Use of recombinant Anti-interleukin 23p19 subunit antibody in treating inflammatory bowel disease

Abstract

The present invention relates to a method for treating inflammatory bowel diseases by using a recombinant anti-interleukin (IL) 23p19 subunit antibody, comprising ulcerative colitis and Crohn's disease, and in particular to a dosage regimen for preventing or treating mild ulcerative colitis and moderate and severe ulcerative colitis by using the anti-IL-23p19 antibody.

Description

Use of recombinant anti-interleukin 23p19 subunit antibody in the treatment of inflammatory bowel disease Technical Field

[0001] The present invention generally relates to the treatment of inflammatory bowel diseases, including ulcerative colitis (eg, mild or moderately severe ulcerative colitis) and Crohn's disease, with anti-IL-23p19 antibodies, and particularly to dosage regimens for treating such diseases. Background Art

[0002] Inflammatory bowel disease (IBD) is an idiopathic inflammatory intestinal disease affecting the ileum, rectum, and colon, with clinical manifestations of diarrhea, abdominal pain, and even bloody stools. Inflammatory bowel diseases include ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis (UC) is a chronic inflammatory disease characterized by inflammation of the colon and rectum. Typical symptoms are recurrent diarrhea, mucus, pus, and blood in the stool accompanied by abdominal pain and tenesmus. UC seriously threatens physical health and affects daily life and psychology. The clinical classification of UC can be divided into primary and chronic recurrent types. UC is more common in European and North American countries. The incidence in my country is lower than that in Western populations, but the number of patients seeking medical treatment has been increasing rapidly in the past 20 years, with a prevalence of 11.6 / 100,000. The disease is more common in young and middle-aged people. Crohn's disease (CD) is a chronic inflammatory granulomatous disease that can affect the entire digestive tract. It presents as a non-continuous, full-thickness inflammation, most commonly affecting the terminal ileum and adjacent colon. The primary lesion is peptic ulceration, which can lead to intestinal stenosis and perforation, and carries a high risk of recurrence. The incidence of Crohn's disease has increased significantly over the past decade.

[0003] The clinical treatment of UC is mainly based on medication and surgery. Thiopurine drugs are the most traditional immunosuppressants, but they have a high incidence of adverse reactions. In terms of biological treatment, anti-TNF-α monoclonal antibodies are used for patients who are ineffective with hormone and immunosuppressant treatment, or who are hormone-dependent or cannot tolerate the above-mentioned drug treatments. Infliximab (IFX) was previously the only biological agent approved for the treatment of UC and CD in my country. In May 2019, ustekinumab ( Ustekinumab) was included in the second batch of urgently needed overseas new drugs by NMPA for the treatment of adult patients with moderate to severe active Crohn's disease (CD) who have insufficient response, loss of response, or intolerance to traditional treatment or tumor necrosis factor α (TNF-α) antagonists. In March 2020, vedolizumab ( Vedolizumab has been approved by the National Medical Products Administration (NMPA) in China for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and leukopenia (CD) who have had an inadequate response, failed response, or are intolerant to conventional therapy or tumor necrosis factor α (TNF-α) inhibitors. Consequently, a variety of biologics targeting specific immune pathways have been investigated as potential treatments for UC. Anti-tumor necrosis factor-α (anti-TNFα) monoclonal antibodies and, more recently, the integrin receptor antagonist vedolizumab have been approved by the US Food and Drug Administration and the European Medicines Agency.

[0004] IL-23 (interleukin-23) is a heterodimeric cytokine that is a member of the IL-12 family. It shares the same p40 subunit and a unique p19 subunit as IL-12. The IL-23 heterodimer activates signaling pathways by binding to the IL-23 receptor (IL-23R) and the β1 subunit of the IL-12 receptor (IL-12Rβ1). Although IL-23 and IL-12 are closely related, these two cytokines play distinct biological roles, with IL-12 and IL-23 driving Th1 and Th17 cell responses, respectively. It can induce naive CD4+ T cells to differentiate into Th17 cells, either alone or with the help of other cytokines such as transforming growth factor-β (TGF-β), IL-6, or IL-1β, and can promote the proliferation, differentiation, and maintenance of Th17 and innate immune cells. Th17 cells stimulate the production of cytokines including IL-17, IL-22, tumor necrosis factor (TNF)-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which in turn stimulate local tissue inflammation and other immune-mediated pathologies through a broad immune-mediated inflammatory state. Chronic inflammation resulting from a dysregulated IL-23 / Th17 / IL-17 response underlies the pathophysiology of multiple autoimmune diseases, including psoriasis, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, and asthma. Several companies are pursuing IL-23-targeted therapies for a wide range of diseases. The first biopharmaceutical to demonstrate clinical benefit in an autoimmune disease was ustekinumab, a monoclonal antibody approved by the US Food and Drug Administration for the treatment of psoriasis, psoriatic arthritis, and CD. Ustekinumab binds to the shared p40 subunit of IL-12 and IL-23; thus, it targets both cytokines, rather than IL-23 specifically. Blocking the IL-12 pathway can prevent Th1 cells from inducing interferon blockade of Th17 cells, thus potentially limiting the clinical activity of antibodies targeting p40. Agents specifically targeting the IL-23p19 subunit have demonstrated clinical activity in psoriasis and CD (Kopp T et al., Nature, Vol. 521, No. 7551, pp. 222-226, 2015; Sands BE et al., Journal of Crohn's and Colitis, Vol. 9, Supplement No. 1, pp. S15-S16, 2015).

[0005] Traditional drugs or biological agents approved for the treatment of ulcerative colitis all have insufficient response rates, loss of response or intolerance, and have adverse reactions of varying types and degrees.

[0006] SUMMARY OF THE INVENTION

[0007] The present inventors unexpectedly discovered that the administration of anti-IL-23p19 antibodies, particularly administration according to the dosage regimen of the present invention, produced satisfactory clinical response rates and clinical remission rates in patients with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, achieved positive therapeutic effects, and no significant or unacceptable adverse reactions were observed. The safety profile was acceptable and controllable, and the antibodies were well tolerated, with good patient compliance.

[0008] The present invention also meets the above needs by providing methods of treating ulcerative colitis using anti-IL-23p19 antibodies.

[0009] Thus, in a first aspect, there is provided a method of preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, in a patient, the method comprising administering to a patient in need thereof an anti-IL-23p19 antibody of the invention.

[0010] In a second aspect, provided is a use of the anti-IL-23p19 antibody of the present invention for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0011] In a third aspect, an anti-IL-23p19 antibody of the present invention is provided for use in preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0012] In a fourth aspect, provided is a use of the anti-IL-23p19 antibody of the present invention in the preparation of a medicament for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0013] In a fifth aspect, a pharmaceutical composition is provided, comprising an effective amount of an anti-IL-23p19 antibody of the present invention and one or more pharmaceutically acceptable excipients.

[0014] In a sixth aspect, a kit is provided comprising an effective amount of an anti-IL-23p19 antibody of the invention and a package insert containing instructions for using the anti-IL-23p19 antibody for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0015] In a seventh aspect, a single dosage unit is provided comprising an effective amount of an anti-IL-23p19 antibody of the invention.

