the past week due to nasal / ocular symptoms for each sleep problem. The RQLQ(S) sleep disorder domain consists of three items, directly copied from the corresponding RQLQ(S) items, asking about: difficulty falling asleep, nighttime awakenings, and failure to obtain good night's sleep. Consistent with RQLQ(S) responses, the options range from 0 (no distress) to 6 (extreme distress), and the scoring method is the same as that used for calculating the overall mean score.

[0041] Postnasal drip, referring to mucus flowing into the back of the throat, is a symptom of allergic rhinitis. It was assessed using a 4-point scale, with 0 points indicating no symptoms and 3 points indicating severe symptoms. Participants were asked to record the severity of their postnasal drip over the past 24 hours. This assessment was collected in the participants' eDiary.

[0042] The Visual Analogue Scale (VAS) for allergic rhinitis control can be assessed as follows. Allergic rhinitis control can be assessed using a 0-100 mm VAS scale containing a single item that assesses the degree of distress caused by allergic symptoms. The scale is anchored at both ends as “no distress” and “extreme distress” to answer the question: “How distressed have your allergic rhinitis symptoms been over the past 7 days?”. Well-controlled allergic rhinitis is defined as a VAS score ≤ 20 on the 0-100 mm scale (Bousquet, J. et al., MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis. J Allergy Clin Immunol. 2016 Aug.;138(2):367-374.e2).

[0043] Nasal peak inspiratory flow (NPIF) was measured as the maximum inspiratory flow rate through both nostrils during inspiration, expressed in L / min. Subjects with an NPIF result >120 L / min were considered to have no nasal obstruction (Mo, S et al., Nasal peak inspiratory flow in healthy and obstructed patients: systematic review and meta-analysis. Laryngoscope. (2021); 131(2):260-7). NPIF was performed at specified time points, and the highest of three readings was taken. NPIF measurements were performed by trained and qualified personnel.

[0044] Vital capacity measurement is used to measure the physiological airflow in forced expiratory volume in one second (FEV1). Normal FEV1 values ​​are typically ≥80% (Barriero, TJ, An approach to interpreting spirometry. Am FamPhysician. (2004); 69(5):1107-14). Lower FEV1 values ​​may indicate more severe asthma or airway restriction or obstruction from other causes. Only subjects with a history of asthma at study enrollment had their FEV1 measured during scheduled visits and at least 6 hours after discontinuation of the last dose of short-acting bronchodilator, using a study-provided spirometer conforming to the recommendations of the American Thoracic Society / European Respiratory Society. The percentage of predicted normal values ​​is based on the Global Lung Function Initiative (GLI) criteria (Quanjer, PH et al., Multi-ethnic reference values ​​for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. (2012); 40(6):1324-43). Vital capacity measurements should be performed by trained and qualified personnel according to the procedures specified in the research reference manual. At least three and at most eight maneuver spirometry measurements must be performed at each time point. Results are reviewed by a center reviewing physician who confirms the highest FEV1 and FVC values ​​at each time point. Where feasible, the research center should perform spirometry within ±1 hour of the baseline time point.

[0045] The TOSS (Total Ocular Symptom Scale) is a clinical outcome assessment tool used to measure the severity of two ocular symptoms reported by patients: itchy / red eyes and tearing. Subjects assessed the severity of each ocular symptom daily (for the past 24 hours) on an eDiary outside the research center using an integer rating scale of 0 to 3 (0 = asymptomatic, 3 = severe) (Pfaar, O. et al., Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI position paper. Allergy. (2014); 69(7):854-67). The individual scores for the two symptoms were then summed to obtain a total score from 0 to 6.

[0046] The Sinus and Nasal Outcome Test (SNOT-22) is a validated participant-reported questionnaire used to assess the impact of disease on health-related quality of life. The questionnaire contains 22 questions assessing sinus and ear function, psychological impact, work productivity, and sleep quality. Participants are asked to recall experiences from the past two weeks and rate their symptoms on a scale of 0 (no problem) to 5 (the most severe problem possible). Scores for each question are summed to obtain a total score, ranging from 0 (no disease) to 110 (the most severe disease). Lower scores indicate less impact. The review time window is the past two weeks. A change in score of 8.9 has been identified as the least clinically significant difference (Hopkins, C. et al., Psychometric validity of the 22-item Sinonasal Outcome Test. Clinical Otolaryngology. (2009); https: / / doi.org / 10.1111 / j.1749-4486.2009.01995.x.).

