Methods of treating tslp-associated inflammatory diseases with anti-tslp antibodies

Abstract

Methods and pharmaceutical uses of anti-TSLP antibodies or their antigen-binding fragments for the treatment of TSLP-related inflammatory diseases (e.g., nasal polyps and / or sinusitis).

Description

Methods of treating TSLP-associated inflammatory diseases with anti-TSLP antibodies

[0001] Cross-reference to Related Applications

[0002] This application claims priority to Chinese Patent Application 202410415684.5, filed April 8, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicine, and relates to methods and medical uses of anti-TSLP antibodies or antigen-binding fragments thereof for treating TSLP-associated inflammatory diseases. BACKGROUND

[0004] Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine produced in response to proinflammatory stimuli that promotes allergic inflammatory responses primarily through its activity on dendritic cells and mast cells. TSLP is an interleukin-7 (IL-7)-like cytokine that was first discovered in the conditioned medium of mouse thymic stromal cells. TSLP is mainly expressed in lung, skin and intestinal epithelial cells. TSLP consists of four alpha-helices and two loops, AB and CD, with three pairs of disulfide bonds consisting of six cysteines and two N-glycosylation sites, and has a molecular weight of about 15-20 kD. The receptor of TSLP is a complex, including two parts, one part is TSLPR, and the other part is IL7Rα. TSLP first binds to TSLPR with relatively low affinity, then recruits IL7Rα binding with high affinity, and finally activates the stat5 and other signaling pathways, leading to the maturation of DC and the differentiation of T cells.

[0005] Myeloid-derived dendritic cells (mDC) are the main effector cells of TSLP. TSLP acts on immature mDC, and mDC secretes cytokines IL-8, eotaxin-2, TARC and MDC, and highly expresses OX40L. In the absence of IL-12, OX40L binds to natural CD4+ T cells, causing them to differentiate into Th2 cells, which in turn secrete Th2 cytokines such as IL-5, IL-4, IL-9, and TNF, inducing Th2 inflammation in the body. In addition, TSLP can also induce DC cells to produce cytokine IL-8, thereby recruiting neutrophils, leading to neutrophil innate immune inflammation. TSLP can also induce DC to produce eotaxin-2, which recruits eosinophils and acts together with IL5 to rapidly induce the body into an inflammatory state of eosinophil infiltration. TSLP also acts on mast cells and natural killer cells, inducing the production of IL-4, IL-6, IgE, and other cytokines to mediate innate inflammation. In summary, TSLP can cause both innate inflammation and Th2 inflammation, thereby causing increased mucus in tissues, airway remodeling leading to tracheal stenosis, and severe cell fibrosis. Anti-TSLP antibodies prevent and control the occurrence and development of inflammation by blocking the interaction of TSLP with the receptor complex, thereby preventing TSLP-targeted immune cells from releasing pro-inflammatory cytokines.

[0006] TEZSPIRE is an anti-TSLP antibody jointly developed by AstraZeneca and Amgen, which has been approved for marketing. It has shown effectiveness in treating asthma and improving the clinical symptoms of chronic rhinosinusitis with nasal polyps (CRSwNP), but TEZSPIRE requires a dosing frequency of 4 weeks. Therefore, developing new methods for treating diseases related to TSLP is an important problem that needs to be solved in the art. SUMMARY

[0007] The present disclosure provides a method of treating an inflammatory disease associated with TSLP, comprising administering an anti-TSLP antibody or antigen binding fragment thereof to a subject in need thereof.

[0008] The present disclosure provides a method of improving the nasal polyp score (NPS), nasal polyp (NP) symptoms, nasal congestion score (NCS), Sino-Nasal Outcome Test 22-Item Scale (SNOT-22) score, and / or Total Symptom Score (TSS) in a subject, comprising administering an anti-TSLP antibody or antigen binding fragment thereof to a subject in need thereof.

[0009] In some embodiments, the subject has an inflammatory disease associated with TSLP. Among others, the inflammatory disease associated with TSLP is selected from the group consisting of sinusitis and / or nasal polyps. Illustratively, the inflammatory disease associated with TSLP is selected from the group consisting of nasal polyps, chronic rhinosinusitis (CRS), chronic rhinosinusitis without nasal polyps (CRSsNP), or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0010] In some specific embodiments, the inflammatory disease associated with TSLP is chronic rhinosinusitis with nasal polyps.

[0011] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered less than 4 times a week.

[0012] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered less than or equal to 6 times a week, 8 times a week, 10 times a week, 12 times a week, 18 times a week, 20 times a week, 24 times a week, 26 times a week, 28 times a week, or 30 times a week.

[0013] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered 6 times a week, 8 times a week, 10 times a week, 12 times a week, 14 times a week, 16 times a week, 18 times a week, 20 times a week, 22 times a week, 24 times a week, 26 times a week, or 28 times a week.

[0014] In some specific embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered 12 times a week or 24 times a week.

[0015] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 50-800 mg, 100-600 mg, 100-500 mg, 100-450 mg, 150-450 mg, 200-600 mg, 200-500 mg, 200-400 mg, 50-600 mg, 50-400 mg, or 50-450 mg.

[0016] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg (including any numerical value between any of the aforementioned point values).

[0017] In some specific embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of about 200 mg or about 400 mg.

[0018] In some specific embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose and frequency selected from any one of the following:

[0019] (1) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 10 weeks.

[0020] (2) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 12 weeks.

[0021] (3) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 14 weeks.

[0022] (4) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 16 weeks.

[0023] (5) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 18 weeks.

[0024] (6) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 20 weeks.

[0025] (7) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 24 weeks.

[0026] (8) the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose of 150-450 mg per dose (e.g., about 150 mg per dose, about 200 mg per dose, about 250 mg per dose, about 300 mg per dose, about 350 mg per dose, about 400 mg per dose, or about 450 mg per dose). The frequency of administration is once every 26 weeks.