[0016] In an eighth aspect, there is provided a use of a kit of parts for preparing a medicament for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0017] In one embodiment of the present invention, a method for preventing or treating inflammatory bowel disease is provided. Preferably, the inflammatory bowel disease is ulcerative colitis (eg, mild, moderate or severe ulcerative colitis) or Crohn's disease.

[0018] In one embodiment of the present invention, a method for preventing or treating ulcerative colitis is provided. Preferably, the ulcerative colitis is moderate to severe ulcerative colitis.

[0019] In one embodiment of the invention, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0020] a) induction therapy phase: administering one or more induction doses of anti-IL-23p19 antibody to a patient in need thereof, wherein each induction dose is 100-1000 mg; and

[0021] b) Maintenance therapy phase: administering one or more maintenance doses of an anti-IL-23p19 antibody to the patient, the first maintenance dose being administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg, wherein the amino acid sequence of the heavy chain CDR1 of the antibody comprises SEQ ID NO.1 or consists of it, the amino acid sequence of the heavy chain CDR2 comprises SEQ ID NO.2 or consists of it, and the amino acid sequence of the heavy chain CDR3 comprises SEQ ID NO.3 or consists of it; and the amino acid sequence of the light chain CDR1 of the antibody comprises SEQ ID NO.4 or consists of it, the amino acid sequence of the light chain CDR2 comprises SEQ ID NO.5 or consists of it, and the amino acid sequence of the light chain CDR3 comprises SEQ ID NO.6 or consists of it.

[0022] In one embodiment of the invention, the induction dose is administered by intravenous injection, and / or the maintenance dose is administered by subcutaneous injection.

[0023] In one embodiment of the invention, administration of the induction dose produces a clinical response and the patient enters a maintenance treatment phase.

[0024] In one embodiment of the present invention, the induction dose is administered 1-3 times, preferably 3 times.

[0025] In one embodiment of the invention, when multiple induction doses are administered, the induction doses are administered at 4 week intervals.

[0026] In one embodiment of the invention, when multiple maintenance doses are administered, the maintenance doses are administered at intervals of 4-8 weeks.

[0027] In one embodiment of the invention, the first maintenance dose is administered 2-8 weeks after the last induction dose. Preferably, the first maintenance dose is administered 4 weeks after the last induction dose.

[0028] In one embodiment of the invention, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0029] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody to patients in need at 4-week intervals, with each induction dose being 100-1000 mg;

[0030] b) maintenance treatment phase: administering maintenance doses of anti-IL-23p19 antibody to the patient at intervals of 4-8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg;

[0031] The amino acid sequence of the antibody heavy chain CDR1 comprises or consists of SEQ ID NO.1, the amino acid sequence of the heavy chain CDR2 comprises or consists of SEQ ID NO.2, and the amino acid sequence of the heavy chain CDR3 comprises or consists of SEQ ID NO.3; the amino acid sequence of the antibody light chain CDR1 comprises or consists of SEQ ID NO.4, the amino acid sequence of the light chain CDR2 comprises or consists of SEQ ID NO.5, and the amino acid sequence of the light chain CDR3 comprises or consists of SEQ ID NO.6, and the boundaries of the CDRs are determined by the AbM rule.

[0032] In one embodiment of the present invention, the ulcerative colitis is moderate to severe ulcerative colitis. In another embodiment, the ulcerative colitis is mild ulcerative colitis.

[0033] In one embodiment of the present invention, the induction dose is administered by intravenous injection. Preferably, the induction dose is administered by intravenous infusion.

[0034] In one embodiment of the invention, the maintenance dose is administered by subcutaneous injection.

[0035] In one embodiment of the invention, three induction doses of anti-IL-23p19 antibody are administered to a patient in need thereof by intravenous infusion at 4-week intervals.

[0036] In one embodiment of the invention, a maintenance dose of an anti-IL-23p19 antibody is administered to a patient in need thereof by subcutaneous injection at 4-week intervals.

[0037] In one embodiment of the invention, a maintenance dose of an anti-IL-23p19 antibody is administered to a patient in need thereof by subcutaneous injection at intervals of 8 weeks.

[0038] In one embodiment of the invention, the induction dose in the method is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.

[0039] In one embodiment of the invention, the induction dose in the method is 200 mg.

[0040] In one embodiment of the invention, the induction dose in the method is 600 mg.

[0041] In one embodiment of the invention, the method wherein the maintenance doses are administered at 4 week intervals after administration of the first maintenance dose.

[0042] In one embodiment of the invention, the first maintenance dose in the method is administered 4 weeks after the last induction dose.

[0043] In one embodiment of the invention, the maintenance dose in the method is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.

[0044] In one embodiment of the invention, the maintenance dose in this method is 200 mg.

[0045] In one embodiment of the present invention, the dosing regimen in the method comprises an extended induction phase: three induction doses of an anti-IL-23p19 antibody are administered to a patient in need at 4-week intervals; if the patient does not achieve a clinical response 2-8 weeks after the last induction dose, the patient is given three extended induction doses, each extended induction dose is 100-1000 mg; if the patient has a clinical response to the extended induction dose, the patient enters a maintenance treatment phase.

[0046] In one embodiment of the invention, wherein a clinical response is not achieved 4 weeks after the last induction dose, the patient is given 3 extended induction doses, each extended induction dose is 100-1000 mg.

[0047] In one embodiment of the invention, the extended induction dose is administered at 4-week intervals.

[0048] In one embodiment of the invention, the prolonged induction dose is administered by intravenous infusion.

[0049] In one embodiment of the invention, the first extended induction dose is administered 4 weeks after the last induction dose.

[0050] In one embodiment of the invention, the extended induction dose in the method is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.

[0051] In one embodiment of the invention, the extended induction dose in this method is 600 mg.

[0052] In one embodiment of the invention, following the extended induction phase, the first maintenance dose is administered 2-8 weeks after the last extended induction dose.

[0053] In one embodiment of the invention, following the extended induction phase, the first maintenance dose is administered 4 weeks after the last extended induction dose.

[0054] In one embodiment of the present invention, after the extended induction phase, a maintenance dose of anti-IL-23p19 antibody is administered to a patient in need thereof by subcutaneous injection at intervals of 4 weeks.

[0055] In one embodiment of the invention, the method comprises administering maintenance doses after an extended induction phase, wherein each maintenance dose is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.

[0056] In one embodiment of the invention, the method comprises administering maintenance doses after the extended induction phase, wherein each maintenance dose is 200 mg.

[0057] The method of the present invention comprises administering to a patient in need thereof at least one induction dose of an anti-IL-23p19 antibody during an induction phase to induce a desired therapeutic effect, wherein the desired therapeutic effect is clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptom relief. If the patient achieves the desired therapeutic effect at the end of the induction phase, then administering to the patient at least one maintenance dose to maintain at least one therapeutic effect achieved during the induction phase, wherein the therapeutic effect is clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptom relief.

[0058] There is no minimum or maximum duration for the induction phase, but it is generally 4, 8, or 12 weeks, with the induction phase typically ending with an end-of-induction assessment performed 4 or 8 weeks after the last induction dose has been administered. For example, a 4-week induction phase may include administration of an induction dose at week 0 and an end-of-induction assessment at week 4. An 8-week induction phase may include administration of an induction dose at weeks 0 and 4 and an end-of-induction assessment at week 8. A 12-week induction phase may include administration of an induction dose at weeks 0, 4, and 8 and an end-of-induction assessment at week 12.