[0047] The Asthma Control Questionnaire-6 (ACQ-6) is a validated participant-reported questionnaire containing six questions to assess the most common asthma symptoms. Data is collected via tablet computer only from participants with asthma at research centers. Questions include: asthma arousal; symptoms upon waking; activity limitation; shortness of breath; wheezing; and use of inhalers / inhalers. Participants with a history of asthma are asked to recall their asthma control over the past week and answer questions using a 7-point scale, where 0 corresponds to no impairment and 6 corresponds to maximum impairment. The ACQ-6 score is calculated by averaging the scores of each question to arrive at a total control score (out of 6), where 0 corresponds to complete asthma control and 6 corresponds to severe asthma out of control. The minimum clinically significant difference in the ACQ-6 was defined as a change of 0.5 points (Juniper, EF et al., Development and validation of a questionnaire to measure asthma control. Eur Respir J. (1999); 14(4):902-7; Juniper, EF et al., Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. (2005); 99(5):553-8).

[0048] The European Five-Dimensional Quality of Life Scale (EQ-5D-5L) is a universal questionnaire for assessing health status, and data can be collected at research centers via tablet computers. The questionnaire contains a descriptive system consisting of five dimensions (mobility, self-care ability, daily activities, pain / discomfort, and anxiety / depression), with each dimension graded on a scale of five: no problem, minor problem, moderate problem, severe problem, and very severe problem. The questionnaire also includes a VAS scale, in which respondents self-assess their health status on the vertical VAS, with the two ends being “the best health status you can imagine” and “the worst health status you can imagine” (EuroQol Group. EuroQol - A new tool for measuring health-related quality of life. HealthPolicy. 1990; 16(3):199-208; Herdman, M. et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. (2011); 20(10):1727-36; Remenschneider, AK et al., The EQ-5D: a new tool for studying clinical outcomes in chronic rhinosinusitis. Laryngoscope. (2015); 125(1):7-15).

[0049] The Work Productivity and Activity Disorders Plus Classroom Disorders Questionnaire: Allergy-Specific Version (WPAI+CIQ:AS) is a patient-reported tool used to assess the degree of impairment in work, classroom, and daily activities for patients with allergic rhinitis (AR). Data can also be collected via tablet at research centers. The questionnaire contains nine items assessing the following: employment status; actual working hours; working hours missed due to allergies; the impact of allergies on productivity during work; attending classes in an academic environment; actual attendance / class time; time missed due to allergies; the impact of allergies on productivity in the classroom environment; and the impact of allergies on daily activities. WPAI+CIQ:AS yields four subgroup scores: absenteeism rate (time missed at work or in class); attendance rate (degree of impairment at work or in class / reduction in productivity during work); loss of work productivity (total work or classroom impairment / absenteeism rate plus attendance rate); and activity disorder. The score is calculated as the percentage of impairment (Reilly, MC, Zbrozek, AS, Dukes, EM. The validity and reproducibility of a workproductivity and activity impairment instrument. Pharmacoeconomics. (1993); 4(5):353-65). The higher the value, the greater the degree of impairment, the lower the productivity, and the worse the outcome.

[0050] The PROMIS Anxiety Short Scale v1.0 - Anxiety 8a can be used in the general population and individuals with chronic diseases. The PROMIS Anxiety Item Registry assesses self-reported fears (fear, panic), anxiety distress (worry, apprehension), hyperarousal (nervousness, nervousness, restlessness), and arousal-related physical symptoms (palpitations, dizziness). The PROMIS Anxiety Short Scale 8a (v1.0) contains 8 questions to assess the subject's symptoms over the past 7 days. Response options range from 1=Never; 2=Rarely; 3=Sometimes; 4=Often; 5=Always. The raw total score is converted to a T-score, with higher scores indicating greater anxiety severity (PROMIS Anxiety Scale 2019, published: March 1, 2019. Accessed: March 8, 2021. Access URL: https: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Anxiety_Scoring_Manual.pdf).

[0051] The PROMIS Depression Short Scale v1.0-Depression 8a can be used in the general population and individuals with chronic illnesses. The PROMIS Depression Scale assesses self-reported negative emotions (sadness, guilt), self-perceptions (self-criticism, feelings of worthlessness), and social cognitions (loneliness, social isolation), as well as decreased positive affect and engagement (loss of interest, meaning, and purpose). The PROMIS Depression Short Scale 8a (v1.0) contains eight questions to assess symptoms experienced by the subject over the past seven days. Response options range from 1=Never; 2=Rarely; 3=Sometimes; 4=Often; 5=Always. The raw total score is converted to a T-score, with higher scores indicating more severe depression (PROMIS Depression Scale 2019, published February 28, 2019. Accessed March 8, 2021. Access URL: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Depression_Scoring_Manual.pdf).