[0027] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is any of the anti-TSLP antibodies or antigen-binding fragments thereof disclosed in WO2020244544, WO2022116858. The disclosure incorporates by reference the antibody sequences, methods of making, and compositions, etc. in the above patents.

[0028] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof comprises any 1, any 2, any 3, any 4, any 5, or 6 CDRs selected from the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 1-6.

[0029] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof 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 set forth 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 set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

[0030] The foregoing CDR sequences are shown in Table 1 below:

[0031] Table 1 CDR sequences of anti-TSLP antibody hu179-33

[0032] The foregoing CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact numbering system. In some particular embodiments, the CDRs are defined according to the Kabat numbering system.

[0033] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is a humanized antibody. In some particular embodiments, the VH of the anti-TSLP antibody or antigen-binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 7, or an amino acid sequence having at least 80%, 90% sequence identity thereto; and the VL of the anti-TSLP antibody or antigen-binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 8, or an amino acid sequence having at least 80%, 90% sequence identity thereto.

[0034] Heavy chain variable region VH (SEQ ID NO: 7):

[0035] Light chain variable region VL (SEQ ID NO: 8):

[0036] Note: underlined portions are CDR regions defined according to the Kabat numbering system.

[0037] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is a humanized antibody, comprising any one or two of the above-described VH, VL.

[0038] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof further comprises an antibody constant region; for example, the heavy chain constant region of the antibody constant region is selected from the group consisting of human IgGl, IgG2, IgG3 and IgG4 constant regions and variants thereof; and the light chain constant region of the antibody constant region is selected from the group consisting of human antibody kappa and lambda chain constant regions and variants thereof.

[0039] For example, the IgGl-YTE constant region used in the present disclosure has a sequence as set forth in SEQ ID NO: 11. The light chain constant region can be selected from the group consisting of human kappa, lambda chain or variants thereof, for example, the constant region of human kappa chain used in the present disclosure has a sequence as set forth in SEQ ID NO: 12.

[0040] > IgGl-YTE heavy chain constant region (SEQ ID NO: 11):

[0041] > kappa light chain constant region (SEQ ID NO: 12):

[0042] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 9 or an amino acid sequence having at least 80%, 90% identity thereto, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 10 or an amino acid sequence having at least 80%, 90% identity thereto.

[0043] Antibody heavy chain (SEQ ID NO: 9):

[0044] Antibody light chain (SEQ ID NO: 10):

[0045] Note: underlined portions are constant regions of antibody heavy chain and antibody light chain, respectively.

[0046] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof comprises any 1 or 2 of the foregoing heavy and light chains.

[0047] In the context of the present disclosure, “at least 80%” “at least 90%” encompasses 80% and above, e.g., 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 between any two of these values.

[0048] In one aspect, the present disclosure provides an anti-TSLP antibody for use in a method of treating chronic rhinosinusitis with nasal polyps (CRSwNP), wherein the method comprises administering the anti-TSLP antibody to a subject in need thereof at a dosing frequency of once every 26 weeks, wherein the dose of the anti-TSLP antibody is between 25 mg and 370 mg, and wherein the anti-TSLP antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH region comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3, and wherein the VL region comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In one embodiment, the anti-TSLP antibody comprises a VH region comprising an amino acid sequence as set forth in SEQ ID NO: 7 and a VL region comprising an amino acid sequence as set forth in SEQ ID NO: 8. In one embodiment, the anti-TSLP antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 9 and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 10.

[0049] In one embodiment, the dose of the anti-TSLP antibody is between 25 mg and 50 mg (e.g., 30 mg). In one embodiment, the dose of the anti-TSLP antibody is between 50 mg and 100 mg, e.g., between 55 mg and 90 mg, between 60 mg and 90 mg, or between 65 mg and 85 mg.

[0050] In one embodiment, the dose of the anti-TSLP antibody is between 100 mg and 175 mg, for example between 100 mg and 115 mg, between 105 mg and 120 mg, between 110 mg and 125 mg, between 115 mg and 130 mg, between 120 mg and 135 mg, between 125 mg and 140 mg, between 130 mg and 145 mg, between 135 mg and 150 mg, between 140 mg and 155 mg, between 145 mg and 160 mg, between 150 mg and 165 mg, between 155 mg and 170 mg, or between 160 mg and 175 mg.

[0051] In one embodiment, the dose of the anti-TSLP antibody is between 175 mg and 190 mg, for example 182 mg.

[0052] In one embodiment, the dose of the anti-TSLP antibody is between 190 mg and 260 mg, for example between 190 mg and 205 mg, between 195 mg and 210 mg, between 200 mg and 215 mg, between 205 mg and 220 mg, between 210 mg and 225 mg, between 215 mg and 230 mg, between 220 mg and 235 mg, between 225 mg and 240 mg, between 230 mg and 245 mg, between 235 mg and 250 mg, between 240 mg and 255 mg, or between 245 mg and 260 mg.

[0053] In one embodiment, the dose of the anti-TSLP antibody is between 260 mg and 305 mg, for example between 260 mg and 275 mg, between 265 mg and 280 mg, between 270 mg and 285 mg, between 275 mg and 290 mg, between 280 mg and 295 mg, between 285 mg and 300 mg, or between 290 mg and 305 mg.

[0054] In one embodiment, the dose of the anti-TSLP antibody is between 305 mg and 355 mg, for example between 305 mg and 320 mg, between 310 mg and 325 mg, between 315 mg and 330 mg, between 320 mg and 335 mg, between 325 mg and 340 mg, between 330 mg and 345 mg, between 335 mg and 350 mg, or between 340 mg and 355 mg.

[0055] In one embodiment, the dose of the anti-TSLP antibody is between 355 mg and 370 mg, for example 364 mg.