[0059] In one embodiment of the present invention, the heavy chain of the anti-IL-23p19 antibody contains an N-glycosylation site located at asparagine 295 of the heavy chain.

[0060] In one embodiment of the invention, the anti-IL-23p19 antibody in the method comprises a heavy chain variable region, VH, comprising or consisting of the sequence of SEQ ID NO: 7, or a sequence at least 90%, 95%, 98% or 99% identical thereto, and a light chain variable region, VL, comprising or consisting of the sequence of SEQ ID NO: 8, or a sequence at least 90%, 95%, 98% or 99% identical thereto.

[0061] In one embodiment of the invention, the anti-IL-23p19 antibody in the method is an IgG1 type antibody, preferably comprising a heavy chain comprising or consisting of SEQ ID NO: 9 or a sequence at least 90%, 95%, 98% or 99% identical thereto, and a light chain comprising or consisting of SEQ ID NO: 10 or a sequence at least 90%, 95%, 98% or 99% identical thereto.

[0062] In one embodiment of the present invention, the anti-IL-23p19 antibody comprises the heavy chain shown in SEQ ID NO: 9 and the light chain shown in SEQ ID NO: 10; for example, the anti-IL-23p19 antibody comprises two heavy chains shown in SEQ ID NO: 9 and two light chains shown in SEQ ID NO: 10, or consists of two heavy chains shown in SEQ ID NO: 9 and two light chains shown in SEQ ID NO: 10.

[0063] In one embodiment of the present invention, the anti-IL-23p19 antibody is recombinantly expressed in HEK 293 cells or CHO cells.

[0064] In one embodiment of the present invention, it also relates to a kit of parts, comprising an effective amount of the above-mentioned anti-IL-23p19 antibody; preferably, it also comprises a package insert printed with instructions for using the anti-IL-23p19 antibody in an individual to prevent or treat inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0065] The present invention also provides a single-dose unit comprising an effective amount of the anti-IL-23p19 antibody of the present invention, and a kit comprising an effective amount of the anti-IL-23p19 antibody of the present invention.

[0066] In one embodiment of the present invention, the present invention also includes use of the kit of parts in the preparation of a medicament for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0067] The anti-IL-23p19 antibody of the present invention is used to prevent or treat inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, in an individual. The method includes administering the antibody once every four or eight weeks during the maintenance phase. This can increase the patient's compliance with the medication, reduce the patient's fear of injections, alleviate the patient's physical and psychological burden, and help maintain long-term remission in the patient.

[0068] In yet another embodiment of the methods of the present invention, the patient is biologic drug naive.

[0069] In an alternative embodiment of the methods of the present invention, the patient is biopharmaceutical-naive.

[0070] This embodiment of the method of the present invention includes administering one, two, or three additional induction doses—referred to as "extended induction doses" to distinguish them from the initial induction dose—if the patient does not achieve a clinical response at the end of the initial induction phase. The dosage and dosing interval during the extended induction phase are generally the same as those during the initial induction phase, but may be modified, such as by increasing the dose of the anti-IL-23p19 antibody or administering it more frequently, if the attending healthcare professional has reason to believe that the patient would benefit from the modification. If the patient achieves a clinical response at the end of the extended induction phase, at least one maintenance dose of the anti-IL-23p19 antibody is administered to maintain the clinical response or other desired therapeutic effect, such as clinical remission, endoscopic remission, mucosal healing, and / or symptom relief. The first maintenance dose is administered 4-12 weeks after the last extended induction dose is administered to the patient. This 4-12 week period accounts for the time variability between administration of the last extended induction dose and assessment at the end of the extended induction phase. This variability may result from changes in dosing frequency during the extended induction phase. In the induction phase of extension, for example, the administration frequency is every 4 weeks and after using the last extended type induction dose for 4 weeks, the induction is extended and assessment is completed. If the patient has achieved clinical response, the first maintenance dose can be used at induction to end assessment visit (i.e., after using the last extended type induction dose for 4 weeks) or can be used at the subsequent visit that is planned to be carried out soon after this. Alternatively, in the induction phase of extension, the administration frequency is every 8 weeks and after using the last extended type induction dose for 8 weeks, the induction is extended and assessment is completed. If the patient has achieved clinical remission, the first maintenance dose can be used at induction to end assessment visit (i.e., after using the last extended type induction dose for 8 weeks) or can be used at the subsequent visit that is planned to be carried out soon after this.

[0071] Other embodiments of the present invention will become apparent by reference to the detailed description which follows.

[0072] Detailed Description of the Invention

[0073] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be varied. In addition, the terminology used herein is only for describing specific embodiments and is not intended to be limiting.

[0074] definition

[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.

[0076] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value.

[0077] The term "and / or" when used to link two or more alternatives should be understood to mean any one of the alternatives or any two or more of the alternatives.

[0078] As used herein, the terms "comprising" or "including" are intended to include the recited elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms "comprising" or "including" are used, unless otherwise indicated, the context of consisting of the recited elements, integers, or steps is also encompassed. For example, when reference is made to an antibody variable region "comprising" a specific sequence, it is intended to encompass an antibody variable region consisting of that specific sequence.

[0079] The p19 subunit of IL-23 (also referred to herein as "IL-23p19" and "p19 subunit") is a 189 amino acid polypeptide containing a 21-amino acid leader sequence (Oppmann et al., Immunity 13:715 (2000), SEQ ID NO:181) and comprises four packed α-helices, designated A, B, C, and D, with an up-up-down-down topology. The four helices are connected by three polypeptide loops. The AB and CD loops are made relatively long because they connect the parallel helices. The short BC loop connects the antiparallel B and C helices. The p19 subunit of IL-23 is a member of the IL-6 family of helical cytokines. This family of cytokines binds to its cognate receptor via three conserved epitopes (sites I, II, and III; Bravo and Heath (2000) EMBO J. 19:2399-2411). The p19 subunit interacts with three cytokine receptor subunits to form a competent signaling complex. When expressed in cells, the p19 subunit initially forms a complex with the p40 subunit, which it shares with IL-12. The p19p40 complex is secreted from cells as a heterodimeric protein and is referred to as IL-23. In one embodiment, the IL-23p19 of the present invention is derived from humans (NCBI: AAG37232) or cynomolgus monkeys (NCBI: AEY84629).

[0080] As used herein, the terms "anti-IL-23p19 antibody," "anti-IL-23p19," "IL-23p19 antibody," or "antibody that binds to IL-23p19" refer to an antibody that is capable of binding to a (human or cynomolgus monkey) IL-23p19 subunit or fragment thereof with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent in targeting (human or cynomolgus monkey) IL-23p19.

[0081] As used herein, the term "antibody" is used in the broadest sense to refer to a protein that contains an antigen binding site, encompassing natural antibodies and artificial antibodies of various structures, including but not limited to complete antibodies and antigen-binding fragments of antibodies.

[0082] The terms "whole antibody," "full-length antibody," "complete antibody," and "intact antibody" are used interchangeably herein to refer to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, which are complementarity determining regions (CDRs), interspersed with more conserved regions, which are framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant region is not directly involved in binding the antibody to the antigen, but exhibits various effector functions.