[0052] The Patient General Impression of Severity (PGI-S) scale and the Patient General Impression of Changes in Condition (PGI-C) scale are used to facilitate the assessment of clinically significant intra-patient changes in TNSS, postnasal drip, and RQLQ(S).

[0053] PGI-S: TNSS requires participants to assess the overall severity of nasal symptoms (nasal congestion, nasal itching, sneezing, runny nose) caused by AR in the past 14 days, with options for answering as: asymptomatic, mild, moderate, severe, and very severe.

[0054] PGI-S: Postnasal drip, which asks participants to assess the overall severity of postnasal drip caused by AR in the past 14 days. The answer options are: asymptomatic, mild, moderate, severe, and very severe.

[0055] PGI-S: The RQLQ(S) requires participants to assess the overall severity of activity limitations (home routine activities, work or school activities, social activities or outdoor activities) caused by AR in the past 7 days, with answer options as: asymptomatic, mild, moderate, severe, and very severe.

[0056] PGI-C: TNSS asks subjects to describe the overall change in their nasal symptoms (nasal congestion, nasal itching, sneezing, runny nose) caused by AR since they started taking the new medication. The answer options are: significant improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and significant worsening.

[0057] PGI-C: Postnasal drip. Subjects are asked to describe the overall change in their postnasal drip caused by AR since they started taking the new drug. The answer options are: significant improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and significant worsening.

[0058] PGI-C: RQLQ(S) asks subjects to describe the overall change in their activity limitation due to AR since they started taking the new drug. The answer options are: significant improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, and significant worsening.

[0059] These characteristics can be measured at baseline and at one or more time points after administration of the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody. For example, they can be measured at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer after initial treatment with the anti-IL-13 antibody or a pharmaceutical composition containing an anti-IL-13 antibody. The difference between the values ​​at specific time points after initial treatment and the baseline values ​​is used to determine whether the characteristic has improved (e.g., decreased).

[0060] On the other hand, this invention provides anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for the treatment of perennial allergic rhinitis. The invention also provides the use of anti-IL-13 antibodies in the preparation of medicaments for the treatment of perennial allergic rhinitis.

[0061] As used herein, unless otherwise stated herein or clearly contradicted by the context, the terms “a,” “an,” “the,” and similar terms used in the context of this disclosure (especially in the context of the claims) shall be construed as covering both the singular and the plural.

[0062] As used herein, the term “about” means within a reasonable range of the value, such as within ±10% of the value.

[0063] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Antibody implementations include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugated antibodies. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0064] An exemplary antibody is an immunoglobulin G (IgG) antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC), which are cross-linked by interchain disulfide bonds. Each of the four polypeptide chains has an amino-terminal region comprising a variable region of approximately 100-125 or more amino acids, primarily responsible for antigen recognition. Each of the four polypeptide chains also has a carboxyl-terminal region containing a constant region primarily responsible for effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further subdivided into subtypes (e.g., IgG1, IgG2, IgG3, and IgG4).

[0065] The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), which contain more conserved regions called framework regions (FRs). CDRs are exposed on the protein surface and are crucial regions for antibody antigen-binding specificity. Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this paper, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," while the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain most of the residues that specifically interact with the antigen. The assignment of amino acid residues in the CDR can be determined using well-known schemes, including those described below: Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Maryland (1991)); Chothia (Chothia et al., Canonical structures for the hypervariable regions of immunoglobulins, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., Standard conformations for the canonical structures of immunoglobulins, Journal of Molecular Biology, 273, 927-948 (1997)); North (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406, 228-256) (2011)); or IMGT (International Immunogenetic Database, accessed at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212).

[0066] Exemplary embodiments of the antibodies disclosed herein also include antibody fragments or antigen-binding fragments comprising at least a portion of an antibody that retains the ability to specifically interact with an antigen, such as Fab, Fab', F(ab')2, Fv fragments, scFv, scFab, disulfide-linked Fvs(sdFv), Fd fragments, and linear antibodies.

[0067] As used herein, the term "anti-IL-13 antibody" refers to an antibody that specifically binds to human IL-13. In some embodiments, the anti-IL-13 antibody binds to human IL-13 with a dissociation constant (KD) ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, or ≤ 0.01 nM (e.g., 10 nM). -8 M or smaller, or 10 -9 M or smaller).