[0056] In some embodiments, the route of administration of the anti-TSLP antibody or antigen binding fragment thereof is oral administration, parenteral administration, transdermal administration; the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, intramuscular injection. In some specific embodiments, the route of administration of the anti-TSLP antibody or antigen binding fragment thereof is subcutaneous injection administration.

[0057] In some embodiments, the anti-TSLP antibody or antigen binding fragment thereof is configured in an injectable form. Illustratively, the injectable form of the anti-TSLP antibody or antigen binding fragment thereof is an injection solution or a lyophilized powder needle, which comprises the anti-TSLP antibody or antigen binding fragment thereof and one or more pharmaceutically acceptable excipients.

[0058] In some embodiments, the pharmaceutical composition comprising the anti-TSLP antibody or antigen binding fragment thereof further comprises a buffer, a stabilizer and / or a surfactant. The buffer is a histidine-acetate buffer or a succinate-sodium succinate buffer. The stabilizer can be selected from one or more of a sugar, an amino acid and EDTA; for example, a sugar, for example one or more of trehalose, sucrose, sorbitol and mannitol; for example, an amino acid, for example histidine, tryptophan and methionine; for example, EDTA. The surfactant is selected from polysorbate, for example polysorbate 80 or polysorbate 20, for example polysorbate 80. For example, the injectable form of the TSLP antibody or antigen binding fragment thereof comprises the anti-TSLP antibody or antigen binding fragment thereof, a histidine-acetate buffer, sucrose and polysorbate 80. WO2022116858 relates to compositions of anti-TSLP antibodies, the entire disclosure of which is incorporated herein.

[0059] In some embodiments, the subject has chronic rhinosinusitis (CRS).

[0060] In some embodiments, the subject has chronic rhinosinusitis without nasal polyps (CRSsNP) or chronic rhinosinusitis with nasal polyps (CRSwNP). In some specific embodiments, the subject has chronic rhinosinusitis with nasal polyps (CRSwNP).

[0061] In some embodiments, the subject has bilateral nasal polyps with a total nasal polyps score (NPS) of ≥5, ≥2 in each nostril, and a nasal congestion score (NCS) of ≥2.

[0062] In some embodiments, the subject has a score of ≥20 on the Sino-Nasal Outcome Test 22-item scale (SNOT-22).

[0063] In some embodiments, the subject has persistent NP symptoms for >4 weeks, for example, rhinorrhea, hyposmia / anosmia, etc.

[0064] In some embodiments, the subject is treated with intranasal corticosteroids (INCS). In some particular embodiments, the intranasal corticosteroid is budesonide.

[0065] In some embodiments, the subject is treated with systemic corticosteroids (SCS) for nasal polyp exacerbation, and / or has a history of NP surgery. Exemplary systemic corticosteroids include, but are not limited to, cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone, dexamethasone, and chloroprednisone.

[0066] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered with a corticosteroid, including various cases of sequential and / or simultaneous administration of the two drugs. Exemplary, the anti-TSLP antibody or antigen-binding fragment thereof and the corticosteroid can be independently formulated and co-administered, and / or independently formulated and sequentially administered. In certain embodiments, the subject is first administered the corticosteroid, and then administered the anti-TSLP antibody or antigen-binding fragment thereof. In certain embodiments, the subject is first administered the corticosteroid, and then administered the anti-TSLP antibody or antigen-binding fragment thereof; and, during the administration period of the anti-TSLP antibody or antigen-binding fragment thereof, the administration of the corticosteroid is maintained.

[0067] In some embodiments, the method improves the subject's nasal polyp score (NPS), nasal polyp (NP) symptoms, nasal congestion score (NCS), and / or total symptom score (TSS) of rhinosinusitis. Among them, the NP symptoms include nasal congestion, rhinorrhea, postnasal drip, headache, facial pain and / or pressure, loss of smell, etc.

[0068] In some embodiments, the subject treated with the anti-TSLP antibody or antigen-binding fragment thereof has a decreased nasal polyp score (NPS), a decreased total symptom score (TSS) of rhinosinusitis, and / or a decreased Sino-Nasal Outcome Test 22 (SNOT-22) score.

[0069] Another aspect of the present disclosure provides the use of an anti-TSLP antibody or antigen-binding fragment thereof in at least one of the following (1)-(2):

[0070] (1) for treating an inflammatory disease associated with TSLP;

[0071] (2) for improving the subject's nasal polyp score (NPS), nasal polyp (NP) symptoms, nasal congestion score (NCS), Sino-Nasal Outcome Test 22 (SNOT-22) score, and / or total symptom score (TSS) of rhinosinusitis.

[0072] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from 50-800 mg, 100-600 mg, 100-500 mg, 100-450 mg, 150-450 mg, 200-600 mg, 200-500 mg, 200-400 mg, 50-600 mg, 50-400 mg, or 50-450 mg, e.g., selected from about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg (including any numerical value between any of the aforementioned point values). In some specific embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from about 200 mg or about 400 mg.

[0073] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from 50-800 mg, 100-600 mg, 100-500 mg, 100-450 mg, 150-450 mg, 200-600 mg, 200-500 mg, 200-400 mg, 50-600 mg, 50-400 mg, or 50-450 mg, e.g., selected from about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, or about 800 mg (including any numerical value between any of the aforementioned point values). In some specific embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dose selected from about 200 mg or about 400 mg.

[0074] In some embodiments, the anti-TSLP antibody or antigen-binding fragment thereof is any of the anti-TSLP antibodies or antigen-binding fragments thereof disclosed in WO2020244544, WO2022116858. For example, the anti-TSLP antibody or antigen-binding fragment thereof is the hu179-33 antibody in the aforementioned patents.

[0075] In some embodiments, the subject has chronic rhinosinusitis (CRS).

[0076] In some embodiments, the subject has chronic rhinosinusitis without nasal polyps (CRSsNP) or chronic rhinosinusitis with nasal polyps (CRSwNP). In some specific embodiments, the subject has chronic rhinosinusitis with nasal polyps (CRSwNP).

