Use of anti-IL-5 antibodies to treat diseases associated with elevated eosinophils

Abstract

The present disclosure relates to the use of anti-IL-5 antibodies to treat diseases associated with elevated eosinophils. In particular to a method and medical application of an anti-IL-5 antibody for treating diseases related to eosinophilic granulocyte elevation, wherein the diseases related to eosinophilic granulocyte elevation are asthma, eosinophilic granulocyte type asthma or eosinophilic polyvasculitis (EGPA).

Description

[0001] The present disclosure claims the priority of CN202311509636.4 and CN202410834652.9, and the entire contents of the foregoing patents are incorporated into the present disclosure by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to the medical use of anti-IL-5 antibodies in treating diseases associated with elevated eosinophils. Background Art

[0003] Interleukin-5 (IL-5) is an important member of the interleukin family. It is also known as T cell replacing factor (TRF), B cell growth factor-II (BCGF-II), IgA-enhancing factor (IgA-EF), and eosinophil differentiation factor (EDF). It is a homodimeric glycoprotein mainly secreted by helper T cells 2 (Th2). Human IL-5 consists of 134 amino acid residues, including a signal peptide consisting of 22 amino acids and 2 glycosylation sites. Active IL-5 is in the form of oligodimers, with two peptide chains connected by disulfide bonds and existing in an antiparallel configuration, while the monomer of IL-5 has no biological activity (Adv Immunol. 1994; 57: 145-90).

[0004] Eosinophils (EOS) are associated with a variety of inflammatory diseases of the lungs, including allergic diseases associated with allergic reactions. Studies have shown that the use of anti-IL-5 antibodies to inhibit the binding of IL-5 to its receptor can significantly reduce the accumulation of eosinophils in the lungs, reduce the level of eosinophils in the blood, tissues, and sputum, and reduce the inflammatory response mediated by eosinophils, improve lung function, and have a good therapeutic effect on severe eosinophilic asthma and recurrent asthma (Drugs. 2017 May; 77 (7): 777-784).

[0005] Mepolizumab is a humanized IgG1κ-type IL-5 monoclonal antibody developed by Glaxosmithkline GSK. It was approved by the U.S. FDA on November 4, 2015 as an additional maintenance therapy for patients with eosinophilic severe asthma aged 12 years and above. In September 2019, the indication population was expanded to pediatric patients aged ≥6 years; the European Union EMA approved it for marketing on December 2, 2015 as an additional maintenance therapy for patients with eosinophilic severe asthma aged 18 years and above; and in October 2018, the applicable population was expanded to people aged 6 years and above. In July 2020, the CDE accepted GSK's application for Nucala's marketing, and on November 17, 2021, it was approved by the China National Medical Products Administration (NMPA) for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). However, Mepolizumab needs to be administered to subjects once every 4 weeks. Therefore, developing new treatment options for IL-5-mediated diseases with low dosing frequency, good therapeutic effects, and higher safety is an important issue that needs to be addressed in this field. Summary of the invention

[0006] In one aspect, the present disclosure provides a method or use for treating an IL-5-mediated disease, comprising administering an anti-IL-5 antibody to a subject in need thereof.

[0007] In some embodiments, the IL-5 mediated disease is a disease associated with elevated eosinophils, for example, Eosinophilic Granulomatosis with Polyangiitis (EGPA), eosinophilic asthma, and hypereosinophilic syndrome.

[0008] In some embodiments, the IL-5 mediated disease is asthma, for example, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma, subeosinophilic asthma, bronchial asthma.

[0009] In some specific embodiments, the subject has eosinophilic asthma.

[0010] In some specific embodiments, the subject suffers from severe asthma, for example, severe eosinophilic asthma.

[0011] In some embodiments, the subject has an absolute blood eosinophil (Eos) count of ≥ 0.15 × 10 9 / L. Specifically, the subject's blood eosinophil (Eos) absolute count is ≥ 0.15×10 9 / L. In some specific embodiments, the subject suffers from asthma, and the subject's blood eosinophil (Eos) absolute count is ≥0.15×10 9 / L.

[0012] In some embodiments, the administration frequency of the anti-IL-5 antibody in the present disclosure is less than or equal to once every 8 weeks. The anti-IL-5 antibody in the present disclosure has a low administration frequency, which can improve patient compliance and provide an economical and efficient treatment plan for IL-5-mediated diseases.

[0013] In some specific embodiments, the anti-IL-5 antibody is administered less than or equal to once in 8 weeks, once in 10 weeks, once in 12 weeks, once in 13 weeks, once in 16 weeks, once in 17 weeks, once in 18 weeks, once in 20 weeks, once in 22 weeks, once in 24 weeks, once in 26 weeks, once in 28 weeks, or once in 30 weeks.

[0014] In some specific embodiments, the administration frequency of the anti-IL-5 antibody is selected from about once in 10 weeks, about once in 12 weeks, about once in 14 weeks, about once in 16 weeks, about once in 18 weeks, about once in 20 weeks, about once in 22 weeks, about once in 24 weeks, about once in 26 weeks, about once in 28 weeks, or about once in 30 weeks.

[0015] In some specific embodiments, the anti-IL-5 antibody is administered about once every 12 weeks, or about once every 24 weeks.

[0016] In some embodiments, the dosage of the anti-IL-5 antibody of the present disclosure is selected from 10-1000 mg, 100-800 mg, 200-800 mg, 150-800 mg, 350-650 mg, 150-400 mg or 400-600 mg.

[0017] In some specific embodiments, the dosage of the anti-IL-5 antibody is selected from about 20 mg, about 23 mg, about 50 mg, about 75 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 220 mg, about 230 mg. g, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg , about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, About 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, or about 890 mg.

[0018] In some specific embodiments, the anti-IL-5 antibody is administered at a dose selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg or about 800 mg.

[0019] In some embodiments, the present disclosure provides a method or use for treating asthma, comprising administering an anti-IL-5 antibody to a subject. The frequency of administration of the anti-IL-5 antibody is less than or equal to once every 8 weeks, and the dosage of the anti-IL-5 antibody is 10-1000 mg. In some specific embodiments, the administration regimen of the anti-IL-5 antibody is selected from any one of the following:

[0020] (1) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 10 weeks.

[0021] (2) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 12 weeks or about once every 3 months.

[0022] (3) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 16 weeks or about once every 4 months.

[0023] (4) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 18 weeks.

[0024] (5) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 20 weeks or about once every 5 months.

[0025] (6) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 22 weeks.

[0026] (7) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 24 weeks or about once every 6 months.

[0027] (8) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 28 weeks or about once every 7 months.

[0028] (9) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 32 weeks or about once every 8 months.

[0029] (10) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 12 weeks or about once every 3 months. In addition, within 20 weeks after the first administration (for example, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, etc.), the single injection dosage is about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg of the anti-IL-5 antibody.

[0030] (11) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 24 weeks or about once every 6 months. In addition, within 20 weeks after the first administration (for example, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, etc.), the single injection dosage is about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg of the anti-IL-5 antibody.

[0031] (12) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 24 weeks or about once every 6 months. In addition, 12 weeks after the first administration, the single injection dosage is about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg of the anti-IL-5 antibody.

[0032] In some embodiments, the present disclosure provides a method or use for treating asthma, comprising administering an anti-IL-5 antibody to a subject, wherein the frequency of administration of the anti-IL-5 antibody is selected from about once every 12 weeks, about once every 24 weeks, or about once every 26 weeks, and the dosage of the anti-IL-5 antibody is selected from 400 mg or 600 mg.

[0033] In some embodiments, the present disclosure provides a method or use for treating asthma, comprising administering an anti-IL-5 antibody to a subject. Wherein, the frequency of administration of the anti-IL-5 antibody is selected from about once every 12 weeks, about once every 24 weeks, or about once every 26 weeks, and the dosage of the anti-IL-5 antibody is selected from 400 mg or 600 mg. And, at about 12 weeks after the first administration, a single injection of 400 mg or 600 mg of the anti-IL-5 antibody is administered.

[0034] In some embodiments, the present disclosure provides a method or use for treating eosinophilic asthma patients, comprising administering an anti-IL-5 antibody to a subject. The frequency of administration of the anti-IL-5 antibody is less than or equal to once every 8 weeks, and the dosage of the anti-IL-5 antibody is 10-1000 mg. In some specific embodiments, the dosage regimen of the anti-IL-5 antibody is selected from any one of the above (1)-(12).

[0035] In some embodiments, the present disclosure provides a method or use for treating eosinophilic asthma, comprising administering an anti-IL-5 antibody to a subject, wherein the frequency of administration of the anti-IL-5 antibody is selected from about once every 12 weeks, about once every 24 weeks, or about once every 26 weeks, and the dosage of the anti-IL-5 antibody is selected from 400 mg or 600 mg.

[0036] In some embodiments, the present disclosure provides a method or use for treating eosinophilic asthma, comprising administering an anti-IL-5 antibody to a subject. Wherein, the frequency of administration of the anti-IL-5 antibody is selected from about once every 12 weeks, about once every 24 weeks, or about once every 26 weeks, and the dosage of the anti-IL-5 antibody is selected from 400 mg or 600 mg. And, at about 12 weeks after the first administration, a single injection of 400 mg or 600 mg of anti-IL-5 antibody is administered.