[0068] As used herein, the term “baseline” means before or at the time of administration of the first dose of anti-IL-13 antibody or a pharmaceutical composition containing anti-IL-13 antibody (week 0).

[0069] Unless otherwise stated, the term "binding" and its grammatical variations as used herein refer to the ability of one protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, such interaction causing the two proteins or molecules to come close to each other (as determined by conventional methods known in the art).

[0070] The "effective amount" of a drug agent refers to the amount that, within the necessary dosage and time period, is sufficient to achieve the desired therapeutic effect.

[0071] Unless otherwise stated, the term “IL-13” as used herein refers to any interleukin-13 isoform derived from humans. This term includes “full-length”, unprocessed IL-13, and any form of IL-13 produced by cell processing. It also includes naturally occurring IL-13 variants, such as splice variants or allelic variants. Exemplary amino acid sequences of human IL-13 are known, for example, NCBI accessions NP_002179.2, NP_001341920.1, NP_001341921.1, NP_001341922.1; UniProtKB accession number P35225.

[0072] The term "loading dose" refers to the dose of medication given at the start of treatment that is higher than the doses given subsequently and at each subsequent dose during the remainder of treatment.

[0073] "Maintenance dose" refers to the subsequent dose of medication given to a patient in order to maintain or prolong the expected therapeutic effect.

[0074] As used in this article, the term "patient" refers to a human patient.

[0075] The term “perennial allergic rhinitis (PAR)” is well known in the art and is generally considered to be a type 2 inflammation-mediated disease (Giavina-Bianchi P et al., United airway disease: current perspectives. J.A.S. Allergy. (2016); 9:93-100). As used herein, PAR refers to the same or substantially the same disease or condition as known in the art as allergic rhinitis triggered by perennial allergens.

[0076] As used herein, “treatment” and its grammatical variations refer to all processes aimed at slowing, controlling, delaying, or stopping the progression of the symptoms or disease disclosed herein, or improving the symptoms or disease of the condition, but this does not necessarily mean the complete elimination of all symptoms or disease of the condition. Treatment includes the administration of proteins, nucleic acids, carriers, or compositions to treat a patient’s (particularly human) disease or condition.

[0077] Example

[0078] Example 1. A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluating the efficacy and safety of lerechizumab in adult subjects with perennial allergic rhinitis.

[0079] This is a phase 3, multinational, multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial designed to evaluate the efficacy and safety of lerechizumab in approximately 450 adult (>18 years) patients with perennial allergic rhinitis whose disease remains poorly controlled after standard treatment (intranasal corticosteroids (INCS), with or without oral antihistamines (OAH), nasal antihistamines (INAH), or combination eye drops with both antihistamine and / or mast cell stabilizing properties for the treatment of allergy symptoms).

[0080] This study has four phases: a screening period (maximum 30 days), an induction period (4 weeks), a randomized treatment period (56 weeks, including an induction period (16 weeks; week 0 to week 16) and a maintenance period (40 weeks; week 16 to week 56)), and a safety follow-up period (SFU, 8 weeks, starting after the week 56 visit). The longest planned duration of participation for each participant in this study is approximately 72 weeks.

[0081] Goals and endpoints: The primary, secondary, and exploratory objectives and endpoints of this study are shown in Table 2.

[0082] Table 2. Goals and Endpoints

[0083] patient group

[0084] The inclusion and exclusion criteria for subjects enrolled in this study are described in the following sections.

[0085] Inclusion criteria Each participant must meet all of the following criteria to be enrolled in this study: 1. Adult subjects must be ≥18 years old when signing the informed consent form (ICF).

[0086] 2. Patients must be diagnosed with PAR by a physician and require treatment for most days of the year to control persistent symptoms, with symptoms lasting more than 12 weeks per year for at least two consecutive years. Subjects must have a history of inadequate response to INCS, even with regular or continuous use (with or without background treatment), meaning they must have moderate to severe nasal symptoms at both the screening period (first visit) and randomization (third visit), with a TNSS score ≥8 (this score is the average of the scores within the two weeks prior to randomization [third visit], measured at least four days per week).

[0087] 3. During the screening period, subjects must have a positive skin prick test (SPT) for indoor allergens (wheal diameter at least 5 mm larger than the negative control), and / or a positive antigen-specific serum IgE test (≥0.70 kU / L) for indoor allergens (e.g., pets, mold, dust mites, cockroaches, horses) using a validated method (central laboratory); in addition, one of the following conditions must be met: a. Subjects must be allergic to at least one type of dust mite, or b. Subjects must be continuously exposed to at least one other (non-house dust mite) perennial allergen during the study period, and this allergen must have elicited a positive skin prick test and / or a positive antigen-specific serum IgE test. (Note: Subjects who are positive only for fungi are ineligible for inclusion), or c. Subjects must have clinical symptoms corresponding to a perennial allergen associated with a positive skin prick test (SPT) or antigen-specific serological test.