[0077] In some embodiments, the subject has bilateral nasal polyps with a total nasal polyp score (NPS) of >5, >2 in each nostril, and a nasal congestion score (NCS) of >2.

[0078] In some embodiments, the subject has a score of >20 on the 22-item Sino-Nasal Outcome Test (SNOT-22).

[0079] In some embodiments, the subject has persistent NP symptoms >4 weeks, e.g., rhinorrhea, hyposmia / anosmia, etc.

[0080] In some embodiments, the subject is treated with intranasal corticosteroids (INCS). In some particular embodiments, the intranasal corticosteroid is budesonide.

[0081] In some embodiments, the subject is treated for a nasal polyp exacerbation with a temporary systemic corticosteroid (SCS) administration, and / or has a history of NP surgery. Exemplary systemic corticosteroids include, but are not limited to, cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone, dexamethasone, and chloroprednisone.

[0082] In some embodiments, the subject treated with the anti-TSLP antibody or antigen binding fragment thereof has a decreased nasal polyp score (NPS), a decreased total symptom score (TSS), and / or a decreased Sino-Nasal Outcome Test 22 (SNOT-22) score.

[0083] The anti-TSLP antibodies in the present disclosure treat sinusitis and / or nasal polyps, can significantly improve the patient's overall symptoms of sinusitis and / or nasal polyps, and the frequency of administration of the anti-TSLP antibodies is significantly reduced, which can reduce the burden on the patient and improve the compliance of the drug.

[0084] The term

[0085] For the purposes of the present disclosure, certain technical and scientific terms are specifically defined below. Unless specifically defined herein, all other technical and scientific terms used in the present disclosure have the meanings that are commonly understood by one of ordinary skill in the art in the field of the present disclosure.

[0086] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise," "comprising," "include," "including," and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to.".

[0087] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0088] "About" or "approximately" means within an acceptable error range for the specifics being measured or determined, such as within 1, 2, 3, or 4 standard deviations, as understood by one of ordinary skill in the art. For example, "about" can mean within 1 or more than 1 standard deviation. Or, "about" or "essentially consisting of" can 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%. In the present disclosure, each instance of the term "about" preceding a number or a range of numbers also includes embodiments of the given number. Unless otherwise indicated, the meaning of "about" or "essentially consisting of" should be assumed to be within an acceptable error range of the particular value stated if that value is recited in the application and claims.

[0089] The term "and / or", such as "X and / or Y" shall be understood to mean "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

[0090] The term "Thymic Stromal Lymphopoietin (TSLP)" is a four alpha-helix bundle type I cytokine and also an epithelial cell-derived cytokine produced in response to proinflammatory stimuli, closely related to interleukin-7 (IL-7), which initiates allergic reactions by stimulating dendritic cells (DCs) and is an important factor in regulating the immune response of the human body. The term "TSLP" includes variants, isoforms, homologs, orthologs and paralogs of TSLP.

[0091] The term "inflammatory disease" or "inflammatory disorder" as used herein refers to any disease or disorder characterized by local inflammation at the site of injury or infection, including but not limited to non-allergic inflammation, allergic inflammation, autoimmune diseases and other disorders characterized by undesirable accumulation of immune cells at a local tissue site. TSLP binding to TSLPR / IL7Rα can cause many inflammatory diseases, including allergic and non-allergic diseases.

[0092] The term "chronic rhinosinusitis (CRS)" is a disease characterized by chronic inflammation of the nasal and sinus mucosa, with a course of more than 12 weeks, and clinical manifestations of nasal discharge, nasal congestion, olfactory decline or loss, and headache and facial swelling. Patients often affect the quality of life due to the prolonged and recurrent nature of the disease. Clinically, CRS can be divided into two subtypes: chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP).

[0093] “CRSwNP” has immunological heterogeneity, and there are significant differences in the immunopathological characteristics of CRSwNP in different countries and regions around the world, which affect the prognosis of the disease. CRSwNP in Caucasians is mainly characterized by T helper cell type 2 (Th2)-mediated eosinophilic inflammation, and the incidence of asthma is high; about 50% of patients in East Asia have non-eosinophilic inflammation.

[0094] “Nasal polyps” (also known as Nasal Polyp, NP in English, and Nasal Granuloma in Chinese) are granulomas growing in the nose or sinuses, which are mostly non-cancerous benign tissues. Symptoms of NP include nasal congestion, rhinorrhea, postnasal drip, headache, facial pain and / or pressure, and loss of smell. The severity of each symptom is reported using a 0-3 point scale, which is divided into 4 grades (see Table 2).

[0095] “NPS” refers to the nasal polyp score (NPS). Subjects are required to undergo endoscopic examination of nasal polyps at specified visits, using the endoscopic nasal polyp scoring system (0-4 point scale). 0 points: no polyps; 1 point: small polyps in the middle meatus below the lower margin of the middle turbinate; 2 points: polyps reaching the lower margin of the middle turbinate; 3 points: large polyps reaching the lower margin of the inferior turbinate or the medial side of the middle turbinate; 4 points: large polyps completely blocking the lower nasal cavity. The total score is the sum of both sides (total score 0-8 points), and the higher the score, the more severe the nasal polyp disease.

[0096] “NCS” refers to the nasal congestion score (Nasal congestion score). The nasal congestion score (NCS), loss of smell, rhinorrhea / postnasal drip, facial pain and / or pressure endpoints are collected through the nasal polyp symptom diary (NPSD).

[0097] “TSS” refers to the total symptoms score (Total symptoms score) of sinusitis. The total symptoms of sinusitis (TSS) are the sum of the scores of the 6 NP symptom items in the NPSD.

[0098] “SNOT-22 score” refers to the Sino-nasal outcome test-22 score. SNOT-22 is used to assess the severity of CRSwNP in subjects. SNOT-22 collects the severity of symptoms and the impact of symptoms reported by patients in the past 2 weeks through a 6-point scale (0-5 points). The total score is the sum of the item scores, and the higher the score, the more severe the disease.