[0083] "Complementarity determining region" or "CDR region" or "CDR" is a region in an antibody variable domain that is highly variable in sequence and forms structurally determined loops ("hypervariable loops") and / or contains antigen contact residues ("antigen contact points"). CDRs are primarily responsible for binding to antigenic epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, and are numbered sequentially starting from the N-terminus. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3.

[0084] In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well-known antibody CDR assignment systems, including, for example, Chothia based on the three-dimensional structure of antibodies and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics database (IMGT) (on the World Wide Web at imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures.

[0085] An exemplary AbM rule is as follows:

[0086] Unless otherwise indicated, in the present invention, when referring to residue positions in the variable region of an antibody (including heavy chain variable region residues and light chain variable region residues), the numbering refers to the position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0087] In one embodiment, the CDRs of an antibody of the invention have boundaries defined by the AbM rule.

[0088] "Antibody fragments" refer to molecules other than intact antibodies that comprise a portion of an intact antibody and bind to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent or bispecific antibodies or fragments thereof; camelid antibodies; and bispecific or multispecific antibodies formed from antibody fragments.

[0089] As used herein, the term "antigen-binding fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antigen-binding fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent or bispecific antibodies or fragments thereof; camelid antibodies; and bispecific or multispecific antibodies formed from antibody fragments.

[0090] The term "pharmaceutical composition" or "formulation" refers to a composition suitable for administration to an animal, preferably a mammal (including a human) comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention is preferably in the form of parenteral administration, such as a solution, suspension, lyophilized powder, concentrated solution, etc.

[0091] The term "kit-of-parts" refers to a pharmaceutical composition comprising one or more separate pharmaceutical compositions, at least one of which comprises an effective amount of an anti-IL-23p19 antibody, and a package insert containing instructions for use of the anti-IL-23p19 antibody for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, particularly according to the dosing regimen of the present invention. The kit-of-parts may further comprise other therapeutic agents having the same or different activities. It will be appreciated that when the kit-of-parts comprises multiple separate pharmaceutical compositions, each of the pharmaceutical compositions may comprise a different dosage and / or be administered by a different route.

[0092] As used herein, the term "single pharmaceutical dosage unit" refers to a single pharmaceutical dosage form comprising an antibody of the present invention to be administered to a patient at the time of administration, such as an injection vial, ampoule, prefilled needle or prefilled syringe containing a solution or lyophilized powder of the drug.

[0093] The terms "patient" and "subject" are used interchangeably to refer to an animal. Preferably, the patient or subject is a mammal, such as a primate (e.g., human, monkey, orangutan), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. More preferably, the patient or subject is a human.

[0094] The term "biologic-naive" patients or subjects refers to patients or subjects who have not previously received treatment with biologic agents, such as anti-tumor necrosis factor-α (TNF-α) antagonists such as adalimumab, infliximab, etc., anti-integrin antibodies such as vedolizumab, or other experimental biological therapies.

[0095] As used herein, the term "parenteral administration" means modes of administration other than enteral and topical administration, usually by injection or infusion, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0096] The term "pharmaceutically acceptable" means that the substances, compositions, dosage forms, etc. described thereafter do not have excessive toxicity, irritation, allergic reactions or other undesirable properties to mammals, especially humans, and have a reasonable benefit / risk ratio when used in animals or humans.

[0097] The term "pharmaceutically acceptable excipient" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to a subject. Examples of pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.

[0098] The term "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the required dosage and for the required period of time. It can be determined by the attending physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. Generally, a "prophylactically effective amount" will be less than a "therapeutically effective amount."

[0099] The term "treat" refers to alleviating or reducing the severity of, slowing or arresting the progression of, or curing at least one symptom or condition.

[0100] The term "prevent" or "preventing" means delaying or preventing the onset of a disorder or its symptoms.

[0101] The term "inflammatory bowel disease" refers to an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon, with clinical manifestations of diarrhea, abdominal pain, and even bloody stools.

[0102] The term "ulcerative colitis" refers to a continuous inflammation of the colonic mucosa and submucosa, primarily affecting the rectum and colon. Disease severity can be categorized as mild, moderate, or severe. The modified Mayo scoring system is used to assess the severity and activity of ulcerative colitis.

[0103] The term "Crohn's disease" refers to a chronic inflammatory granulomatous disease of unknown cause that can affect the entire digestive tract. It is a non-continuous full-thickness inflammation with the main lesion being peptic ulcers.

[0104] The term "week 0" refers to the time of first administration of the IL-23p19 antibody. The term "week 4" refers to the fourth week from the time of first administration of the IL-23p19 antibody. The term "week 8" refers to the eighth week from the time of first administration of the IL-23p19 antibody. Other similar terms should be interpreted accordingly.

[0105] As used herein, the "modified Mayo score" is derived from the Mayo scoring system for the severity and activity of ulcerative colitis (Schreder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987; 317(26): 16 25-9), which does not use the physician's global assessment according to the recommendation of the U.S. Food and Drug Administration (FDA). It consists of three items: number of bowel movements, blood in the stool, and endoscopic findings, with scores ranging from 0 to 9.

[0106] As used herein, the "symptom Mayo score" refers to the modified Mayo score excluding endoscopic findings, with a score of 0 to 6.

[0107] As used in this article, the "partial Mayo score" refers to the Mayo score that excludes endoscopic findings, namely, the score that includes bowel movements, blood in stool, and physician's global assessment. It is used only to assess clinical recurrence and is not an indicator of efficacy.

[0108] As used herein, “clinical remission” was the primary endpoint of the study and was defined as a modified Mayo score of 0 for hematochezia, 1 for the frequency of bowel movements, and 1 for endoscopic findings.

[0109] As used herein, "clinical response" refers to a decrease in the modified Mayo score by ≥30% and ≥2 points relative to the baseline value, and a decrease in the hematochezia score by ≥1 point relative to the baseline or a score of 0 or 1 point.

[0110] As used herein, "symptom relief" refers to a stool frequency score of 0 or 1 and a blood in stool score of 0.

[0111] As used herein, "endoscopic remission" refers to an endoscopic score of 0 or 1 in the modified Mayo Clinic score. An endoscopic score of 0 is considered to be endoscopic complete remission.

[0112] As used herein, "mucosal healing" refers to endoscopic remission and histopathologically centered Geboes index remission.

[0113] As used herein, "induction dose" refers to the first dose of an anti-IL-23p19 antibody administered to a patient for the purpose of inducing clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief. An "induction dose" can be a single administration. An "induction dose" can also be administered multiple times. References herein to "induction dose" generally refer to the dose administered during the induction phase of therapy, unless otherwise indicated or clearly contradicted by the context.

[0114] As used herein, "induction therapy phase" refers to the phase during which an "induction dose" is administered in order to induce clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief.

[0115] As used herein, an "extended induction phase" refers to a phase of treatment of a patient that includes administering an anti-IL-23p19 antibody to the patient for the purpose of inducing clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief, because clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief was not achieved during the initial induction treatment phase. The "extended induction phase" can be a 4, 8, or 12 week period.