[0088] 4. Subjects with a known history of dermatographia, or those found to have the condition in a skin prick test (SPT) and with a positive serum IgE test result, may participate in this study.

[0089] 5. Subjects with comorbid asthma must have been on permitted routine asthma treatment and have stable conditions within 3 months prior to screening.

[0090] 6. For women of childbearing potential (WOCBP), the use of highly effective contraception should comply with local regulations regarding contraceptive methods for clinical study participants. Both women of childbearing potential (WOCBP) and women of childbearing potential (WNOCBP) are eligible to participate in this study.

[0091] 7. Participants must understand the nature of this study and sign a written informed consent form approved by the Institutional Ethics Committee (IEC) / Institutional Review Board (IRB) before undergoing any study-related procedures.

[0092] 8. Willing and able to comply with all clinical visits, research-related procedures and questionnaires, especially including receiving required background medications and completing the eDiary daily.

[0093] 9. Subjects must complete at least 4 out of 7 days of eDiary within 2 weeks prior to the randomized group visit (3rd visit [baseline]).

[0094] Exclusion criteria Participants meeting any of the following criteria will be excluded from this study: 1. Previously received Regizumab.

[0095] 2. Currently enrolling any other clinical studies involving the investigational drug, or any other type of medical research that is deemed scientifically or medically incompatible with this study.

[0096] 3. Individuals who received the study drug within 8 weeks prior to randomization or within 5 half-lives (whichever is longer).

[0097] 4. Individuals with known hypersensitivity to levothyroxine or any of its excipients.

[0098] 5. Patients with contraindications or intolerance to mometasone furoate or any background treatments used during the study.

[0099] 6. Individuals currently receiving allergen immunotherapy (subcutaneous immunotherapy or sublingual immunotherapy [SCIT / SLIT]).

[0100] However, patients who had discontinued SCIT / SLIT for ≥3 years prior to randomization and were not receiving maintenance AIT regimens were eligible for enrollment.

[0101] 7. Individuals who received any rescue medication during the screening and induction periods.

[0102] 8. Prior to baseline (3rd visit; randomization), the patient had received any biologics or systemic immunosuppressants for inflammatory or autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis), including the following: The patient has used B-cell depletion biologics, including rituximab, within the past 6 months.

[0103] Other biological agents have been used within 5 half-lives (if known) or 8 weeks (whichever is longer).

[0104] The patient had used systemic immunosuppressants within 4 weeks prior to the baseline period (3rd visit).

[0105] 9. Subjects with a history of seasonal allergic rhinitis exacerbations should be excluded if they are expected to experience seasonal exacerbations during any of the following periods: the induction period (4 weeks), the first 16 weeks after randomization (i.e., the induction period), or the last 4 weeks of the maintenance period (weeks 52 to 56).

[0106] 10. It is expected that their daily environmental exposure will change significantly over two consecutive weeks within the two weeks prior to week 16 or the four weeks prior to week 56.

[0107] 11. A known history of recurrent acute or chronic sinusitis, defined as requiring systemic antibiotic treatment within 3 months prior to screening, or requiring more than 4 sessions of systemic antibiotic treatment within 2 years prior to screening.

[0108] 12. Individuals with a known history of ≥2 severe asthma exacerbations within the past year, where a severe asthma exacerbation is defined as any asthma worsening requiring systemic corticosteroid therapy for at least 3 days and / or requiring hospitalization. A single parenteral administration of corticosteroids for an asthma worsening will also be considered a severe asthma exacerbation.

[0109] 13. Individuals with a history of nasal polyps or those with nasal polyps during the screening period (first visit).

[0110] 14. Individuals with moderate to severe nasal septum deviation.

[0111] 15. Those who have undergone any sinus / nasal surgery within 12 months prior to the screening period (first visit), or who plan to undergo surgery during the study period.

[0112] 16. Individuals with a known history of rhinitis secondary to other causes (e.g., drug-induced rhinitis, vasomotor rhinitis).