[0099] The three-letter and one-letter codes for amino acids used in the present disclosure are as described in J. Biol. Chem, 243, p3558 (1968).

[0100] "Antibody" is used in the broadest sense, and includes various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies and antibody fragments (or antigen binding fragments, or antigen binding portions), so long as they exhibit the desired antigen-binding activity. An antibody can refer to an immunoglobulin, which is a tetrameric structure consisting of two identical heavy chains and two identical light chains connected by disulfide bonds between them. The amino acid compositions and arrangement orders of the constant regions of the heavy chains of immunoglobulins are different, and thus their antigenicities are different. Accordingly, immunoglobulins can be divided into five types, or called isotypes of immunoglobulins, i.e., IgM, IgD, IgG, IgA and IgE, and the corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain, respectively. The same type of Ig can be further divided into different subtypes according to the differences in the amino acid compositions of the hinge regions and the number and position of the disulfide bonds of the heavy chains, such as IgG can be divided into IgG1, IgG2, IgG3 and IgG4. The light chains are divided into κ chain or λ chain by the constant regions. Each of the five types of Ig can have κ chain or λ chain. The sequences of about 110 amino acids near the N-terminus of the heavy chain and light chain of the antibody are quite different, which are variable regions (V regions); the remaining amino acid sequences near the C-terminus are relatively stable, which are constant regions (C regions). The variable region includes three hypervariable regions (CDRs) and four relatively conserved framework regions (FRs). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR). Each light chain variable region (VL) and heavy chain variable region (VH) is composed of three CDR regions and four FR regions, arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminal to the carboxyl terminal. The three CDR regions of the light chain are LCDR1, LCDR2 and LCDR3; the three CDR regions of the heavy chain are HCDR1, HCDR2 and HCDR3.

[0101] For the determination or definition of CDRs, the determination of the delineation 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 achieved by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. Various 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, the contact definition, the conformational definition.

[0102] The amino acid sequence boundaries of CDRs can be determined by various well-known schemes, such as the "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering convention, the "ABM" numbering convention, the "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001), and the ImMunoGenTics (IMGT) numbering convention (Lefranc, M.P. et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16;9:2278), etc.

[0103] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be utilized to perform the antigen-binding function of an antibody. Illustrative examples of binding fragments encompassed by the term "antigen-binding fragment" include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a dsFv, a stable antigen-binding fragment of a VH and VL formed by an interchain disulfide bond; (vi) a scFv; (vii) diabodies, bispecific antibodies, and multispecific antibodies comprising a scFv, a dsFv, a Fab, etc.

[0104] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in both of the compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent 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 in the comparison times 100. For example, if 6 of 10 positions in two sequences are matched or homologous, then the two sequences are 60% homologous. If 95 of 100 positions in two sequences are matched or homologous, then the two sequences are 95% homologous. Typically, the comparison is performed using the best alignment of two sequences. For example, comparisons can be performed using the BLAST algorithm, in which the parameters of the algorithm are selected to give the largest match between the sequences over their entire length. The following references are directed to the BLAST algorithm, which is frequently used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410; Gish, W. et al. (1993) Nature Genet. 3:266-272; Madden, T.L. et al. (1996) Meth. Enzymol. 266:131-141; Altschul, S.F. et al. (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al. (1997) Genome Res. 7:649-656. Other routine BLAST algorithms, such as those provided by NCBI BLAST, are also well known to those of skill in the art.

[0105] "Administering" and "treatment" when applied to an animal, human, test subject, cell, tissue, organ or biological fluid means the contact of an exogenous drug, therapeutic agent, diagnostic agent or composition with the animal, human, test subject, cell, tissue, organ or biological fluid. "Administering" and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research and experimental methods. Treatment of a cell includes contact of a reagent with a cell, as well as contact of a reagent with a fluid that is in contact with a cell. "Administering" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by a reagent, diagnostic, binding composition or by another cell. "Treatment" when applied to a human, veterinary or research subject means therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0106] "Treatment" means the administration of an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient having one or more symptoms of a disease, where the therapeutic agent is known to have a therapeutic effect on those symptoms. 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 to inhibit the progression of such symptoms to any clinically measurable extent. The amount of therapeutic agent effective to alleviate any particular symptom of a disease (also referred to as a "therapeutically effective amount") can vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired therapeutic effect in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical detection method typically used by a physician or other health care professional to assess the severity or progression of the symptom. While embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) can not be effective in alleviating every symptom of a target disease, it is determined that a statistically significant number of patients should have alleviation of the target disease symptoms according to any statistical test known in the art, such as the Student's t-test, the chi-square test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), the Jonckheere-Terpstra test, and the Wilcoxon test.

[0107] "Effective amount" includes an amount that is sufficient to ameliorate or prevent the symptoms or conditions of a medical disease. An effective amount also means an amount that is sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on such factors as the condition to be treated, the overall health status of the patient, the method route and dose of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxic effects.

[0108] The terms "subject," "patient" mean a mammal, especially a primate, and especially a human. DETAILED DESCRIPTION

[0109] The present disclosure is further described in connection with the following examples, which are not intended to be limiting of the scope of the present disclosure. The experimental methods in the examples of the present disclosure are generally performed according to conventional methods, such as those described in Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Eds. E. Harlow and D. Lane (1988); or those described in Molecular Cloning: A Laboratory Manual, Second Edition, Sambrook et al., Cold Spring Harbor Laboratory Press (1989), unless otherwise stated. Reagents not specifically noted were purchased from commercial suppliers and used according to the manufacturer's instructions.