[0116] As used herein, an "extended induction dose" refers to an additional induction dose of an anti-IL-23p19 antibody, wherein the additional induction dose is administered to a patient in order to induce clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief because clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief was not achieved during the initial induction phase. An "extended induction dose" can be a single administration or, alternatively, a series of doses. There is no minimum or maximum duration for an extended induction phase, but it is generally 4 weeks, 8 weeks, or 12 weeks. An extended end-of-induction phase is generally an extended end-of-induction assessment performed 4 or 8 weeks after the last extended induction dose has been administered. An "extended induction dose" is administered during the extended induction therapy phase.

[0117] As used herein, a "maintenance (treatment) phase" refers to a treatment phase that includes administering an anti-IL-23p19 antibody to a patient to maintain the desired therapeutic effect, which is clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief. A "maintenance phase" follows the induction treatment phase or extends the induction treatment phase and is therefore initiated once the desired therapeutic effect - clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptomatic relief - is achieved.

[0118] As used herein, a "maintenance dose" refers to a subsequent dose of an anti-IL-23p19 antibody that is administered to maintain or prolong the desired therapeutic effect, i.e., clinical remission, clinical response, endoscopic remission, mucosal healing, and / or symptom relief. A "maintenance dose" is administered after an induction dose. A "maintenance dose" can be a single dose or, alternatively, a series of doses. Following the completion of the induction phase, the first dose administered during the maintenance phase is referred to as the "first maintenance dose."

[0119] In some embodiments, the dosing regimens of the invention comprise an induction treatment phase followed by a maintenance treatment phase, wherein the induction treatment phase and the maintenance treatment phase are as described herein.

[0120] In other embodiments, the dosing regimens of the invention comprise an induction treatment phase followed by an extended induction phase, and followed by a maintenance treatment phase, wherein the induction treatment phase, extended induction phase, and maintenance treatment phase are as described herein.

[0121] In some embodiments, the Mayo score, preferably the modified Mayo score, is performed at the end of the induction treatment phase. In particular, the Mayo score, preferably the modified Mayo score, is performed at weeks 11-12.

[0122] In some embodiments, the Mayo score, preferably the modified Mayo score, is performed at the end of the extended induction phase. In particular, the Mayo score, preferably the modified Mayo score, is performed at weeks 23-24.

[0123] In some embodiments, a safety follow-up period of 8 weeks is conducted after the last maintenance dose.

[0124] In some embodiments, the dosing regimen of the present invention comprises:

[0125] a) induction therapy phase: administering one or more induction doses of anti-IL-23p19 antibody to a patient in need thereof, wherein each induction dose is 100-1000 mg; and

[0126] b) Maintenance treatment phase: the patient is administered one or more maintenance doses of anti-IL-23p19 antibody, with the first maintenance dose being administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg.

[0127] In some embodiments, the induction treatment phase comprises administering to the patient one or more induction doses of an anti-IL-23p19 antibody, wherein each induction dose is 100-1000 mg. Preferably, the induction dose is administered by intravenous injection. More preferably, the induction dose is administered by intravenous infusion.

[0128] In some embodiments, administration of the induction dose produces a clinical response and the patient enters a maintenance treatment phase.

[0129] In some embodiments, the induction dose can be administered one or more times, for example, once, twice, three times, or four times. Preferably, the induction dose is administered 1-3 times. More preferably, the induction dose is administered 3 times. When multiple induction doses are administered, the induction doses are administered at 4-week intervals. It will be understood that the induction doses may be equal or unequal.

[0130] In one embodiment, the patient develops a clinical response 2-8 weeks after the last induction dose of the induction phase and subsequently receives a maintenance phase. In some embodiments, the first maintenance dose is administered 2-8 weeks after the last induction dose. Preferably, the first maintenance dose is administered 4 weeks after the last induction dose.

[0131] In some embodiments, the maintenance treatment phase comprises administering to the patient one or more maintenance doses of an anti-IL-23p19 antibody, wherein each maintenance dose is 100-1000 mg. Preferably, the maintenance dose is administered by subcutaneous injection.

[0132] In one embodiment, the maintenance dose can be administered once or multiple times. In one embodiment, when multiple maintenance doses are administered, the maintenance doses are administered at intervals of 4-8 weeks. Preferably, the maintenance doses are administered at intervals of 4 or 8 weeks. It will be appreciated that when multiple maintenance doses are administered, the maintenance doses may be equal or unequal. In particular, the maintenance treatment phase continues for 32 weeks starting from the administration of the first maintenance dose.

[0133] In a specific embodiment of the present invention, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the dosing regimen comprises administering three induction doses of the anti-IL-23p19 antibody to the patient in need thereof at 4-week intervals, each induction dose being 100-1000 mg.

[0134] In a specific embodiment of the present invention, the method comprises administering maintenance doses of anti-IL-23p19 antibody to the patient at intervals of 4-8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, and each maintenance dose being 100-1000 mg.

[0135] In one embodiment, the dosage regimen of the present invention comprises:

[0136] a) Induction therapy phase: administering three induction doses of anti-IL-23p19 antibody to patients in need thereof at 4-week intervals, wherein each induction dose is 100-1000 mg; and

[0137] b) Maintenance treatment phase: the patient is administered a maintenance dose of anti-IL-23p19 antibody at intervals of 4-8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg.

[0138] In a specific embodiment of the present invention, the anti-IL-23p19 antibody is an antibody that specifically binds to IL-23p19 and comprises the following 6 CDRs:

[0139] - a heavy chain VH CDR1 comprising or consisting of GYTFTSYLMH (SEQ ID NO: 1);

[0140] - a heavy chain VH CDR2 comprising or consisting of YINPYNEGTN (SEQ ID NO: 2);

[0141] - a heavy chain VH CDR3 comprising or consisting of NWDLPY (SEQ ID NO: 3);

[0142] - a light chain VL CDR1 comprising or consisting of RASQSISDYLH (SEQ ID NO: 4);

[0143] - a light chain VL CDR2 comprising or consisting of YASQSMS (SEQ ID NO: 5); and

[0144] - A light chain VL CDR3 comprising or consisting of QQGHSFPFT (SEQ ID NO: 6).

[0145] In particular, the boundaries of the CDRs are determined by AbM rules.

[0146] In a specific embodiment, the inflammatory bowel disease is ulcerative colitis (UC) or Crohn's disease (CD).

[0147] In a specific embodiment, the UC is moderate to severe ulcerative colitis, which includes but is not limited to moderate to severe active ulcerative colitis (modified Mayo score 4 to 9, with an endoscopic score ≥ 2). In a specific embodiment, the UC is mild ulcerative colitis.

[0148] In a specific embodiment, the method administers three induction doses of an anti-IL-23p19 antibody to a patient in need thereof by intravenous infusion at four-week intervals.

[0149] In a specific embodiment, the method administers a maintenance dose of an anti-IL-23p19 antibody to a patient in need thereof by subcutaneous injection at intervals of 4-8 weeks, eg, 4 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0150] In one embodiment, the induction dose in this method is 100-1000 mg, such as 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg. It is understood that the induction dose can be 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg, or a range consisting of any two thereof, such as 200-900 mg, 200-800 mg, 200-600 mg, etc. In one embodiment, the induction dose is 200 mg. In another embodiment, the induction dose is 600 mg.