[0037] In some embodiments, the anti-IL-5 antibody reduces the blood eosinophil (Eos) level of subjects with diseases associated with elevated eosinophils (e.g., eosinophilic asthma). In some specific embodiments, the anti-IL-5 antibody reduces the blood Eos level by more than 80% compared to the baseline. In some specific embodiments, the anti-IL-5 antibody reduces the blood Eos level by more than 80% compared to the baseline and maintains ≥100 days (e.g., 105, 108, 110, 113, 120, 130, 150, 160, 165, 169, 170 days, etc.).

[0038] In some embodiments, the anti-IL-5 antibody reduces acute asthma attacks in subjects with asthma or eosinophilic asthma. In some specific embodiments, the anti-IL-5 antibody reduces the rate of moderate to severe acute asthma attacks by ≤0.4, such as 0.4, 0.36, 0.35, 0.32, 0.3, 0.28, 0.25, 0.22, 0.2, 0.18, 0.15, etc. In some specific embodiments, the anti-IL-5 antibody reduces the rate of severe acute asthma attacks by ≤0.4, ≤0.3, or ≤0.2. For example, 0.15, 0.18, 0.2, 0.22, 0.25, 0.28, 0.3, 0.35, 0.4, etc.

[0039] In some embodiments, the present disclosure provides methods or uses for treating eosinophilic granulomatosis with polyangiitis (EGPA). In some embodiments, EGPA is selected from relapsed EGPA or refractory EGPA.

[0040] In some embodiments, the method or use for treating EGPA comprises administering an anti-IL-5 antibody to a subject. The frequency of administration of the anti-IL-5 antibody is less than or equal to once every 8 weeks, and the dosage of the anti-IL-5 antibody is 10-1000 mg. In some specific embodiments, the administration regimen of the anti-IL-5 antibody is selected from any one of the above (1)-(9).

[0041] In some embodiments, the method or use for treating EGPA comprises administering an anti-IL-5 antibody to a subject, wherein the frequency of administration of the anti-IL-5 antibody is selected from about once every 12 weeks, about once every 24 weeks, or about once every 26 weeks, and the dosage of the anti-IL-5 antibody is selected from 400 mg or 600 mg.

[0042] In the context of the present disclosure, recurrent EGPA is defined as: the subject must have at least one confirmed history of EGPA relapse in the past 2 years (requiring an increase in OCS dosage to ≥7.5 mg / d, or an increase in immunosuppressant dosage, or new immunosuppressant treatment), and the most recent relapse was at least 12 weeks or more before screening.

[0043] In the context of the present disclosure, refractory EGPA is defined as: failure to achieve EGPA remission with an induction regimen containing OCS for at least 3 months within 6 months prior to screening; or the onset of EGPA symptoms during OCS reduction (dose ≥ 7.5 mg / d).

[0044] As used in this disclosure, OCS is also known as "Oral corticosteroids".

[0045] In some embodiments, the OCS is selected from prednisone, prednisolone, or an equivalent hormone.

[0046] In some embodiments, the method provided by the present disclosure reduces or maintains the absolute blood eosinophil count of the subject. In some specific embodiments, compared with the screening period or baseline, the subject has a reduced or maintained absolute blood eosinophil count after receiving treatment with an anti-IL-5 antibody. In some specific embodiments, compared with the screening period or baseline, the subject has a reduced absolute blood eosinophil count after receiving treatment with an anti-IL-5 antibody. In some specific embodiments, at least 1, 2, 3, 4, 5, 8, 10, 12, 15, 18, 20, 22, 24, 26, 28, 30, 32, 36, 40 or 50 weeks after a single administration of the anti-IL-5 antibody, the blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% compared to the baseline before treatment. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 20 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 22 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 24 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 26 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 30 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 34 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to pre-treatment baseline for at least 40 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0047] In some embodiments, the subject suffers from asthma, and the subject has improvement in at least one of the following indicators after administration of the anti-IL-5 antibody: forced expiratory volume in one second (FEV1), FEV1% of predicted value, forced vital capacity (FVC), peak expiratory flow (PEF), exhaled nitric oxide (FeNO), Asthma Control Questionnaire (ACQ-6) score, Asthma Quality of Life Questionnaire (AQLQ) score, and any change from baseline in the foregoing.

[0048] In some embodiments, the subject suffers from eosinophilic asthma, and the subject has improvement in at least one of the following parameters after administration of the anti-IL-5 antibody:

[0049] 1) Absolute blood eosinophil (Eos) count and its change from baseline; 2) Lung function FEV1, FEV1% predicted, FVC and PEF and their changes from baseline, FeNO and its change from baseline at each evaluation time point; 3) Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores; 4) Annualised Asthma Exacerbation Rate (AAER) was used to evaluate acute asthma exacerbations, which was defined as the total frequency of acute asthma exacerbations × 365.25 / total follow-up time (days) after the start of treatment.

[0050] In some embodiments, the subject suffers from EGPA, and the method provided by the present disclosure increases or maintains the reduction in the subject's oral glucocorticoid (OCS, prednisone / prednisolone or equivalent hormone) dosage compared to baseline. In some embodiments, the method increases the reduction in the oral glucocorticoid (OCS, prednisone / prednisolone or equivalent hormone) dosage compared to baseline.

[0051] In some embodiments, the subject suffers from EGPA, and the methods provided herein increase the reduction in OCS dosage from baseline, or reduce the dosage of oral glucocorticoid (OCS) in a subject suffering from EGPA.

[0052] In some implementation schemes, subjects are required to receive a stable dose of OCS (≥7.5 mg / d and ≤50 mg / d) from 4 weeks before randomization to the 2nd week after randomization; starting from the 2nd week, if the subject's BVAS=0, the OCS dose can be gradually reduced according to the hormone reduction plan recommended by the protocol; if BVAS≠0, the researcher can gradually reduce the OCS dose based on clinical judgment.

[0053] In some embodiments, the subject with EGPA is treated with the anti-IL-5 antibody at week 12 and has:

[0054] (1) The reduction in OCS usage compared to the baseline is ≥40%, or ≥45%; illustratively, the reduction in OCS usage compared to the baseline is 40%, 41%, 42%, 43%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 55%, 60%, etc.

[0055] and / or,

[0056] (2) The proportion of subjects whose OCS dosage reaches ≤5 mg / d is ≥40%, or is ≥45%; illustratively, the proportion of subjects whose OCS dosage reaches ≤5 mg / d is 40%, 42%, 43%, 44%, 45%, 46%, 48%, 50%, 52%, 53%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 65%, 66%, 68%, etc.

[0057] In some embodiments, the subject suffers from EGPA, and the methods provided herein increase the proportion of subjects who achieve EULAR remission of EGPA after administration of an anti-IL-5 antibody.

[0058] In some embodiments, EULAR remission is defined as a BVAS score of 0 and an OCS (prednisone / prednisolone or equivalent hormone) dose ≤ 7.5 mg / d; if a subject achieves EULAR remission, BVAS = 1 at a subsequent visit and there is no need to increase the OCS dose to > 7.5 mg / d, or to add other clinical interventions, the subject is considered to be in sustained remission of EGPA.

[0059] In some embodiments, at week 12 after subjects with EGPA are treated with anti-IL-5 antibodies, the proportion of subjects achieving EULAR remission is ≥50%, ≥55%, ≥60% or ≥65%; exemplarily, the proportion of subjects achieving EULAR remission is 50%, 51%, 52%, 52%, 53%, 55%, 56%, 58%, 60%, 61%, 62%, 63%, 65%, 67%, 68%, 69%, 70%, 72%, 75%, 76%, 78%, etc.

[0060] In some embodiments, the subject suffers from EGPA, and the methods provided herein reduce the proportion of subjects experiencing (severe) relapse of EGPA after administration of an anti-IL-5 antibody, and / or delay the time to first (severe) relapse.

[0061] In some embodiments, EGPA relapse is defined as new onset, recurrence, or worsening of clinical symptoms (BVAS>0) after EGPA remission, and the need to increase the existing OCS dosage to >7.5 mg / d or increase the immunosuppressant dosage or add new immunosuppressant treatment.

[0062] In some embodiments, severe EGPA relapse is defined as meeting the criteria for relapse and BVAS ≥ 6 (involving at least 2 organ systems in addition to general symptoms [myalgia, arthralgia / arthritis, fever > 38°C or weight loss > 2 kg]) or life-threatening. The time of relapse is defined as the time of increasing the dose of OCS or immunosuppressant, or adding new immunosuppressant therapy (whichever occurs first).

[0063] In some embodiments, the subject suffers from EGPA, and the methods provided herein increase the proportion of subjects whose EGPA is in remission after administration of an anti-IL-5 antibody.

[0064] In some embodiments, EGPA remission is defined as a BVAS score of 0 and an OCS (prednisone / prednisolone or equivalent hormone) dose of ≤4 mg / d. If a subject achieves EGPA remission, BVAS=1 at a subsequent visit and does not require an increase in OCS dose to >4 mg / d, or additional clinical interventions, then the subject is considered to be in sustained EGPA remission.