[0110] Example 1. Anti-TSLP antibody treatment of chronic rhinosinusitis with nasal polyps (CRSwNP)

[0111] 1. Test drug

[0112] 1) Anti-TSLP antibody, the preparation method thereof is described in WO2022116858, and the corresponding name is hu179-33 antibody. The sequences of the heavy chain and the light chain of the anti-TSLP antibody are shown as SEQ ID NO: 9 and 10 in the present disclosure, and are formulated into an injection solution with a specification of 1ml:0.1g.

[0113] 2) Placebo, dosage form is injection solution, specification is: 1ml.

[0114] 2. Enrolled subjects

[0115] 1) Age ≥ 18 years old and ≤ 75 years old, men and women are not limited.

[0116] 2) Body weight ≥ 40kg.

[0117] 3) Chronic rhinosinusitis with nasal polyps (CRSwNP) meeting the diagnostic criteria of “Chinese Guide for the Diagnosis and Treatment of Chronic Rhinosinusitis (2018)”.

[0118] 4) Bilateral nasal polyps at screening and baseline, NPS total score ≥ 5, ≥ 2 points in each nostril.

[0119] 5) NCS score ≥ 2 at screening and baseline.

[0120] 6) SNOT-22 ≥ 20 at screening and baseline.

[0121] 7) Documented persistent NP symptoms > 4 weeks before screening, such as rhinorrhea, hyposmia / anosmia, etc.

[0122] 8) The subject needs to receive standard treatment including intranasal corticosteroids (INCS), and the condition and treatment are stable within 4 weeks before randomization.

[0123] 9) Previous NP surgery and / or AECRS (or contraindication / intolerance) receiving SCS treatment within 2 years before randomization.

[0124] 3. Clinical protocol

[0125] 3.1 Study flow

[0126] It is divided into 6 stages: screening period, lead-in period, baseline, double-blind treatment period, extension treatment period and follow-up period.

[0127] Screening period (W-5 to W-3): Enrolled CRSwNP subjects, gender unrestricted, with bilateral nasal polyps, NPS total score ≥5, ≥2 score in each nostril, NCS ≥2 score, received stable standard treatment within 4 weeks before randomization, had a history of nasal polyp exacerbation with temporary systemic glucocorticoid treatment within 2 years before randomization, and / or had a history of NP surgery. After the subject signed the informed consent form, the screening period examination was completed during the screening period.

[0128] Run-in period (W-2 to W-1): During the run-in period, the subject was required to record the nasal polyp symptom diary in the ePRO system every day and fill in the subject diary. The run-in visit will preliminarily assess the subject's compliance with the use of the ePRO system. The subject's compliance was formally calculated from W-1, and the subject was required to have a compliance of ≥70% within 7 days before randomization.

[0129] Baseline (D1): The subjects who passed the screening will complete the relevant evaluation examination again during the baseline period, and the subject's compliance will be evaluated. The subjects who meet all the inclusion criteria and do not meet any of the exclusion criteria will obtain the random number and drug number during the baseline period, and are randomly assigned to each dosing regimen test group or placebo group in a ratio of 1:1:1:1.

[0130] Double-blind treatment period (W1 to W24): The subjects completed 2 test drug administrations on D1 and D85.

[0131] After all subjects completed the 24-week double-blind treatment period, they could voluntarily choose whether to enter the extension treatment period, and the subjects who refused to extend the treatment would directly enter the follow-up period.

[0132] Extension treatment period (W25-W72): All subjects received subcutaneous injection of hu179-33 antibody injection 400 mg Q24W.

[0133] Follow-up period (12 / 24 weeks): The subjects entered the follow-up period after the treatment period.

[0134] 3.2 Dosing regimen

[0135] Test group:

[0136] 1) Group A: D1 subcutaneous injection: 2 x anti-TSLP antibody injection 100 mg (1 ml) + 2 x placebo 1 ml. D85 subcutaneous injection: 4 x placebo 1 ml.

[0137] 2) Group B: D1 subcutaneous injection: 4 x anti-TSLP antibody injection 100 mg (1 ml); D85 subcutaneous injection: 4 x placebo 1 ml.

[0138] 3) Group C: D1, D85 subcutaneous injection: 4 x anti-TSLP antibody injection 100 mg (1 ml).

[0139] Control group:

[0140] D1, D85 subcutaneous injection: 4x placebo 1 ml.

[0141] 4. Outcome assessment

[0142] 1) Nasal polyp score (NPS)

[0143] Subjects were required to have an endoscopic examination of nasal polyps at the scheduled visits using the endoscopic nasal polyp scoring system (0-4 scale). 0 points: no polyps; 1 point: small polyps in the middle meatus below the inferior turbinate; 2 points: polyps reaching the inferior turbinate; 3 points: large polyps reaching the inferior turbinate, or large polyps reaching 2 points and with polyps in the middle turbinate; 4 points: large polyps completely obstructing the lower nasal cavity. The total score is the sum of both sides (total score 0-8 points), the higher the score, the more severe the nasal polyp disease.

[0144] 2) Nasal polyp symptom diary (NPSD)

[0145] The subjects were required to fill in the ePRO daily to record the evaluation of the symptoms (nasal congestion, rhinorrhea, postnasal drip, headache, facial pain and / or pressure, loss of smell) caused by nasal polyps (NP) in the past 24 hours, and the severity of each symptom was reported using a 0-3 point scale divided into 4 grades (see Table 2).

[0146] Table 2 Symptom severity score

[0147] The NP symptom score at each evaluation time point was the average score of each item in the NPSD in the past 7 days, and the nasal congestion score (NCS), loss of smell, rhinorrhea / postnasal drip, facial pain and / or pressure evaluation endpoints were collected through the NPSD. The total symptom score (TSS) of sinusitis was the sum of the scores of the 6 NP symptom items in the NPSD.