[0151] In a specific embodiment, the maintenance dose can be administered once or multiple times. It will be appreciated that the maintenance doses may be equal or unequal. When multiple maintenance doses are administered, the maintenance doses are administered at intervals of 2-8 weeks. In a specific embodiment, the maintenance doses are administered at intervals of 2-8 weeks, e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, after the first maintenance dose is administered. In particular, the maintenance doses are administered at intervals of 4 weeks or 8 weeks. In particular, the maintenance treatment phase continues for 32 weeks from the administration of the first maintenance dose.

[0152] In a specific embodiment, the first maintenance dose in the method is administered 2-8 weeks after the last induction dose, for example 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks. Preferably, the first maintenance dose is administered 4 weeks after the last induction dose of the induction treatment phase.

[0153] In a specific embodiment, the maintenance dose in the method is 100-1000 mg, for example, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. It is understood that the maintenance dose can be 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg or a range consisting of any two thereof, for example, 200-900 mg, 200-800 mg, 200-600 mg, etc. In particular, the maintenance dose is 200 mg.

[0154] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0155] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody to patients in need by intravenous infusion at 4-week intervals, with each induction dose being 100-1000 mg;

[0156] b) Maintenance treatment phase: maintenance doses of anti-IL-23p19 antibody are administered to the patient by subcutaneous injection at intervals of 4-8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, and each maintenance dose is 100-1000 mg.

[0157] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0158] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody to patients in need by intravenous infusion at 4-week intervals, with each induction dose ranging from 200 to 600 mg;

[0159] b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4-8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, and each maintenance dose is 200-600 mg.

[0160] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0161] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody to patients in need by intravenous infusion at 4-week intervals, with each induction dose ranging from 200 mg to 600 mg;

[0162] b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, and each maintenance dose is 200-600 mg.

[0163] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0164] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody by intravenous infusion to patients in need at 4-week intervals, with each induction dose being 200 mg or 600 mg;

[0165] b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, and each maintenance dose is 200 mg.

[0166] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0167] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody by intravenous infusion to patients in need at 4-week intervals, with each induction dose being 200 mg or 600 mg;

[0168] b) Maintenance treatment phase: maintenance doses of anti-IL-23p19 antibody are administered to the patient by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 4 weeks after the last induction dose, and each maintenance dose is 200 mg.

[0169] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0170] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody by intravenous infusion to patients in need at 4-week intervals, with each induction dose being 200 mg or 600 mg;

[0171] b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, each maintenance dose is 200 mg, and administration continues until week 44.

[0172] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0173] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody by intravenous infusion to patients in need at 4-week intervals, with each induction dose being 200 mg or 600 mg;

[0174] b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 4 weeks after the last induction dose, each maintenance dose is 200 mg, and administration continues until week 44.

[0175] In a specific embodiment, the method further comprises:

[0176] a) At the end of the induction phase, the Mayo score was assessed at weeks 11-12.

[0177] b) During the maintenance treatment phase, subjects who achieved a clinical response at weeks 12-13 were re-randomized in a 1:1 ratio to receive either 200 mg of anti-IL-23p19 antibody subcutaneously every 4 weeks or 200 mg of anti-IL-23p19 antibody subcutaneously every 8 weeks, with treatment continuing until week 44. Safety follow-up continued until week 52.

[0178] In one embodiment, the method further comprises

[0179] a) At the end of the induction treatment phase, the Mayo score was assessed at week 12 to evaluate the subjects' response to the study drug;

[0180] b) At the start of the maintenance treatment phase, subjects who achieved a clinical response at Week 12 were re-randomized in a 1:1 ratio to receive either 200 mg subcutaneous injection every 4 weeks or 200 mg subcutaneous injection of anti-IL-23p19 antibody every 8 weeks, with dosing continuing until Week 44. Safety follow-up continued until Week 52.

[0181] In one embodiment, the dosing regimen of the present invention further comprises an extended induction phase (or extended induction phase) performed after the induction phase described herein and before the maintenance phase. In one embodiment, the patient does not achieve a clinical response 2-8 weeks after receiving the last induction dose of the induction phase and therefore receives an extended induction phase.

[0182] In one embodiment, the dosing regimen of the invention comprises an extended induction phase followed by an induction therapy phase and preceded by a maintenance therapy phase:

[0183] a1) Extended induction phase: administer one or more extended induction doses of anti-IL-23p19 antibody to the patient, wherein the extended induction dose is 100-1000 mg; preferably, once the administration of the extended induction dose produces a clinical response, the patient enters the maintenance treatment phase.

[0184] In one embodiment, the extended induction dose is administered by intravenous injection. More preferably, the extended induction dose is administered by intravenous infusion.

[0185] In one embodiment, the first extended induction dose is administered 2-8 weeks after the last induction dose of the induction treatment phase, preferably 2, 3, 4, 5, 6, 7 or 8 weeks after the last induction dose, more preferably 4 weeks after the last induction dose.

[0186] In one embodiment, the extended induction dose can be administered one or more times, for example, once, twice, three times, or four times. Preferably, the extended induction dose is administered 1-3 times. More preferably, the extended induction dose is administered 3 times. It will be appreciated that the extended induction doses may be equal or unequal. In some embodiments, when multiple extended induction doses are administered, the extended induction doses are administered at 4-week intervals.

[0187] In one embodiment, once the administration of the extended induction dose produces a clinical response, the patient can receive a maintenance treatment phase.

[0188] In one embodiment, the patient achieves a clinical response 2-8 weeks after receiving the last extended induction dose of the extended induction phase and then receives the maintenance phase.

[0189] In a specific embodiment, the dosing regimen in this method further comprises an extended induction treatment phase: after administering three induction doses of an anti-IL-23p19 antibody to a patient in need thereof at 4-week intervals, if the patient does not achieve a clinical response 2-8 weeks after the last induction dose, the patient is given three extended induction doses, each extended induction dose is 100-1000 mg; if the patient has a clinical response to the extended induction dose, the patient enters the maintenance treatment phase.

[0190] In a specific embodiment, the dosing regimen in this method further comprises an extended induction treatment phase: after administering three induction doses of an anti-IL-23p19 antibody to a patient in need thereof at 4-week intervals, if the patient does not achieve a clinical response 4 weeks after the last induction dose, the patient is given three extended induction doses, each extended induction dose is 100-1000 mg; if the patient has a clinical response to the extended induction dose, the patient enters a maintenance treatment phase.

[0191] In a specific embodiment, each extended induction dose in the method is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. It is understood that the extended induction dose can be 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or a range consisting of any two thereof, such as 200-900 mg, 200-800 mg, 200-600 mg, etc. In particular, the extended induction dose is 600 mg.

[0192] In some embodiments, the dosing regimen of the present invention further comprises a maintenance treatment phase performed after the extended induction phase as described herein. In particular, the maintenance treatment phase is substantially the same as the maintenance treatment phase performed after the induction treatment phase as described herein.

[0193] In some embodiments, the dosing regimen of the present invention comprises:

[0194] a) Induction therapy phase: administering one or more induction doses of anti-IL-23p19 antibody to a patient in need thereof, wherein each induction dose is 100-1000 mg;

[0195] a1) extended induction phase: administering one or more extended induction doses of an anti-IL-23p19 antibody to the patient, wherein the extended induction dose is 100-1000 mg; preferably, once the administration of the extended induction dose produces a clinical response, the patient enters a maintenance treatment phase; and

[0196] b) Maintenance treatment phase: the patient is administered one or more maintenance doses of anti-IL-23p19 antibody, with the first maintenance dose being administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg.