[0065] In some embodiments, the Birmingham Vasculitis Activity Score (BVAS) of a subject with EGPA is reduced by 3 points or more, 3.5 points or more, or 4 points or more compared to baseline at week 12 after receiving anti-IL-5 antibody treatment. Exemplarily, BVAS is reduced by 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0 points compared to baseline.

[0066] In some embodiments, the subject suffers from EGPA, and the subject has improvement in at least one of the following parameters after administration of the anti-IL-5 antibody:

[0067] 1) The reduction in the dosage of oral corticosteroids (OCS, prednisone / prednisolone or equivalent hormones) at 12 and 24 weeks of treatment compared with baseline increased; 2) The proportion of subjects with OCS dosage ≤5mg / d at 12 and 24 weeks of treatment increased; 3) The proportion of subjects with OCS dosage reduction of more than 50% at 12 and 24 weeks of treatment compared with baseline increased; 4) The proportion of subjects achieving EULAR remission of EGPA at 12 and 24 weeks of treatment increased; 5) The proportion of subjects achieving EULAR remission of EGPA at 12 weeks of treatment and lasting to 24 weeks increased; 6) The proportion of subjects with EGPA relapse at 12 and 24 weeks of treatment decreased; 7) The time to first relapse of EGPA was delayed; 8) The proportion of subjects with severe relapse of EGPA at 12 and 24 weeks of treatment decreased; 9) The time to first severe relapse of EGPA was delayed.

[0068] In some embodiments, the subject suffers from EGPA, and the subject has improvement in at least one of the following parameters after administration of the anti-IL-5 antibody:

[0069] 1) The reduction in OCS dosage compared with baseline at 24 and 48 weeks of treatment increased; 2) The proportion of subjects with OCS dosage ≤5mg / d at 24 and 48 weeks of treatment increased; 3) The proportion of subjects with OCS dosage reduction of more than 50% at 24 and 48 weeks of treatment compared with baseline increased; 4) The cumulative number of weeks of EGPA remission after 48 weeks of treatment, which was classified as 0 weeks; >0 weeks to <12 weeks; 12 weeks to <24 weeks; 24 weeks to <36 weeks or ≥36 weeks; 5) The proportion of subjects with EGPA relapse at 24 and 48 weeks of treatment increased; 6) The time to first relapse of EGPA was delayed; 7) The proportion of subjects with severe relapse of EGPA at 24 and 48 weeks of treatment increased; 8) The time to first severe relapse of EGPA was delayed; 9) The proportion of subjects with EGPA remission after 24 weeks of treatment and lasting to 48 weeks increased.

[0070] In some embodiments, the subject has EGPA, and the subject has an improvement in at least one of the following indicators after administration of the anti-IL-5 antibody: forced expiratory volume in one second (FEV1), FEV1% predicted, forced vital capacity (FVC), peak expiratory flow (PEF), exhaled nitric oxide (FeNO), asthma control questionnaire (ACQ-6) score, sinonasal outcome test (SNOT-22) score, serum immunoglobulin E (IgE), Mingham vasculitis activity score (BVAS), vasculitis damage index (VDI), asthma quality of life questionnaire (AQLQ) score, and any change from baseline in the foregoing.

[0071] In another aspect, the present disclosure provides a method or use of reducing the absolute eosinophil count in a subject, comprising administering an anti-IL-5 antibody to a subject in need thereof.

[0072] In some embodiments, the subject suffers from a disease associated with elevated eosinophils. In some specific embodiments, the subject has an absolute blood eosinophil (Eos) count of ≥0.15×10 9 / L.

[0073] In some embodiments, "reducing" eosinophils refers to a decrease in the amount of eosinophils observed in the blood and / or sputum of a patient following administration of at least one anti-IL-5 antibody.

[0074] In some embodiments, the subject suffers from asthma, for example, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, uncontrolled eosinophilic asthma, eosinophilic asthma, subeosinophilic asthma, bronchial asthma.

[0075] In some specific embodiments, the subject has eosinophilic asthma.

[0076] In some specific embodiments, the subject suffers from severe asthma, for example, severe eosinophilic asthma.

[0077] In some embodiments, the present disclosure provides a method for reducing the absolute eosinophil count in a subject, comprising: a) identifying that the subject suffers from asthma; b) administering an anti-IL-5 antibody to the subject. In some specific embodiments, the subject has an absolute blood eosinophil (Eos) count of ≥0.15×10 9 / L.

[0078] In some embodiments, the present disclosure provides a method for reducing the absolute eosinophil count in a subject, comprising: a) measuring the absolute blood eosinophil count in the subject for a first time; b) after administering a therapeutically effective amount of an anti-IL-5 antibody to the subject, measuring the absolute blood eosinophil count in the subject for a second time; c) comparing the first measurement and the second measurement to determine the effectiveness of the treatment. In some specific embodiments, the subject has an absolute blood eosinophil (Eos) count of ≥0.15×10 before receiving treatment (e.g., screening period and / or baseline). 9 / L.

[0079] In some embodiments, the anti-IL-5 antibody is administered less than or equal to once every 8 weeks. For example, the anti-IL-5 antibody is administered less than or equal to once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 13 weeks, once every 16 weeks, once every 17 weeks, once every 18 weeks, once every 20 weeks, once every 22 weeks, once every 24 weeks, once every 26 weeks, once every 28 weeks, or once every 30 weeks.

[0080] In some specific embodiments, the administration frequency of the anti-IL-5 antibody is selected from about once in 10 weeks, about once in 12 weeks, about once in 14 weeks, about once in 16 weeks, about once in 18 weeks, about once in 20 weeks, about once in 22 weeks, about once in 24 weeks, about once in 26 weeks, about once in 28 weeks, or about once in 30 weeks.

[0081] In some specific embodiments, the anti-IL-5 antibody is administered about once every 12 weeks, or about once every 24 weeks.

[0082] In some embodiments, the dosage of the anti-IL-5 antibody of the present disclosure is selected from 10-1000 mg, 100-800 mg, 200-800 mg, 150-800 mg, 350-650 mg or 400-600 mg. For example, selected from about 20 mg, about 23 mg, about 50 mg, about 75 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg 0mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg g, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, or about 890 mg.

[0083] In some specific embodiments, the anti-IL-5 antibody is administered at a dose selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg or about 800 mg.

[0084] In some specific embodiments, the administration regimen of the anti-IL-5 antibody is selected from any one of the following:

[0085] (1) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 10 weeks.

[0086] (2) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 12 weeks or about once every 3 months.

[0087] (3) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 16 weeks or about once every 4 months.

[0088] (4) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 18 weeks.

[0089] (5) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 20 weeks or about once every 5 months.

[0090] (6) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg, or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 22 weeks.

[0091] (7) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 24 weeks or about once every 6 months.

[0092] (8) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg, or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 28 weeks or about once every 7 months.

[0093] (9) The dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg. The frequency of administration of the anti-IL-5 antibody is about once every 32 weeks or about once every 8 months.

[0094] In some specific embodiments, the blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% compared to the pre-treatment baseline for at least 1, 2, 3, 4, 5, 8, 10, 12, 15, 18, 20, 22, 24, 26, 28, 30, 32, 36, 40 or 50 weeks after a single administration of the anti-IL-5 antibody. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline for at least 20 weeks after a single administration of the anti-IL-5 antibody to the subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 22 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 24 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the pre-treatment baseline in at least 26 weeks after a single administration of an anti-IL-5 antibody to a subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the baseline before treatment in at least 30 weeks after a single administration of the anti-IL-5 antibody to the subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the baseline before treatment in at least 34 weeks after a single administration of the anti-IL-5 antibody to the subject. In some specific embodiments, the absolute blood eosinophil count is reduced by more than 50%, 55%, 60%, 65%, 70%, 75% or 80% compared to the baseline before treatment in at least 40 weeks after a single administration of the anti-IL-5 antibody to the subject.

[0095] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 400 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline for at least 20 weeks after a single administration of the anti-IL-5 antibody to the subject.

[0096] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 400 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline in the 22 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0097] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 400 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline in the 24 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0098] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 400 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline in the 26 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0099] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 600 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline for at least 22 weeks after a single administration of the anti-IL-5 antibody to the subject.

[0100] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 600 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline in the 24 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0101] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 600 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline in the 26 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0102] In some specific embodiments, the dose of the anti-IL-5 antibody that binds to IL-5 administered to the subject is 600 mg, and the absolute blood eosinophil count is reduced by at least 70%, 75% or 80% compared to the pre-treatment baseline in the 30 weeks following a single administration of the anti-IL-5 antibody to the subject.

[0103] Anti-IL-5 antibody

[0104] In some embodiments, the anti-IL-5 antibody administered in any of the methods or uses provided by the present disclosure has a half-life of more than 80 days, supporting long-term administration. For example, in different dose groups of 150, 300, and 400 mg, the elimination half-life (t 1 / 2 ) ranges from 86 to 100 days.

[0105] In some embodiments, the anti-IL-5 antibody administered in any of the methods or uses provided herein has a peak concentration time (T max ) median was 24.5 days. In some embodiments, the anti-IL-5 antibody administered in any of the methods of treatment or use disclosed herein has a T of 75, 150, 300 and 400 mg. max In some embodiments, the anti-IL-5 antibody administered in any method of treatment or use of the present disclosure is administered at a peak concentration (C max ) were 2.36, 11.1, 19.4, 40.7 and 57.0 μg / mL, respectively.