[0113] 17. Received any live or attenuated live vaccine (including BCG vaccination or treatment) within 4 weeks of the baseline period (3rd visit), or is scheduled to receive an attenuated live vaccine (or receive BCG treatment) during the study period and within 4 weeks of the last administration of the investigational drug (IP). Note: The following are not considered live vaccines: messenger RNA vaccines, vaccines containing inactivated virus components, and / or non-replicating viral vector vaccines.

[0114] 18. Individuals with a known history of HIV infection or who are HIV serologically positive.

[0115] 19. Currently, there is active or chronic infection with hepatitis B virus (HBV) (i.e., positive for hepatitis B surface antigen [HBsAg] and / or positive for polymerase chain reaction).

[0116] 20. Currently infected with hepatitis C virus (HCV) (HCV RNA positive).

[0117] 21. Known to have cirrhosis and / or chronic hepatitis of any cause.

[0118] 22. Be diagnosed with an active endoparasitic infection, or be at high risk of such an infection.

[0119] 23. A known or suspected history of immunosuppression, including a history of invasive opportunistic infections (such as tuberculosis [TB], histoplasmosis, listeriosis, coccidioidomycosis, Pneumocystis pneumonia, and aspergillosis), even if the infection has been cured; or, in the investigator's opinion, a history of unusually frequent, recurrent, or persistent infections.

[0120] 24. Any of the following types of infection occurred within 3 months of screening, or occurred during the screening or introduction period: a. Severe infection (requiring hospitalization and / or treatment with IV or equivalent oral antibiotics).

[0121] b. Opportunistic infections [as defined in Winthrop KL, Novosad SA, Baddley JW et al., Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 2015; 74(12):2107-16].

[0122] c. Individuals with symptomatic herpes zoster infection that has not yet healed during the screening period. Note: Herpes zoster is considered to be in an active and persistent state until all blisters have dried and crusted over.

[0123] d. Chronic (symptoms, signs, and / or treatment lasting 6 weeks or longer)

[0124] e. Recurrent (including but not limited to recurrent cellulitis, chronic osteomyelitis)

[0125] Subjects with only recurrent, mild, and uncomplicated oral herpes and / or genital herpes may be admitted with the discretion of the medical monitor.

[0126] 25. Subjects with an active or acute infection requiring systemic antibiotics, antiviral drugs, antiparasitic drugs, antiprotozoal drugs, or antifungal drugs within two weeks prior to baseline (third visit). Note: Subjects may be screened again after infection resolution. Subjects with vaginal or oral candidiasis who are receiving only symptomatic treatment and do not require systemic anti-infective medication may be considered for inclusion in the study, provided they meet other study inclusion criteria. Inclusion of subjects with other uncomplicated localized infections should be discussed with the sponsor-designated medical monitor.

[0127] 26. History of malignant tumors within 5 years prior to screening (first visit; exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has received adequate treatment, and cervical carcinoma in situ).

[0128] 27. Having any other medical or psychological condition that, in the researcher's opinion, may suggest the presence of a new and / or not yet fully understood disease, may pose an unreasonable risk to the participant's participation in this clinical study, may lead to unreliable participation, or may interfere with the study evaluation.

[0129] 28. Suffering from serious comorbidities that researchers believe would adversely affect participation in the study.

[0130] 29. Clinically significant laboratory test results were obtained from biochemical or hematological examinations performed during the screening period (first visit) or the baseline period (third visit), based on the researcher's judgment.

[0131] 30. Female subjects who are pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study.

[0132] 31. Has recently undergone nasal perforation that has not yet fully healed, may experience nasal symptoms during the screening period (first visit), or plans to undergo a new nasal perforation during the study period.

[0133] 32. Eli Lilly employees, family members of Eli Lilly employees, or any third-party organizations involved in this study.

[0134] Those whose employees need to be excluded.

[0135] 33. Those who are directly subordinate to the staff of this research center and their immediate family members, where immediate family members are defined as spouses, parents, children or siblings (whether biological or legally adopted).

[0136] 34. The subject or caregiver is unable or unwilling to remain engaged throughout the study, or is unwilling to comply with study restrictions and procedures (including subcutaneous administration of study drugs).

[0137] 35. Individuals with a history of chronic alcoholism, intravenous drug abuse, or other illicit drug abuse within the two years prior to screening.

[0138] 36. Based on the researcher's judgment, other aspects are unsuitable for inclusion in this study.

[0139] Research drugs:

[0140] The pharmaceutical composition containing 125 mg / mL lerechizumab or placebo is provided in the form of a sterile pre-filled syringe equipped with a pre-loaded needle safety device (PFS-NSD) for subcutaneous administration to patients. The lerechizumab sequence is provided in Table 1. The placebo solution is identical in appearance and volume to the active solution, except that it does not contain lerechizumab.