[0197] In some embodiments, the maintenance treatment phase comprises administering to the patient one or more maintenance doses of an anti-IL-23p19 antibody, wherein the maintenance dose is 100-1000 mg. Preferably, the maintenance dose is administered by subcutaneous injection.

[0198] In a specific embodiment, the maintenance dose can be administered once or multiple times. It will be appreciated that the maintenance doses can be equal or unequal. When multiple maintenance doses are administered, the maintenance doses are administered at intervals of 2-8 weeks, for example, 2, 3, 4, 5, 6, 7, or 8 weeks. In particular, the maintenance doses are administered at intervals of 4 or 8 weeks. In particular, the maintenance treatment phase lasts for 32 weeks from the administration of the first maintenance dose.

[0199] In a specific embodiment, the dosing regimen in this method further comprises administering a first maintenance dose 2-8 weeks after the last extended induction dose, for example 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks after the last extended induction dose. Preferably, the first maintenance dose is administered 4 weeks after the last extended induction dose of the extended induction phase.

[0200] In a specific embodiment, the method comprises administering a maintenance dose of an anti-IL-23p19 antibody to a patient in need thereof by subcutaneous injection at 4-week intervals following the extended induction phase.

[0201] In a specific embodiment, the method further comprises administering a maintenance dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg after the extended induction phase. It is understood that the maintenance dose is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or a range consisting of any two thereof, such as 200-900 mg, 200-800 mg, 200-600 mg, etc. In particular, the maintenance dose is 200 mg.

[0202] In a specific embodiment, the dosing regimen in this method further comprises providing subjects who fail to achieve a clinical response at week 12 with the option of entering an extended induction phase and receiving 600 mg of an anti-IL-23p19 antibody by intravenous infusion at weeks 12, 16, and 20.

[0203] In a specific embodiment, after the extended induction dose, subjects who achieve a clinical response enter a maintenance treatment phase, with the first maintenance dose being administered 4 weeks after the last extended induction dose, with a subcutaneous injection of 200 mg of anti-IL-23p19 antibody, for up to 56 weeks.

[0204] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0205] a) Induction therapy phase: Administer three induction doses of anti-IL-23p19 antibody by intravenous infusion to patients in need at 4-week intervals, with each induction dose being 200 mg or 600 mg;

[0206] b) Maintenance treatment phase: the patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 4 weeks after the last induction dose, and each maintenance dose is 200 mg, wherein the amino acid sequence of the heavy chain CDR1 of the antibody comprises SEQ ID NO.1 or consists of it, the amino acid sequence of the heavy chain CDR2 comprises SEQ ID NO.2 or consists of it, and the amino acid sequence of the heavy chain CDR3 comprises SEQ ID NO.3 or consists of it; the amino acid sequence of the light chain CDR1 of the antibody comprises SEQ ID NO.4 or consists of it, the amino acid sequence of the light chain CDR2 comprises SEQ ID NO.5 or consists of it, and the amino acid sequence of the light chain CDR3 comprises SEQ ID NO.6 or consists of it, and the boundaries of the CDRs are determined by the AbM rule.

[0207] In a specific embodiment, the dosing regimen in this method further comprises an extended induction treatment phase: three induction doses of the anti-IL-23p19 antibody are administered to a patient in need at intervals of 4 weeks; if the patient does not achieve a clinical response 4 weeks after the last induction dose, the patient is given three extended induction doses, each extended induction dose is 600 mg; if the patient has a clinical response to the extended induction dose, the patient enters a maintenance treatment phase, wherein the first maintenance dose is administered 4 weeks after the last extended induction dose, and 200 mg of the anti-IL-23p19 antibody is injected subcutaneously, and the administration is continued for 56 weeks, wherein the amino acid sequence of the heavy chain CDR1 of the antibody comprises SEQ ID NO.1 or consists of it, the amino acid sequence of the heavy chain CDR2 comprises SEQ ID NO.2 or consists of it, and the amino acid sequence of the heavy chain CDR3 comprises SEQ ID NO.3 or consists of it; the amino acid sequence of the light chain CDR1 of the antibody comprises SEQ ID NO.4 or consists of it, the amino acid sequence of the light chain CDR2 comprises SEQ ID NO.5 or consists of it, and the amino acid sequence of the light chain CDR3 comprises SEQ ID NO. NO. 6 or consisting thereof, wherein the CDR boundaries are determined by AbM rules.

[0208] In one embodiment, the dosage regimen of the present invention comprises:

[0209] a) Induction therapy phase: 3 induction doses of anti-IL-23p19 antibody, each 200 mg or 600 mg, are administered to patients in need by intravenous infusion at 4-week intervals; and

[0210] a1) Extended induction phase: Administer 3 extended induction doses of anti-IL-23p19 antibody to patients in need thereof by intravenous infusion at 4-week intervals, each extended induction dose is 600 mg; and

[0211] b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 4 weeks after the last extended induction dose, each maintenance dose is 200 mg, and administration continues until week 56.

[0212] In a specific embodiment, the method comprises administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises:

[0213] a) Induction therapy phase: Three induction doses of anti-IL-23p19 antibody were administered to patients in need by intravenous infusion at 4-week intervals, with each induction dose being 200 mg or 600 mg. The Mayo Clinic score was performed at week 12 to evaluate the therapeutic response of the subjects to the anti-IL-23p19 antibody.

[0214] b) Maintenance treatment phase: Subjects who achieved clinical response at week 12 were re-randomized and administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with each maintenance dose being 200 mg. Administration continued until week 44, and safety follow-up continued until week 52.

[0215] c) Extended induction phase: Subjects who fail to achieve a clinical response at week 12 may choose to enter the clinical induction phase and receive 600 mg of anti-IL-23p19 antibody intravenous infusion at weeks 12, 16, and 20. Mayo Clinic scores will be performed at week 24 to evaluate the efficacy of the subjects' anti-IL-23p19 antibody.

[0216] d) Maintenance treatment phase: Subjects who achieved clinical response in the extended induction phase at week 24 entered the maintenance treatment phase and received 200 mg of anti-IL-23p19 antibody by subcutaneous injection at 4-week intervals until week 56. Safety follow-up continued until week 64. Subjects who did not achieve clinical response at week 24 terminated the study.

[0217] In a specific embodiment, the administration is by subcutaneous injection or intravenous infusion.

[0218] In one embodiment, the subject must have previously received at least one biologic treatment or be a first-time user of a biologic: a. Previous treatment with at least one biologic treatment refers to treatment with an anti-tumor necrosis factor-α (TNF-α) antagonist such as adalimumab, infliximab, an anti-integrin antibody such as vedolizumab, or other experimental biologic therapies, to which the patient had a poor response, failed to respond, or was intolerant; b. Subjects who are first-time users of biologics must meet at least one of the following criteria:

[0219] - Inadequate treatment with, lack of response to, or intolerance to oral 5-aminosalicylic acid;

[0220] - Inadequate treatment or intolerance to oral corticosteroids;

[0221] - Inadequate treatment with or intolerance to immunomodulatory agents (6-mercaptopurine or azathioprine);

[0222] - Patients who have not responded to or are intolerant to JAK (Janus Kinases) inhibitor therapy / investigational therapy.