[0106] In some embodiments, the anti-IL-5 antibody is any type of anti-IL-5 antibody disclosed in WO2019062831 and WO2020200099. The present disclosure incorporates the antibody sequences, preparation methods, compositions and other related contents in the above patents into the present disclosure by reference.

[0107] In some embodiments, the anti-IL-5 antibody comprises any one, any two, any three, any four, any five or six CDRs selected from HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO: 1 to SEQ ID NO: 6.

[0108] In some embodiments, the anti-IL-5 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively; and / or the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively.

[0109] The aforementioned CDR sequences are shown in the following table:

[0110] Table 1. Antibody CDR sequences

[0111] Antibody h1705-008 HCDR1 HYYMA (SEQ ID NO:1) HCDR2 SISYEGDITYYGDSVKG (SEQ ID NO:2) HCDR3 QTLRESFDY (SEQ ID NO:3) LCDR1 RASQDIANYLS (SEQ ID NO:4) LCDR2 GTSNLEV (SEQ ID NO:5) LCDR3 LQDKEFPRT (SEQ ID NO:6)

[0112] The CDRs are defined according to the Kabat numbering system.

[0113] In some embodiments, the anti-IL-5 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, HCDR3, respectively, as shown in SEQ ID NO: 7, and the light chain variable region comprises LCDR1, LCDR2, LCDR3, respectively, as shown in SEQ ID NO: 8. The CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact numbering systems.

[0114] In some embodiments, the anti-IL-5 antibody is a humanized antibody. In some specific embodiments, the VH of the anti-IL-5 antibody comprises the amino acid sequence shown in SEQ ID NO: 7, or an amino acid sequence having at least 80%, 90% sequence identity thereto; and the VL comprises the amino acid sequence shown in SEQ ID NO: 8, or an amino acid sequence having at least 80%, 90% sequence identity thereto.

[0115] Heavy chain variable region VH (SEQ ID NO: 7):

[0116] EVQLVESGGGLVQPGGSLRLSCAASGFTFS HYYMA WVRQAPGKGLEWVT SISYEGDITYYGDSVKG RFTISRDNSKNTLYLQMNSLRAEDTATYYCAS QTLRESFDY WGQGTLVTVSS

[0117] Heavy chain variable region VL (SEQ ID NO: 8):

[0118] DIQMTQSPSSVSASVGDRVTITC RASQDIANYLS WYQQKPGKSPKLLIY GTS NLEV GVPSRFSGSRSGTDFTLTISSLQPEDFATYYC LQDKEFPRT FGGGTKVEIK

[0119] Note: The underlined part is the CDR region defined according to the Kabat numbering system.

[0120] In some embodiments, the anti-IL-5 antibody is a humanized antibody comprising any one or two of the above-mentioned VH and VL.

[0121] In some embodiments, the anti-IL-5 antibody further comprises an antibody constant region; for example, the heavy chain constant region of the antibody constant region is selected from human IgG1, IgG2, IgG3 and IgG4 constant regions and variants thereof; the light chain constant region of the antibody constant region is selected from human antibody κ and λ chain constant regions and variants thereof.

[0122] The above light chain variable region and light chain constant region sequences are combined to form a light chain sequence, and each heavy chain variable region and heavy chain constant region are combined to form a heavy chain sequence. An exemplary humanized antibody constant region sequence is shown below:

[0123] >Heavy chain IgG1 constant region:

[0124] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP

[0125] AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

[0126] CPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYV

[0127] DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP

[0128] IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQ

[0129] PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ

[0130] KSLSLSPGK

[0131] SEQ ID NO: 11

[0132] >Light chain kappa constant region:

[0133] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE

[0134] SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0135] SEQ ID NO: 12

[0136] In some embodiments, the anti-IL-5 antibody comprises a heavy chain and a light chain, wherein the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:9, or at least 80%, 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:10, or at least 80%, 90% identical thereto.

[0137] Antibody heavy chain (SEQ ID NO:9):

[0138]

[0139] Antibody light chain (SEQ ID NO: 10):

[0140]

[0141] Note: The underlined part is the CDR region defined according to the Kabat numbering system, and the slanted part shows the constant region of the antibody heavy chain and the antibody light chain.

[0142] In some embodiments, the anti-IL-5 antibody comprises any one or two of the aforementioned heavy chains and light chains.

[0143] In the context of the present disclosure, "at least 80%" and "at least 90%" encompass 80% and above, for example at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range therebetween.

[0144] In some embodiments, the anti-IL-5 antibody is administered orally, parenterally, or transdermally; the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-IL-5 antibody is administered by subcutaneous injection.

[0145] In some embodiments, the anti-IL-5 antibody is configured in an injectable form. Exemplarily, the injectable form of the anti-IL-5 antibody is an injection solution or a lyophilized powder injection, which comprises the anti-IL-5 antibody and one or more pharmaceutically acceptable excipients.

[0146] In some embodiments, the pharmaceutical composition comprising an anti-IL-5 antibody further comprises a buffer, a stabilizer and / or a surfactant. Exemplarily, the buffer is selected from any one of acetic acid-sodium acetate, succinic acid-sodium succinate, histidine-hydrochloride and citric acid-sodium citrate buffer. In some specific embodiments, the buffer is acetic acid-sodium acetate or succinic acid-sodium succinate buffer. In some embodiments, the pH of the buffer is preferably 5.0 to 6.5. Exemplarily, the surfactant can be selected from polysorbate 20, polysorbate 80, polyhydroxyalkylene, Triton, sodium dodecyl sulfate, sodium lauryl sulfate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, In some specific embodiments, the surfactant is polysorbate 80 or polysorbate 20. Exemplarily, the stabilizer is selected from sugar or amino acid; wherein the sugar can be selected from sucrose, trehalose, mannitol or sorbitol, preferably sucrose. The amino acid is selected from glycine, methionine and proline. WO2020200099A relates to a composition of anti-IL-5 antibodies, and WO2020200099A is incorporated into the present disclosure by reference in its entirety.

[0147] In some embodiments, in the pharmaceutical composition, the concentration of the buffer is about 10 mM to about 40 mM, or about 20 mM to about 30 mM.

[0148] In some embodiments, the anti-IL-5 antibody concentration is about 1 mg / ml to about 120 mg / ml. In some specific embodiments, the anti-IL-5 antibody concentration is about 80 mg / ml to about 120 mg / ml. In some specific embodiments, the anti-IL-5 antibody concentration is about 100 mg / ml.

[0149] In some embodiments, the surfactant is polysorbate 80. In some embodiments, the concentration of polysorbate 80 is about 0.1 mg / ml to about 0.6 mg / ml, about 0.2 mg / ml to about 0.6 mg / ml, or about 0.4 mg / ml. In some embodiments, the stabilizer is a sugar or an amino acid. In some embodiments, the concentration of the sugar is about 50 mg / ml to about 80 mg / ml, about 70 mg / ml to about 75 mg / ml, or about 72 mg / ml. In some embodiments, the concentration of the amino acid is about 8 mg / ml. Exemplarily, the sugar is selected from sucrose, trehalose, mannitol and sorbitol, preferably sucrose; the amino acid is selected from glycine, methionine and proline.

[0150] In some embodiments, the pharmaceutical composition comprises the following ingredients:

[0151] about 1 mg / ml to about 120 mg / ml of an anti-IL-5 antibody; about 10 mM to about 40 mM acetic acid-sodium acetate buffer, pH about 5.0 to about 6.5; and about 0.1 mg / ml to about 0.6 mg / ml polysorbate 80.

[0152] or,

[0153] About 80 mg / ml to about 120 mg / ml of an anti-IL-5 antibody; about 10 mM to about 30 mM acetic acid-sodium acetate buffer, pH about 5.0 to about 5.8; about 0.2 mg / ml to about 0.6 mg / ml polysorbate 80 and about 70 mg / ml to about 80 mg / ml sucrose.

[0154] or,

[0155] About 100 mg / ml of anti-IL-5 antibody, about 30 mM acetic acid-sodium acetate buffer, pH about 5.5, about 0.4 mg / ml of polysorbate 80 and about 72 mg / ml of sucrose.

[0156] In some embodiments, the anti-IL-5 antibody injection administered to the subject in the present disclosure comprises: about 100 mg / ml of anti-IL-5 antibody, about 30 mM acetic acid-sodium acetate buffer, pH of about 5.5, about 0.4 mg / ml of polysorbate 80 and about 72 mg / ml of sucrose. In some embodiments, the injection is a reconstituted solution obtained by reconstituting the liquid preparation comprising the aforementioned components after lyophilization.

[0157] The anti-IL-5 antibody disclosed in the present invention can effectively reduce the number of eosinophils, relieve inflammatory reactions, and is used to treat eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and other related diseases. In addition, compared with existing treatments, the anti-IL-5 antibody has a significantly reduced frequency of administration, which can reduce the burden on patients, improve drug compliance, and has controllable safety.

[0158] the term

[0159] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure belongs.

[0160] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including, but not limited to,".

[0161] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0162] "About" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by a person of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" may mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially including" may mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each case in which a number or numerical range is preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially including" should be assumed to be within an acceptable error range for that specific value.