[0148] 5. Study results (primary analysis)

[0149] Overall, 177 subjects were screened, of which 114 were randomized: 29 were assigned to the hu179-33 antibody 200 mg Q24W group, 28 to the hu179-33 antibody 400 mg Q24W group, 29 to the hu179-33 antibody 400 mg Q12W group, and 28 to the placebo group. One subject in the hu179-33 antibody 200 mg Q24W group and one in the placebo group withdrew during the double-blind treatment period, and the remaining subjects completed the double-blind treatment period observation.

[0150] Change from baseline in NPS at Week 24: The NPS scores of each dose group of hu179-33 antibody were decreased from baseline after 24 weeks of administration. The least square mean (95% CI) of the change from baseline of the hu179-33 antibody 200 mg Q24W group, 400 mg Q24W group, and 400 mg Q12W group were -2.16 (-2.82, -1.50), -2.23 (-2.88, -1.58), and -2.52 (-3.16, -1.89), respectively. The least square mean (95% CI) of the change from baseline of the placebo group compared with each dose group of hu179-33 antibody were -0.95 (-1.90, 0.00), -1.02 (-1.94, -0.10), and -1.32 (-2.24, -0.39), respectively. The P values were 0.0506, 0.0307, and 0.0056, respectively.

[0151] Proportion of subjects with NPS ≤1 point per nostril at Week 24: The proportions of subjects with NPS ≤1 point per nostril of the hu179-33 antibody 200 mg Q24W group, 400 mg Q24W group, and 400 mg Q12W group at Week 24 were 27.6%, 39.3%, and 37.9%, respectively. The rate difference (95% CI) between the placebo group and each dose group of hu179-33 antibody were 13.6 (-6.8, 33.9), 25.0 (3.0, 47.0), and 23.2 (1.6, 44.8), respectively.

[0152] The incidence of TEAEs in each dose group of hu179-33 antibody was similar to that in the placebo group. The number of cases (incidence) of TEAEs in the hu179-33 antibody 200 mg Q24W group, 400 mg Q24W group, and 400 mg Q12W group were 17 cases (58.6%), 18 cases (64.3%), and 20 cases (69.0%), respectively, and that in the placebo group was 21 cases (75.0%). No TEAE of special interest occurred.

[0153] Three cases of severe TEAEs occurred in 2 subjects (7.1%) in the hu179-33 antibody 400 mg Q24W group, and the PTs were dizziness, large intestinal polyp, and gastric polyp, respectively. One case of severe TEAE occurred in 1 subject (3.6%) in the placebo group, and the PT was hemorrhoids. All the other TEAEs were mild or moderate.

[0154] The most common TEAE system organ class (SOC) category in each dose group of hu179-33 antibody was infectious and parasitic diseases, and the incidence was similar to that in the placebo group. The PTs with an incidence of ≥5% in any group included upper respiratory tract infection and influenza. The second most common TEAE SOC category was metabolic and nutrition disorders, and the incidence was similar to that in the placebo group. The PTs with an incidence of ≥5% in any group included hyperuricemia, hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia.

[0155] The overall safety of the study was good, and the incidence of adverse events in each test drug group was similar to that in the placebo group, and no adverse events occurred that led to permanent drug discontinuation or death.

[0156] Example 2: Pharmacokinetic study of anti-TSLP antibody in cynomolgus monkeys

[0157] 1) Test drug: anti-TSLP antibody, which was prepared according to the method described in WO2022116858, corresponding to the antibody hu179-33, and the antibody heavy chain and light chain sequences are shown as SEQ ID NO: 9 and 10 in the present disclosure.

[0158] 2) Test method: 6 cynomolgus monkeys were selected for the test, 3 males and 3 females, and a single subcutaneous injection of 3 mg / kg of anti-TSLP antibody was given. All animals were collected before drug administration, 2h, 8h, 24h, 48h, 72h, 96h, 120h (D6), 168h (D8), 336h (D15), 504h (D22), 672h (D29), 840h (D36), 1008h (D43), 1176h (D50), 1344h (D57), 1512h (D64), 1680h (D71), 1848h (D78), 2016h (D85) after drug administration, and serum was separated. ELISA analysis method was used to detect the drug concentration in serum. The pharmacokinetic parameters t1 / 2 (half-life), T max (peak time), C max (peak concentration), AUC (area under the curve), and Waston was used to calculate the mean, standard deviation, etc. The experimental results are shown in Table 3, and the data are expressed as mean ± standard deviation.

[0159] Table 3: Statistics of anti-TSLP antibody pharmacokinetic parameters

[0160] Example 3: Pharmacokinetic study of anti-TSLP antibody (reference antibody) in cynomolgus monkeys

[0161] 1) Test drug: Tezepelumab was used as the reference antibody, which was obtained by self-preparation.

[0162] 2) Test method: 3 cynomolgus monkeys, male, were selected for the test, and a single subcutaneous injection of 3 mg / kg of reference antibody Tezepelumab was given. All animals were collected at pre-dose, 2h, 8h, 24h (D2), 48h (D3), 72h (D4), 96h (D5), 120h (D6), 168h (D8), 336h (D15), 504h (D22), 672h (D29) after the start of administration, and serum was separated. The concentration of the reference antibody in each serum sample was determined by ELISA. The pharmacokinetic parameters t 1 / 2 , T max , C max , AUC were calculated for each animal using WinNonlin non-compartment model (NCA). The experimental results are shown in Table 4, and the data are expressed as mean ± standard deviation.

[0163] Table 4: Pharmacokinetic parameters of the reference anti-TSLP antibody

[0164] Example 4: Safety, tolerability, pharmacokinetics, and pharmacodynamics of a single subcutaneous injection of anti-TSLP antibody in healthy subjects and mild asthma patients - randomized, double-blind, dose-escalation, placebo-controlled phase I clinical trial

[0165] 1. Test drug

[0166] 1) Anti-TSLP antibody, which was prepared according to the method described in WO2022116858, corresponding to the antibody named hu179-33. The sequences of the heavy and light chains of the anti-TSLP antibody are shown as SEQ ID NO: 9 and 10 in the present disclosure, and the antibody was formulated into an injection solution with a specification of 1 mL: 0.1 g.