[0141] INCS mometasone furoate nasal spray is administered at a dose of 100 μg daily (2 sprays, 50 μg in each nostril).

[0142] Research Design: The research design of this experiment is as follows: Figure 1 As shown.

[0143] Subjects meeting the inclusion and exclusion criteria were randomly assigned to the following treatment groups in a 1:1:1 ratio via an interactive online response system at baseline (3rd visit) after the screening and induction periods: Lerechizumab Q2W / Q4W group: Lerechizumab 500 mg loading dose was administered at weeks 0 and 2, followed by 250 mg Q2W until week 16 (induction period), and then 250 mg Q4W until week 56 (maintenance period).

[0144] Lerechizumab Q2W / Q8W group: Lerechizumab 500 mg loading dose was administered at weeks 0 and 2, followed by 250 mg Q2W until week 16 (induction period), and then 250 mg Q8W until week 56 (maintenance period). To maintain blinding, subjects received placebo (PBO) every 8 weeks starting 4 weeks after week 16 administration.

[0145] PBO group: PBO Q2W to week 16 (induction period) and PBO Q4W to week 56 (maintenance period).

[0146] Random grouping is stratified based on the following factors: Allergic rhinitis classification (PAR, PAR + seasonal AR [defined as positive for both one perennial allergen and one seasonal allergen]). Allergic rhinitis classification is based on SPT and / or serum IgE results at study enrollment. PAR: Subjects sensitized to indoor allergens but not to seasonal allergens; PAR + seasonal AR: Subjects sensitized to indoor allergens and sensitized to at least one seasonal allergen; Regions (North America, Europe, and the rest of the world); and Baseline use of oral antihistamines (OAH) / intranasal antihistamines (INAH) (using INAH, using OAH but not INAH, not using OAH or INAH).

[0147] The treatment groups were completely blinded by the participants, researchers, and research center staff.

[0148] Intranasal mometasone furoate will be used as background therapy during the 4-week introduction period and throughout the randomized treatment period (weeks 0 to 56). Additional background therapy may be provided throughout the study, starting from the introduction period. During safety follow-up, investigators may decide at their discretion whether subjects can continue using background therapy (including mometasone furoate).

[0149] Statistical analysis was performed on primary, secondary, and exploratory endpoints.

Claims

1. A method of treating perennial allergic rhinitis in a patient in need, the method comprising administering to the patient a therapeutically effective amount of an anti-IL-13 antibody, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

2. A method for treating perennial allergic rhinitis, the method comprising: Patients with perennial allergic rhinitis were selected, and a therapeutically effective amount of anti-IL-13 antibody was administered to the patients, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and the VL comprises LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO:

6.

3. The method according to claim 1 or 2, wherein the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO:

8.

4. The method according to any one of claims 1-3, wherein the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO:9 and a light chain as shown in SEQ ID NO:

10.

5. The method according to any one of claims 1-4, wherein the anti-IL-13 antibody is lerechizumab.

6. The method according to any one of claims 1-5, wherein the anti-IL-13 antibody is administered subcutaneously to the patient.

7. The method according to any one of claims 1-6, wherein the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg.

8. The method according to any one of claims 1-7, wherein the anti-IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg every two weeks.

9. The method of claim 8, wherein the patient further receives a loading dose of the anti-IL-13 antibody of 500 mg.

10. The method of claim 9, wherein the loading dose is administered to the patient in week 0 and week 2.

11. The method according to any one of claims 1-10, wherein the patient receives treatment with the anti-IL-13 antibody for approximately 16 weeks.

12. The method according to any one of claims 1-11, wherein the patient further receives maintenance therapy for approximately 40 weeks.

13. The method of claim 12, wherein during the maintenance period, the patient receives a maintenance dose of 250 mg of anti-IL-13 antibody every 4 weeks.

14. The method of claim 12, wherein during the maintenance period, the patient receives a maintenance dose of 250 mg of anti-IL-13 antibody every 8 weeks.

15. The method according to any one of claims 1-14, further comprising determining the patient’s total nasal symptom score (TNSS) before, during and after the treatment.

16. The method according to any one of claims 1-14, further comprising determining the patient's standardized version of the RQLQ(S) score before, during and after the treatment.

17. The method according to any one of claims 1-14, further comprising determining the patient's postnasal drip score before, during and after the treatment.

18. The method according to any one of claims 1-17, wherein the anti-IL-13 antibody is administered to the patient using a subcutaneous administration device.