[0163] The term "and / or", such as "X and / or Y" should be understood to mean "X and Y" or "X or Y" and should be used to provide clear support for both meanings or either meaning.

[0164] As used herein, the term "asthma" means an inflammatory disease of the airways characterized by reversible airflow obstruction and bronchospasm. Common symptoms include wheezing, coughing, chest tightness and shortness of breath. Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by a history of respiratory symptoms, such as wheezing, shortness of breath, chest tightness and coughing, which vary in time and intensity, and variable expiratory airflow limitation.

[0165] In the methods of the present disclosure, "asthma" can be "mild asthma", "moderate asthma" or "severe asthma". Exemplarily, asthma severity can be evaluated according to the Global Initiative for Asthma (GINA) guidelines. In particular, asthma severity can be retrospectively evaluated from the level of treatment required to control symptoms and acute attacks. For example, once a patient has been receiving controller treatment for several months, they can be evaluated and, if appropriate, attempts to slow treatment to find the patient's lowest effective treatment level. Asthma severity is not a static characteristic, but may change after months or years.

[0166] In some embodiments, the present disclosure defines:

[0167] "Severe acute attack": at least one of the following two conditions must be met: 1) the use of systemic glucocorticoids or the increase in the dose of systemic glucocorticoids for maintenance therapy for ≥ 3 days; 2) asthma attacks that require emergency or hospitalization or lead to death while using systemic glucocorticoids. In addition, other evidence supporting acute asthma attacks must be provided, including but not limited to worsening asthma symptoms or lung function, or increased frequency of use of relief medications.

[0168] Moderate exacerbation: A change in treatment is required to prevent an asthma exacerbation from progressing to a severe exacerbation; one or more of the following events occur simultaneously, including worsening asthma symptoms or lung function, or increased frequency of reliever medication use lasting two or more days, but is usually not severe enough to require treatment with systemic corticosteroids.

[0169] The start time of acute asthma exacerbation was defined as the date of initiation of systemic glucocorticoid treatment or increase in stable dose (severe) or the first day of treatment change (moderate) or the date of emergency department visit or hospitalization (whichever occurred first); the end time of acute asthma exacerbation was defined as the last day of systemic glucocorticoid treatment or increase in stable dose (severe) or the last day of treatment change (moderate) or the date of discharge (whichever occurred later). If the interval between acute asthma exacerbations (last end time to current start time) was ≤7 days, it was considered a recurrence of the previous acute asthma exacerbation rather than a new acute exacerbation.

[0170] In the methods of the present disclosure, "asthma" includes but is not limited to "mild eosinophilic asthma", "moderate eosinophilic asthma" or "severe eosinophilic asthma".

[0171] "Mild eosinophilic asthma" is mild asthma with an eosinophilic type. Exemplarily, a subject with mild eosinophilic asthma can have mild asthma and the following blood eosinophils: greater than or equal to 150 eosinophils per μL of blood in the past 12 months, greater than or equal to 200 eosinophils per μL of blood in the past 12 months, greater than or equal to 300 eosinophils per μL of blood in the past 12 months, or greater than or equal to 350 eosinophils per μL of blood in the past 12 months.

[0172] "Moderate eosinophilic asthma" is moderate asthma with an eosinophilic phenotype. Exemplarily, a subject with moderate eosinophilic asthma can have moderate asthma and the following blood eosinophils: greater than or equal to 150 eosinophils per μL of blood in the past 12 months, greater than or equal to 200 eosinophils per μL of blood in the past 12 months, greater than or equal to 300 eosinophils per μL of blood in the past 12 months, or greater than or equal to 350 eosinophils per μL of blood in the past 12 months.

[0173] "Severe eosinophilic asthma" is severe asthma with an eosinophilic type. Exemplarily, a subject with severe eosinophilic asthma can have severe asthma and the following blood eosinophils: greater than or equal to 150 eosinophils per μL of blood in the past 12 months, greater than or equal to 200 eosinophils per μL of blood in the past 12 months, greater than or equal to 300 eosinophils per μL of blood in the past 12 months (preferred), or greater than or equal to 350 eosinophils per μL of blood in the past 12 months.

[0174] As used herein, the term "eosinophilic granulomatosis with polyangiitis" (EGPA) means an autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in people with a history of allergic hypersensitivity (atopy) of the airways. EGPA may also be referred to as Churg-Strauss syndrome (CSS) or allergic granulomas. EGPA typically presents in three stages. The early (prodromal) stage is characterized by airway inflammation; almost all patients experience asthma and / or allergic rhinitis. The second stage is characterized by abnormally high eosinophil counts (hypereosinophilic syndrome), which causes tissue damage, most commonly to the lungs and digestive tract. The third stage is vasculitis, which can ultimately lead to cell death and can be life-threatening.

[0175] Subjects with EGPA may meet one or more of the following criteria: a) asthma; b) blood eosinophil levels greater than 10% of the white blood cell differential count; c) presence of mononeuropathy or polyneuropathy; d) unfixed pulmonary infiltrates; e) presence of paranasal sinus abnormalities; e) histologic evidence of extravascular eosinophils. For classification purposes, a patient should be said to have EGPA if at least four of the six criteria listed above are positive.

[0176] As used herein, one day before the first administration (D-1) is defined as the “baseline.” The “screening period” refers to the period from Day 28 to Day 2 (D-28 to D-2) before administration.

[0177] The three letter codes and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0178] As used herein, the term "antibody" is used in the broadest sense, covering various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. Antibodies may refer to immunoglobulins, which are tetrapeptide chain structures formed by two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of the heavy chain of immunoglobulins are different, so their antigenicity is also different. Based on this, immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain, respectively. The same class of Ig can be divided into different subclasses according to the difference in the amino acid composition of its hinge region and the number and position of the heavy chain disulfide bonds, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4. Light chains are divided into κ chains or λ chains by different constant regions. Each of the five types of Ig can have a kappa chain or a lambda chain. The sequences of about 110 amino acids near the N-terminus of the antibody heavy chain and light chain vary greatly, which is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable, which is the constant region (C region). The variable region includes three hypervariable regions (CDRs) and four relatively conservative framework regions (FRs). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDR regions and four FR regions, arranged in the order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0179] For the determination or definition of CDRs, the deterministic depiction of CDRs and the identification of residues comprising the binding site of the antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be accomplished by any of the various techniques known to those skilled in the art, such as X-ray crystallography. A variety of analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definitions, and conformational definitions.

[0180] The amino acid sequence boundaries of CDRs can be determined by various well-known schemes, for example: "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), "Chothia" numbering convention, "ABM" numbering convention, "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001) and ImMunoGenTics (IMGT) numbering convention (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16; 9: 2278), etc.

[0181] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retains the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Exemplary examples of binding fragments encompassed by the term "antigen-binding fragment" include: (i) Fab fragment, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge on the hinge region, (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) dsFv, a stable antigen-binding fragment formed by interchain disulfide bonds between VH and VL; (vi) scFv; (vii) diabodies, bispecific antibodies and multispecific antibodies comprising fragments such as scFv, dsFv, Fab, etc.

[0182] The terms "specific binding", "selective binding", "selectively binds" and "specifically binds" refer to the binding of an antibody to a predetermined epitope on an antigen. -8 M, for example, less than about 10 -9 M, 10 - 10 M, 10 -11 Binds with an affinity (KD) of M or less.

[0183] The term "KD" refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. Typically, the antibodies of the present disclosure have a dissociation equilibrium constant of less than about 10-7 M, such as less than about 10 -8 M, 10 -9 M or 10 -10 The IL-5 binding protein has a dissociation equilibrium constant (KD) of M or less, e.g., as determined in a BIACORE instrument using surface plasmon resonance (SPR) technology.

[0184] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When the positions in the two compared sequences are occupied by the same base or amino acid monomer subunit, for example, if every position of the two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared × 100. For example, when the sequences are optimally aligned, if 6 out of 10 positions in the two sequences match or are homologous, then the two sequences are 60% homologous; if 95 out of 100 positions in the two sequences match or are homologous, then the two sequences are 95% homologous. Typically, when two sequences are aligned, the comparison is made to give the maximum percentage homology. For example, the comparison can be performed by the BLAST algorithm, in which the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm which is frequently used for sequence analysis: BLAST ALGORITHMS: Altschul, SF et al., (1990) J. Mol. Biol. 215:403-410; Gish, W. et al., (1993) Nature Genet. 3:266-272; Madden, TL et al., (1996) Meth. Enzymol. 266:131-141; Altschul, SF et al.,

[0185] (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al., (1997) Genome Res. 7:649-656. Other conventional BLAST algorithms such as those provided by NCBI BLAST are also well known to those skilled in the art.

[0186] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. "Administering" and "treating" can refer to, for example, treatment, pharmacokinetics, diagnosis, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic, a combination composition, or by another cell. "Treatment" as applied to humans, veterinary medicine, or research subjects refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0187] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or inhibit the development of such symptoms to any clinically measurable degree. The amount of therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") may vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the disease symptom has been alleviated can be evaluated by any clinical test method commonly used by physicians or other professional health care personnel to evaluate the severity or progression of the symptom. Although embodiments of the present disclosure (e.g., treatment methods or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0188] An "effective amount" includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical disease. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's general health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0189] The terms "subject", "patient" and "subject" refer to mammals, particularly primates, and especially humans.