[0167] 2) Placebo, in the form of an injection solution, with a specification of: 1 mL.

[0168] 2. Research method

[0169] Eligible healthy adults (18-55 years old) were randomly administered a single subcutaneous injection of anti-TSLP antibody (five groups: 50 mg, 100 mg, 200 mg, 400 mg, and 600 mg) or placebo in the ratio of 8:2, and the follow-up period for each group was 113 to 253 days.

[0170] 3. Research results

[0171] 50 healthy subjects were enrolled and completed the treatment. All treatment-related adverse events (TRAEs) were mild to moderate in severity. The incidence of TRAEs was 45.0% (18 / 40) and 20.0% (2 / 10) in the anti-TSLP antibody group and placebo group, respectively. The most common TRAEs (≥5%) in the anti-TSLP antibody group were headache (10.0%), injection site bruising (5.0%), and increased troponin I (5.0%). Anti-TSLP antibody absorption was slow, reaching maximum serum concentration (Cmax) after 6.995-17.591 days. The area under the concentration-time curve increased with increasing dose. The mean half-life was 69.7-84.9 days across the dose range of 50 mg to 600 mg. The overall incidence of ADA positivity was similar between the anti-TSLP antibody group and the placebo group, and no clear impact on the corresponding pharmacokinetic characteristics of all ADA-positive subjects was observed.

[0172] Conclusion: The pharmacokinetic characteristics of a single subcutaneous injection of anti-TSLP antibody in the dose range of 50 mg to 600 mg in healthy adult subjects were slightly higher than the dose proportionality, and the safety and tolerability were acceptable. The overall safety and tolerability of anti-TSLP antibody were good in the dose range of 50 mg to 600 mg.

Claims

1. A method for treating an inflammatory disease associated with TSLP, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-TSLP antibody or an antigen-binding fragment thereof; wherein: The anti-TSLP antibody or antigen-binding fragment thereof is administered less frequently than once every four weeks; Preferably, the inflammatory disease associated with TSLP is selected from sinusitis and / or nasal polyps.

2. The method according to claim 1, wherein The inflammatory disease associated with TSLP is selected from nasal polyps, chronic sinusitis (CRS), chronic sinusitis without nasal polyps (CRSsNP) or chronic sinusitis with nasal polyps (CRSwNP); preferably, the inflammatory disease associated with TSLP is chronic sinusitis with nasal polyps.

3. The method according to claim 1 or 2, wherein: The anti-TSLP antibody or antigen-binding fragment thereof is administered at a frequency of less than or equal to once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 18 weeks, once every 20 weeks, or once every 24 weeks; Preferably, the anti-TSLP antibody or antigen-binding fragment thereof is administered once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, once every 18 weeks, once every 20 weeks, once every 22 weeks, once every 24 weeks, once every 26 weeks, or once every 28 weeks.

4. The method according to any one of claims 1 to 3, wherein: The anti-TSLP antibody or antigen-binding fragment thereof is administered at a dosage of 50-800 mg, 100-600 mg, 200-600 mg, 150-450 mg, or 200-400 mg; Preferably, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dosage selected from about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg.

5. The method according to any one of claims 1 to 4, wherein: The anti-TSLP antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously, preferably by subcutaneous injection.

6. The method according to any one of claims 1 to 5, wherein the anti-TSLP antibody or antigen-binding fragment thereof 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.

7. The method according to any one of claims 1 to 6, wherein the anti-TSLP antibody or antigen-binding fragment thereof 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 at least 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8 or at least 90% identical thereto.

8. The method according to any one of claims 1 to 7, wherein: The anti-TSLP antibody or antigen-binding fragment thereof 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 at least 90% identical thereto, and the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10 or at least 90% identical thereto.

9. The method according to any one of claims 1 to 8, wherein: The method further comprises administering to the subject an intranasal glucocorticoid (INCS) and / or a systemic glucocorticoid (SCS); preferably, the intranasal glucocorticoid is budesonide.

10. The method according to any one of claims 1 to 9, wherein: The method improves the subject's nasal polyp score (NPS), nasal polyp (NP) symptoms, nasal congestion score (NCS), nasal sinus outcome test 22 scale (SNOT-22) score and / or total sinusitis symptom score (TSS).

11. Use of an anti-TSLP antibody or an antigen-binding fragment thereof in at least one of the following (1)-(2): (1) For the treatment of inflammatory diseases associated with TSLP; (2) used to improve the subjects' nasal polyp score (NPS), nasal polyp (NP) symptoms, nasal congestion score (NCS), nasosinusitis outcome test 22-item scale (SNOT-22) score and / or total sinusitis symptom score (TSS); in, The anti-TSLP antibody or antigen-binding fragment thereof is administered less than once every 4 weeks, preferably less than or equal to once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 18 weeks, once every 20 weeks, or once every 24 weeks, more preferably once every 8 weeks, once every 10 weeks, once every 12 weeks, once every 14 weeks, once every 16 weeks, once every 18 weeks, once every 20 weeks, once every 22 weeks, once every 24 weeks, once every 26 weeks, or once every 28 weeks; Preferably, the anti-TSLP antibody or antigen-binding fragment thereof is administered at a dosage of 50-800 mg, 100-600 mg, 200-600 mg, 150-450 mg or 200-400 mg, more preferably about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg; Preferably, the inflammatory disease associated with TSLP is selected from sinusitis and / or nasal polyps, preferably nasal polyps, chronic sinusitis (CRS), chronic sinusitis without nasal polyps (CRSsNP) or chronic sinusitis with nasal polyps (CRSwNP), more preferably chronic sinusitis with nasal polyps; Preferably, the anti-TSLP antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously, more preferably by subcutaneous injection; Preferably, the anti-TSLP antibody or antigen-binding fragment thereof is as defined in any one of claims 6-8.