19. The method of claim 18, wherein the subcutaneous application device is selected from a pre-filled syringe, a disposable pen-type injection device, a microneedle device, a micro-infusion device, a needle-free injection device, or an auto-injector device.

20. The method according to any one of claims 1-19, further comprising administering an intranasal corticosteroid to the patient.

21. The method of claim 20, wherein the intranasal corticosteroid is mometasone furoate.

22. The method of claim 20 or 21, wherein the intranasal corticosteroid and the anti-IL-13 antibody are administered simultaneously, in parallel, or sequentially.

23. The method according to any one of claims 1-22, wherein the patient has a history of inadequate response to intranasal corticosteroids prior to treatment.

24. The method according to any one of claims 1-23, wherein the patient has moderate or severe nasal symptoms and a TNSS score ≥8 prior to the treatment.

25. The method according to any one of claims 1-24, wherein the patient is 18 years of age or older.

26. An anti-IL-13 antibody for treating perennial allergic rhinitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

27. A pharmaceutical composition comprising an anti-IL-13 antibody for treating perennial allergic rhinitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

28. Use of an anti-IL-13 antibody in the preparation of a medicament for treating perennial allergic rhinitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 as shown in SEQ ID NO: 1, HCDR2 as shown in SEQ ID NO: 2, and HCDR3 as shown in SEQ ID NO: 3; and the VL comprises LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO:

6.

29. An anti-IL-13 antibody for the use of claim 26, wherein the anti-IL-13 antibody comprises VH as shown in SEQ ID NO: 7 and VL as shown in SEQ ID NO:

8.

30. An anti-IL-13 antibody for the use of claim 26 or 29, wherein the anti-IL-13 antibody comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO:

10.

31. An anti-IL-13 antibody for use as described in claim 26, 29 or 30, wherein the anti-IL-13 antibody is lerechizumab.

32. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-31, wherein the anti-IL-13 antibody is administered subcutaneously to a patient.

33. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-32, wherein the anti-IL-13 antibody is administered at a dose of 250 mg to 500 mg.

34. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-33, wherein the anti-IL-13 antibody is administered subcutaneously at a dose of 250 mg every two weeks.

35. An anti-IL-13 antibody for use as claimed in any one of claims 34, wherein the anti-IL-13 antibody is further administered at a loading dose of 500 mg.

36. An anti-IL-13 antibody for use as claimed in claim 35, wherein the loading dose is administered at week 0 and week 2.

37. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-36, wherein the anti-IL-13 antibody is administered for a period of approximately 16 weeks.

38. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-37, wherein the anti-IL-13 antibody is further administered for a maintenance period of approximately 40 weeks.

39. An anti-IL-13 antibody for use as claimed in claim 38, wherein the anti-IL-13 antibody is administered at a dose of 250 mg of the anti-IL-13 antibody every 4 weeks during the maintenance period.

40. An anti-IL-13 antibody for use as claimed in claim 38, wherein the anti-IL-13 antibody is administered at a dose of 250 mg of the anti-IL-13 antibody every 8 weeks during the maintenance period.

41. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-40, further comprising determining the total nasal symptom score (TNSS) of the patient before, during and after treatment.

42. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-41, further comprising determining the patient’s RQLQ(S) score before, during and after treatment.

43. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-41, further comprising determining the postnasal drip score of the patient before, during and after treatment.

44. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-43, wherein the anti-IL-13 antibody is administered using a subcutaneous administration device.

45. An anti-IL-13 antibody for the use of claim 44, wherein the subcutaneous administration device is selected from a prefilled syringe, a disposable pen injection device, a microneedle device, a microinfusion device, a needle-free injection device, or an auto-injector device.

46. ​​An anti-IL-13 antibody for use as described in any one of claims 26 or 29-45, further comprising administration of an intranasal corticosteroid.

47. An anti-IL-13 antibody for use as claimed in any one of claims 46, wherein the intranasal corticosteroid is mometasone furoate.

48. An anti-IL-13 antibody for use as claimed in claim 46 or 47, wherein the intranasal corticosteroid and the anti-IL-13 antibody are administered simultaneously, in parallel, or sequentially.

49. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-48, wherein the patient has a history of inadequate response to intranasal corticosteroids prior to treatment.

50. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-49, wherein the patient has moderate or severe nasal symptoms and a TNSS score ≥8 prior to the treatment.

51. An anti-IL-13 antibody for use as described in any one of claims 26 or 29-50, wherein the patient is 18 years of age or older.

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