[0190] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0191] Furthermore, the present disclosure includes an agent for treating a disease associated with IL-5, the agent comprising the monoclonal antibody or an antibody fragment thereof of the present disclosure as an active ingredient. DETAILED DESCRIPTION

[0192] The present disclosure is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples of the present disclosure that do not specify specific conditions are usually carried out under conventional conditions, such as the Antibody Technology Laboratory Manual and the Molecular Cloning Manual published by the Cold Spring Harbor Laboratory; or under the conditions recommended by the raw material or product manufacturer. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0193] Example 1. Preparation of anti-IL-5 antibodies

[0194] Referring to the method described in WO2020200099, the anti-IL-5 antibody h1705-008 was prepared, and the sequences of its heavy chain and light chain are shown in SEQ ID NOs: 9 and 10 in the present disclosure. The anti-IL-5 antibody was formulated into an injection with a specification of 1 mL: 0.1 g.

[0195] Example 2. Safety, tolerability, pharmacokinetics and pharmacodynamics of a single subcutaneous injection of anti-IL-5 antibody in healthy subjects

[0196] 1. Trial Drugs

[0197] 1) The anti-IL-5 antibody prepared in Example 1.

[0198] 2) Placebo: the dosage form is injection solution, the specification is: 1mL.

[0199] 2. Enrollment of subjects

[0200] 1) Aged ≥18 and ≤55, regardless of gender.

[0201] 2) Body mass index (BMI) must be ≥19 and ≤24 kg / m at screening 2 , weight ≥45kg.

[0202] 3) Blood eosinophil count ≥ 0.15 × 10 at screening and baseline 9 / L.

[0203] 4) Glutamate alanine aminotransferase (AST), glutamate aspartate aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin ≤ upper limit of normal range (ULN) at screening.

[0204] 3. Clinical plan

[0205] There are 5 dose groups of 20mg, 75mg, 150mg, 300mg and 400mg. The subjects in each group were admitted to the Phase I clinical trial ward one day before administration (D-1), ate a standard meal and avoided strenuous exercise. The next morning, anti-IL-5 antibody injection or placebo was injected subcutaneously in the abdomen. The subjects underwent a total of 155 days of safety observation and PK / PD analysis. The study process is divided into a screening period (day -28 to day -2), a baseline period (day -1, admission), an observation period (days 1 to 6, requiring hospitalization for observation) and a follow-up period (days 7 to 155).

[0206] 4. Results

[0207] A total of 42 subjects were enrolled and completed the study. After administration, anti-IL-5 antibody was absorbed slowly, and the time to peak concentration (T max ) was 24.5 days, and the T max Between 8.5 and 14 days. The peak concentrations (C max The geometric mean of the anti-IL-5 antibody was 2.36, 11.1, 19.4, 40.7 and 57.0 μg / mL, respectively. 1 / 2 ) ranged from 86 days to 100 days. At the same time, after a single subcutaneous injection of anti-IL-5 antibody, the C max , the area under the plasma concentration-time curve from 0 to 154 days (AUC 0-154day ) and to infinity (AUC 0-inf) increased in a dose-proportional manner. In addition, pharmacodynamic biomarkers of peripheral blood eosinophils were also detected. After a single subcutaneous injection of anti-IL-5 antibodies in each dose group, the mean value of peripheral blood eosinophils gradually decreased compared with the baseline level, and slowly recovered after reaching the lowest value. However, there was no significant decrease in peripheral blood eosinophils in the placebo group compared with the baseline. PK / PD correlation analysis showed that after medication, as the plasma concentration of anti-IL-5 antibodies increased, the level of peripheral blood eosinophils showed a downward trend. In addition, anti-IL-5 antibodies showed good immunogenicity, good safety and tolerability in healthy subjects.

[0208] As shown in Table 2, a single subcutaneous administration of anti-IL-5 antibody can reduce blood Eos by about 80% compared with the baseline, and the decrease lasts until 3 months after administration.

[0209] Table 2. Decrease in blood Eos compared with baseline (%)

[0210]

[0211]

[0212] 6. Clinical significance

[0213] Anti-IL-5 antibody is a potential treatment for diseases associated with elevated eosinophilia because it has a favorable safety profile and demonstrated efficacy in reducing eosinophil levels in healthy subjects.

[0214] Example 3. Safety, tolerability and pharmacokinetic / pharmacodynamic study of a single subcutaneous injection of anti-IL-5 antibody in asthma patients

[0215] 1. Trial Drugs

[0216] 1) The anti-IL-5 antibody prepared in Example 1.

[0217] 2) Placebo: the dosage form is injection solution, the specification is: 1mL.

[0218] 2. Enrollment of subjects

[0219] 1) Applicants must be ≥18 and ≤65 years old;

[0220] 2) Body weight ≥40kg at screening;

[0221] 3) Clear diagnosis of asthma;

[0222] 4) The condition is stable 4 weeks before screening, and no medication is used or standard asthma treatment drugs are used. Treatment drugs include asthma maintenance treatment drugs and / or emergency relief drugs used as needed. If asthma maintenance treatment drugs are used, stable usage and stable condition are required. Asthma maintenance treatment drugs include one or more of inhaled corticosteroids (ICS), inhaled long-acting β2 receptor agonists (LABA), and inhaled long-acting cholinergic receptor antagonists (LAMA). Emergency relief drugs are limited to short-acting β2 receptor agonists (SABA) or short-acting cholinergic receptor antagonists (SAMA) inhaled on demand;

[0223] 5) Blood eosinophil count ≥ 0.15×10 at screening and baseline 9 / L;

[0224] 6) Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin ≤ upper limit of normal range (ULN) at screening;

[0225] 7) During the screening period, the FEV1 / predicted value of the pulmonary function test before using bronchodilators should be ≥45% (the test time should be between 6:00 am and 12:00 pm). Short-acting bronchodilators should be discontinued for at least 4 hours before the test; long-acting bronchodilators should be discontinued for at least 24 hours (for preparations with a frequency of use of 2 times / day) or at least 36 hours (for preparations with a frequency of use of once / day).

[0226] 3. Clinical plan

[0227] This trial is divided into a screening period (day -28 to day -2), a baseline period (day -1), a dosing period (day 1 to day 2), and a follow-up period (day 3 to day 281). The visit dates during the follow-up period are days 4, 5, 8, 11, 15, 29, 43, 64, 92, 120, 155, 183, 225, and 281. The dose groups and dosing schedule are as follows:

[0228] 1) 400 mg of anti-IL-5 antibody was administered by subcutaneous injection;

[0229] 2) anti-IL-5 antibody was administered at a dose of 600 mg, subcutaneously;

[0230] 3) Placebo, administered by subcutaneous injection.

[0231] 4. Results Evaluation

[0232] 4.1PK / PD evaluation

[0233] The sample type for PK evaluation was serum. The detection method was ELISA (enzyme-linked immunosorbent assay) to quantitatively determine the concentration of anti-IL-5 antibodies in human serum samples. PK blood sampling was performed according to the flow chart, and NCA (non-compartmental analysis) was used to calculate PK parameters.

[0234] The sample type for PD evaluation is whole blood, and the detection method is the automatic blood routine analysis instrument of the research center. The absolute count of blood eosinophils at each time point is detected according to the test flow chart, and the percentage change relative to the baseline is calculated.

[0235] 4.2 Safety evaluation

[0236] This trial is conducted through physical examination, vital signs, 12-lead electrocardiogram, laboratory tests (blood routine, urine routine, blood biochemistry, coagulation function), and adverse events / serious adverse events for safety assessment. All examination items are carried out according to the trial flow chart, and the research physician may increase the number of examinations and examination items as appropriate according to clinical needs (such as when AE or SAE occurs).

[0237] 4.3 Pulmonary function assessment

[0238] The values ​​and percentage changes from baseline in FEV1 and FVC were evaluated.

[0239] 5. Clinical Results

[0240] The pharmacokinetic data of anti-IL-5 antibody in patients with eosinophilic phenotype asthma after a single subcutaneous injection are shown in Table 3. Within the dose range of 400 mg to 600 mg, the t 1 / 2 The time is 72.6 to 75.1 days, T max Between 10.3 and 13.9. Moreover, a single subcutaneous injection of anti-IL-5 antibody can effectively reduce the Eos level in patients with eosinophilic phenotype asthma, with the maximum reduction reaching more than 80%.

[0241] Table 3. Pharmacokinetic data

[0242]

[0243] Table 4. Decrease in blood Eos compared with baseline (%)

[0244]

[0245]

[0246] Example 4. Pharmacodynamic characteristics, efficacy and safety of multiple subcutaneous injections of anti-IL-5 antibodies in patients with eosinophilic asthma

[0247] 1. Trial Drugs

[0248] 1) The anti-IL-5 antibody prepared in Example 1.

[0249] 2) Placebo: the dosage form is injection solution, the specification is: 1mL.

[0250] 2. Enrollment of subjects

[0251] 1) Aged ≥18 and ≤75 years old, regardless of gender;

[0252] 2) Weight ≥40kg;

[0253] 3) A history of asthma of at least 1 year that meets the diagnostic criteria of the "Guidelines for the Prevention and Treatment of Bronchial Asthma (2020 Edition)";

[0254] 4) Records of receiving medium or high daily doses of inhaled corticosteroids (ICS) for at least 3 months before randomization (refer to the Guidelines for the Prevention and Treatment of Bronchial Asthma (2020 Edition)), and at least one other asthma control drug [including long-acting β2 receptor agonists (LABA), long-acting cholinergic receptor antagonists (LAMA) or leukotriene receptor antagonists (LTRA)] and / or oral corticosteroids, with the dosage and condition being stable within 4 weeks before randomization;

[0255] 5) A history of at least one asthma attack within 1 year before randomization, and patients who were treated with systemic glucocorticoids or had received maintenance treatment with systemic glucocorticoids with a dose increase of ≥3 days;

[0256] 6) The absolute blood eosinophil count during the screening period and baseline is ≥ 0.15×10 9 / L;

[0257] 7) FEV1 before inhaled bronchodilator during the screening period and baseline was ≥40% and <80% of the predicted value;

[0258] 8) Asthma Control Questionnaire (ACQ-6) score ≥1.5 during screening and baseline.

[0259] 3. Clinical plan

[0260] The subjects in this study were randomly assigned to the anti-IL-5 antibody injection 400mgQ24W group (400mg, Q24W, 1 dose in total) or the anti-IL-5 antibody injection 600mgQ12W group (600mg, Q12W, 2 doses in total) or the anti-IL-5 antibody injection 600mgQ24W group (600mg, Q24W, 1 dose in total) or the placebo group according to 2:2:2:1 for treatment. The drug was administered by subcutaneous injection in the abdomen, and the first dose was defined as D1, and two doses were administered on D1 and D85 respectively. The dose grouping and administration schedule are as follows:

[0261] 1) Anti-IL-5 antibody, 400 mg, Q24W group: 400 mg anti-IL-5 antibody injection and 200 mg placebo were administered on D1; 600 mg placebo was administered on D85.

[0262] 2) Anti-IL-5 antibody, 600 mg, Q12W group: 600 mg anti-IL-5 antibody injection was administered by injection on D1; 600 mg anti-IL-5 antibody injection was administered by injection on D85.

[0263] 3) Anti-IL-5 antibody, 600 mg, Q24W group: 600 mg anti-IL-5 antibody injection was administered by injection on D1; 600 mg placebo was administered by injection on D85.

[0264] 4) Placebo group: 600 mg placebo was injected on D1; 600 mg placebo was injected on D85.

[0265] 4. Results Evaluation

[0266] 4.1 Effectiveness Evaluation

[0267] 1) The absolute count of blood eosinophils (Eos) at each evaluation time point and its changes compared with the baseline.

[0268] 2) Pulmonary function FEV1, FEV1% of predicted value, FVC and PEF and their changes compared with baseline, FeNO and its changes compared with baseline at each evaluation time point.

[0269] 3) The Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores were completed by the subjects themselves.

[0270] 4) The annualised asthma exacerbation rate (AAER) was used to evaluate acute asthma exacerbations, which was defined as the total frequency of acute asthma exacerbations × 365.25 / total follow-up time after the start of treatment (days). Acute asthma exacerbations that met the protocol requirements included moderate and severe acute exacerbations.

[0271] 4.2 Safety evaluation

[0272] The safety of the investigational drugs is evaluated by collecting adverse events (TEAEs) that occur during treatment, including physical examination, laboratory tests (blood routine, urine routine, blood biochemistry, coagulation test), vital signs (body temperature, pulse, respiration, blood pressure), electrocardiogram, etc.

[0273] 4.3PK / PD evaluation

[0274] The sample type for PK evaluation was serum, and the detection method was ELISA (enzyme-linked immunosorbent assay) to quantitatively determine the concentration of anti-IL-5 antibodies in human serum samples, and PK blood sampling was performed according to the flow chart.

[0275] PD evaluation: The sample type for eosinophil detection is whole blood, and the detection method is the automatic blood routine analysis instrument of the research center. The absolute count of blood eosinophils at each time point is detected according to the test flow chart, and the percentage change relative to the baseline is calculated.

[0276] 5. Clinical Results

[0277] The overall safety of patients with eosinophilic asthma receiving anti-IL-2 antibodies in all dose groups was good, and most TEAEs were mild to moderate; there was no dose-dependent increase in the occurrence of TEAEs. The reduction in Eos is shown in Table 5. Anti-IL-2 antibodies can significantly reduce the blood Eos level of asthma patients. The 600mg Q24W group had a reduction of >80% from the baseline for more than 113 days, and the 600mg Q12W group maintained a reduction of more than 80% to 169 days. All three dose groups of anti-IL-5 antibodies can effectively reduce acute asthma attacks, and the annualized rate of moderate to severe attacks is significantly lower than that of the placebo group (0.18-0.36 vs. 2.10); the annualized rate of severe attacks is also numerically lower than that of the placebo group.

[0278] Table 5. Decrease in blood Eos compared with baseline (%)

[0279]

[0280]

[0281] Table 6. Asthma exacerbation events

[0282]

[0283] Example 5. Efficacy and safety of multiple subcutaneous injections of anti-IL-5 antibodies in patients with eosinophilic granulomatosis with polyangiitis (EGPA)

[0284] 1. Trial Drugs

[0285] 1) The anti-IL-5 antibody prepared in Example 1.

[0286] 2) Placebo, which is a simulation of anti-IL-5 antibody injection.

[0287] 2. Study Population

[0288] 2.1 Inclusion criteria

[0289] 1) Aged ≥ 18 years old, regardless of gender;

[0290] 2) EGPA was diagnosed for at least 6 months (the diagnostic criteria were in line with the current domestic expert consensus);

[0291] 3) History of recurrent or refractory EGPA:

[0292] a) Recurrent EGPA is defined as: the subject must have at least one confirmed history of EGPA relapse in the past 2 years (needing to increase the OCS (Oral corticosteroids) dose to ≥7.5 mg / d, or increase the immunosuppressant dose, or add new immunosuppressant treatment), and the most recent relapse time is at least 12 weeks or more before screening;

[0293] b) Refractory EGPA is defined as: failure to achieve EGPA remission after at least 3 months of induction therapy with OCS within 6 months before screening; or the onset of EGPA symptoms during OCS reduction (dose ≥ 7.5 mg / d).

[0294] 4) Receiving a stable dose (≥7.5 mg / d and ≤50 mg / d) of OCS (prednisone / prednisolone or equivalent hormone) within 4 weeks before randomization.

[0295] 2.2 Exclusion criteria

[0296] 1) Patients with other diseases associated with elevated eosinophils, including but not limited to hypereosinophilic syndrome (HES) and eosinophilic esophagitis;

[0297] 2) combined with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA);

[0298] 3) Life-threatening EGPA (such as severe alveolar hemorrhage, rapidly progressive glomerulonephritis, severe central nervous system involvement or severe cardiac involvement, etc.) within 3 months before randomization;

[0299] 4) Patients diagnosed with malignant tumors within 5 years before randomization (except for malignant tumors with low risk of metastasis and death, such as adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix, etc.);

[0300] 5) Known immunodeficiency (except for immunodeficiency caused by the use of OCS or other immunosuppressants to treat EGPA);

[0301] 6) poorly controlled hypertension (systolic blood pressure ≥180 mmHg and / or diastolic blood pressure ≥110 mmHg during the screening period);

[0302] 7) Uncontrolled severe cardiovascular and cerebrovascular diseases, including but not limited to myocardial infarction, unstable angina, heart failure, stroke and subarachnoid hemorrhage;

[0303] 8) History of infection requiring clinical intervention within 4 weeks before randomization, including but not limited to respiratory tract infection;

[0304] 9) Known parasitic infection within 6 months before randomization;

[0305] 10) Receiving OCS (prednisone / prednisolone or equivalent hormone) dose > 50 mg / d, or receiving intravenous, subcutaneous or intramuscular glucocorticoid treatment within 4 weeks before randomization;

[0306] 11) Obvious abnormalities in laboratory tests during screening: a) WBC < 3.0 × 10 9 / L; b)Hb≤90g / L; c)PLT<100×10 9 / L; d) ALT>3×ULN; e) AST>3×ULN; f) ALP≥2×ULN; g) TBIL>1.5×ULN; h) PT>ULN+3s; i) Cr>1.5×ULN; j) combined with active hepatitis B (positive hepatitis B surface antigen and peripheral blood HBVDNA≥1×10 3 IU [or copies] / mL), or hepatitis C antibody positive, or HIV positive, or Treponema pallidum antibody positive.

[0307] 3. Dosage regimen

[0308] Scheme I: screening period (up to 4 weeks), treatment period (24 weeks), and safety follow-up period (24 weeks). Subjects who meet the inclusion criteria and do not meet the exclusion criteria will receive 600 mg of anti-IL-5 antibody injection Q12W for a total of 2 doses, with a treatment period of 24 weeks, and a 24-week safety follow-up after the treatment period.

[0309] Scheme II: screening period (up to 4 weeks), treatment period (24 weeks), and safety follow-up period (24 weeks). Subjects who met the inclusion criteria and did not meet the exclusion criteria were randomly assigned to the anti-IL-5 antibody group (600 mg, Q12W, 4 doses in total) or the placebo group for 48 weeks of treatment, and a 24-week safety follow-up was performed after the end of the treatment period.

[0310] The experimental drug in this study was administered by subcutaneous injection in the abdomen, and the first administration was defined as D1. The dosing schedule is as follows:

[0311] Table 7. Dosage regimen

[0312]

[0313] 4. Results Evaluation

[0314] 4.1 Effectiveness Evaluation

[0315] 1) Reduction in OCS usage from baseline.

[0316] 2) The proportion of subjects who achieved EULAR remission in EGPA.

[0317] 3) The proportion of subjects with EGPA (severe) relapse and the time to first (severe) relapse.

[0318] 3) The proportion of subjects with EGPA remission.

[0319] 4) Changes in lung function FEV1, FEV1% predicted value, FVC, FeNO and serum IgE compared with baseline at each evaluation time point. Other endpoint indicators include BVAS, VDI, ACQ-6, SNOT-22 and SF-36 scores.

[0320] 4.2 Safety evaluation

[0321] The safety of investigational drugs is evaluated by collecting TEAEs, including physical examination, laboratory tests (blood routine, urine routine, blood biochemistry, coagulation test), vital signs (body temperature, pulse, respiration, blood pressure), electrocardiogram, etc.

[0322] 5. Clinical Results

[0323] 5.1 Validity Results:

[0324] This study showed that the administration of 600 mg Q12W of anti-IL-5 antibody in the Phase II stage can reduce the OCS [prednisone / prednisone or equivalent hormones] dosage in EGPA patients. The average baseline OCS [prednisone / prednisone or equivalent hormones] dosage of the 10 subjects who had completed the 12-week visit was 10.25 mg / d, and the OCS [prednisone / prednisone or equivalent hormones] at the 12th week visit was 5.40 mg / d, an average reduction of 4.85 mg / d, and an average reduction of 49%.

[0325] In 6 subjects (60%), the OCS dosage reached ≤5 mg / d in the 12th week of treatment;

[0326] In 3 subjects (30%), the OCS dosage decreased by more than 50% from baseline at week 12 of treatment;

[0327] In 7 subjects (70%), the OCS dosage reached EULAR remission (BVAS score of 0 and OCS [prednisone / prednisolone or equivalent hormone] dosage ≤7.5mg / d) at week 12 of treatment;

[0328] No patient experienced a recurrence of EGPA. No subject experienced a recurrence or severe recurrence of EGPA during the period;

[0329] The average baseline score of the Birmingham Vasculitis Activity Score (BVAS) was 4.5 points. The average score at visit V3 (D15) was 0.1 points, a decrease of 4.4 points from the baseline. The average score at visit V4 (D29) was 0.3 points, a decrease of

[0330] The average score of V5 (D57) visit was 0.2 points, which was 4.3 points lower than the baseline; the average score of V6 (D85) visit was 0.1 points, which was 4.4 points lower than the baseline.

[0331] 5.2 Safety Results:

[0332] This study showed that anti-IL-5 antibodies have good safety. Among the 10 subjects, 7 (70.0%) subjects experienced at least one treatment-emergent adverse event (TEAE), all of which were mild or moderate, and no severe TEAE occurred. No TEAEs that led to suspension or permanent discontinuation of the trial drug, withdrawal from the trial, or death were reported, and no adverse events of special concern (AESI) were reported.

Claims

1. Use of an anti-IL-5 antibody in the preparation of a medicament for treating a disease associated with elevated eosinophils; the disease associated with elevated eosinophils is preferably asthma, eosinophilic asthma, or eosinophilic granulomatosis with polyangiitis (EGPA).

2. The use according to claim 1, wherein Subjects with the above-mentioned disease associated with elevated eosinophils have an absolute blood eosinophil (Eos) count of ≥ 0.15 × 10 9 / L; Preferably, the subject suffers from eosinophilic asthma.

3. The use according to claim 1 or 2, wherein: (1) The anti-IL-5 antibody reduces the blood eosinophil (Eos) level in a subject with a disease associated with elevated eosinophils; preferably, the anti-IL-5 antibody reduces the blood Eos level by more than 80% compared with the baseline, and more preferably, the anti-IL-5 antibody reduces the blood Eos level by more than 80% compared with the baseline and maintains the reduction for ≥100 days; (2) The anti-IL-5 antibody reduces acute asthma attacks in subjects with asthma or eosinophilic asthma; preferably, the anti-IL-5 antibody reduces the attack rate of moderate to severe acute asthma to ≤0.4, or the anti-IL-5 antibody reduces the attack rate of severe acute asthma to ≤0.4, preferably ≤0.3, and more preferably ≤0.

2.

4. The use according to claim 1, wherein The disease associated with increased eosinophils is eosinophilic granulomatosis with polyangiitis (EGPA); preferably, it is relapsed or refractory EGPA.

5. The use according to any one of claims 1 to 4, wherein: (1) Anti-IL-5 antibodies reduce the amount of oral corticosteroids (OCS) used in subjects with EGPA. (2) Anti-IL-5 antibodies reduce the Birmingham Vasculitis Activity Score (BVAS) in subjects with EGPA, (3) Anti-IL-5 antibodies reduce the proportion of subjects with EGPA recurrence, and / or, (4) anti-IL-5 antibodies increase the proportion of subjects achieving EULAR remission; Preferably, the subjects with EGPA receive anti-IL-5 antibody treatment at week 12: The reduction in OCS usage from baseline is ≥40%, preferably ≥45%; The proportion of subjects achieving OCS dosage of ≤5 mg / d was ≥40%, preferably ≥45%; The proportion of subjects achieving EULAR remission is ≥50%, preferably ≥55%, ≥60% or ≥65%; The Birmingham Vasculitis Activity Score (BVAS) is reduced by more than 3 points compared with the baseline, preferably more than 3.5 points, or more than 4 points.

6. The use according to any one of claims 1 to 5, wherein: The administration frequency of the anti-IL-5 antibody is less than or equal to once in 8 weeks; preferably, less than or equal to once in 10 weeks, once in 12 weeks, once in 14 weeks, once in 16 weeks, once in 18 weeks, once in 20 weeks, once in 24 weeks, once in 26 weeks or once in 28 weeks; preferably, the administration frequency of the anti-IL-5 antibody is selected from about once in 10 weeks, about once in 12 weeks, about once in 14 weeks, about once in 16 weeks, about once in 18 weeks, about once in 20 weeks, about once in 22 weeks, about once in 24 weeks, about once in 26 weeks, about once in 28 weeks or about once in 30 weeks; and / or, The dosage of the anti-IL-5 antibody is selected from 10-1000 mg, 100-800 mg, 200-800 mg, 150-800 mg, 350-650 mg or 400-600 mg; preferably, the dosage of the anti-IL-5 antibody is selected from about 20 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 600 mg, about 650 mg or about 800 mg.

7. The use according to any one of claims 1 to 6, wherein: The dosage of the anti-IL-5 antibody is 400-600 mg, and the administration frequency of the anti-IL-5 antibody is once every 24 weeks; The dosage of the anti-IL-5 antibody is 400-600 mg, and the frequency of administration of the anti-IL-5 antibody is once every 24 weeks; and within 20 weeks after the first administration, the anti-IL-5 antibody is administered once at a dose of 400-600 mg; preferably, the anti-IL-5 antibody is administered once at a dose of 400-600 mg 12 weeks after the first administration; or, The dosage of the anti-IL-5 antibody is 400-600 mg, and the administration frequency of the anti-IL-5 antibody is once every 12 weeks.

8. The use according to any one of claims 1 to 7, wherein the anti-IL-5 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively; and The light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; Preferably, the anti-IL-5 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 90% identity thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 90% identity thereto; Preferably, the anti-IL-5 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9 or having at least 90% identity thereto, and the light chain comprises an amino acid sequence as shown in SEQ ID NO:10 or having at least 90% identity thereto.

9. The use according to any one of claims 1 to 8, wherein The anti-IL-5 antibody is administered by injection, preferably intravenous or subcutaneous injection.

10. The use according to any one of 1 to 9, wherein The anti-IL-5 antibody is an anti-IL-5 antibody injection, which comprises an anti-IL-5 antibody, a buffer and a surfactant; The buffer is preferably selected from acetic acid-sodium acetate, succinic acid-sodium succinate, histidine-hydrochloride and citric acid-sodium citrate buffer; wherein the concentration of the buffer is preferably 10 mM to 40 mM, and the pH of the buffer is preferably 5.0 to 6.5; The concentration of the anti-IL-5 antibody is preferably 80 mg / ml to 120 mg / ml; The surfactant is preferably polysorbate 80, and the concentration is preferably 0.1 mg / ml to 0.6 mg / ml; Preferably, the injection further comprises a stabilizer, wherein the stabilizer is a sugar or an amino acid, wherein the sugar is selected from sucrose, trehalose, mannitol and sorbitol; wherein the amino acid is selected from glycine, methionine and proline; the concentration of the sugar is preferably 70 mg / ml to 75 mg / ml, and the concentration of the amino acid is preferably 8 mg / ml.

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