[0223] In one embodiment, the heavy chain of the IL-23p19 antibody of the invention contains an N-glycosylation site located at asparagine 295 of the heavy chain. Thus, in one embodiment, the anti-IL-23p19 antibody of the invention is a glycosylated antibody, for example, an antibody glycosylated at asparagine 295.

[0224] In a specific embodiment, the anti-IL-23p19 antibody comprises a heavy chain variable region, VH, and a light chain variable region, VL, wherein the heavy chain variable region comprises or consists of the sequence of SEQ ID NO: 7, or a sequence at least 90%, 95%, 98% or 99% identical thereto, and the light chain variable region comprises or consists of the sequence of SEQ ID NO: 8, or a sequence at least 90%, 95%, 98% or 99% identical thereto:

[0225] Sequence (SEQ ID NO:7)

[0226] Sequence (SEQ ID NO:8)

[0227] In one embodiment, the IL-23p19 antibody of the present invention comprises a heavy chain and / or a light chain, wherein the heavy chain comprises or consists of the sequence of SEQ ID NO: 9, or a sequence with at least 90%, 95%, 98% or 99% identity thereto, and wherein the light chain comprises or consists of the sequence of SEQ ID NO: 10, or a sequence with at least 90%, 95%, 98% or 99% identity thereto. In a specific embodiment, the IL-23p19 antibody is an IgG1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises or consists of the sequence of SEQ ID NO: 9, or a sequence with at least 90%, 95%, 98% or 99% identity thereto, and wherein the light chain comprises or consists of the sequence of SEQ ID NO: 10, or a sequence with at least 90%, 95%, 98% or 99% identity thereto. In one embodiment, the IL-23p19 antibody of the invention comprises or consists of two said heavy chains and two said light chains, eg, two identical said heavy chains and two identical said light chains.

[0228] In one embodiment, the IL-23p19 antibody of the present invention comprises a heavy chain represented by SEQ ID NO: 9 and a light chain represented by SEQ ID NO: 10; for example, the IL-23p19 antibody comprises two heavy chains represented by SEQ ID NO: 9 and two light chains represented by SEQ ID NO: 10, or consists of two heavy chains represented by SEQ ID NO: 9 and two light chains represented by SEQ ID NO: 10.

[0229] Sequence (SEQ ID NO:9)

[0230] Sequence (SEQ ID NO:10)

[0231] Preferably, the IL-23p19 antibody is the anti-IL-23p19 antibody 17D1-YTE disclosed in PCT Application No. PCT / CN2019 / 121261 (International Filing Date: November 27, 2019, International Publication No. WO2020 / 108530A1), which comprises a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. This patent application is incorporated herein in its entirety, as if fully set forth herein.

[0232] In a specific embodiment, the anti-IL-23p19 antibody comprises the heavy chain sequence shown in SEQ ID NO:9 and the light chain sequence shown in SEQ ID NO:10.

[0233] In one embodiment, the IL-23p19 antibody of the present invention is a full-length antibody. In one embodiment, the IL-23p19 antibody of the present invention also encompasses antigen-binding fragments.

[0234] In a specific embodiment, the anti-IL-23p19 antibody is recombinantly expressed in HEK 293 cells or CHO cells.

[0235] The IL-23p19 antibody of the present invention can be formulated into a preparation for administration. For example, the formulation of the anti-IL-23p19 antibody of the present invention is 100.0 mg / mL of anti-IL23p19 subunit antibody, 0.76 mg / mL of histidine, 1.08 mg / mL of histidine hydrochloride, 50.00 mg / mL of sorbitol, 0.5 mg / ml of polysorbate 80, pH 6.0. Preferably, the formulation of the IL-23p19 antibody can be prepared according to the method for preparing the preparation comprising the anti-IL-23p19 antibody, its preparation method and use disclosed in PCT application number PCT / CN2021 / 093219 (International filing date: May 12, 2021, International publication number WO2021 / 228113A1). This patent application is incorporated herein in its entirety, as if its entirety were set forth herein.

[0236] Single dose unit

[0237] A single-dose unit comprising an effective amount of an anti-IL-23p19 antibody of the present invention, preferably comprising a fixed dose of 100 mg to 1000 mg. The single-dose unit is used for administration according to the dosage regimen of the present invention to prevent or treat inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0238] The unit dosage forms described herein are preferably for parenteral administration, e.g., for injection, e.g., intravenous injection (including intravenous infusion) or subcutaneous injection. The unit dosage form can be a vial, ampoule, or pre-filled syringe for injection containing a solution or lyophilized powder of an IL-23p19 antibody. More preferably, the unit dosage form described herein is a pre-filled syringe containing a solution or lyophilized powder of an IL-23p19 antibody for parenteral administration.

[0239] In one embodiment, the IL-23p19 antibody is placed in a pre-filled syringe. Preferably, the pre-filled syringe contains 200 mg / mL or 600 mg / mL of IL-23p19 antibody solution.

[0240] Complete set of medicine boxes

[0241] A kit of parts comprising an effective amount of the anti-IL-23p19 antibody of the present invention, specifically, further comprising a package insert printed with instructions for using the anti-IL-23p19 antibody to prevent or treat ulcerative colitis in an individual.

[0242] application

[0243] Use of the anti-IL-23p19 antibody, single-dose unit, and kit of parts of the present invention in preparing a medicament for preventing or treating inflammatory bowel disease, such as ulcerative colitis, Crohn's disease, or colitis (especially moderate to severe ulcerative colitis).

[0244] It will be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present invention. The scope of the present invention is limited only by the appended claims.

[0245] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the invention belongs. In this document, technical and scientific terms not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which the invention belongs.

[0246] Any embodiments, technical features and definitions described herein may be arbitrarily combined to form embodiments that are not directly recorded in the specification but are consistent with the spirit of the present invention, and these embodiments are also included in the scope of the present invention.

[0247] The dosing regimens described herein (including the active agent IL-23p19 antibody, dosage, mode of administration, dosing interval, number of doses, or duration of administration, etc.) and any of their features can be applied to any aspect of the present invention, such as aspects 1 to 8 as described above. Moreover, any embodiment, technical feature, definition, and any combination thereof described herein for one aspect can also be applied to other aspects, such as aspects 1 to 8 as described above. For example, any embodiment, technical feature, definition, and any combination thereof described herein for the first or second aspect can be equally applied to aspects 3 to 8 as described above. Example

[0248] The following examples are provided to illustrate the present invention. These examples are illustrative only and do not limit the scope of the present invention and the appended claims in any way. Likewise, the present invention is not limited to any specific preferred embodiments described herein. Those skilled in the art may modify the present invention without departing from the spirit and scope of the present invention.

[0249] Example 1. Preparation and purification of IL-23p19 antibody

[0250] According to PCT application number PCT / CN2019 / 121261, an antibody 17D1-YTE that specifically binds to IL-23p19 was obtained. The antibody has a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. PCT application number PCT / CN2019 / 121261 is hereby incorporated by reference in its entirety.

[0251] Briefly, the antibody was recombinantly expressed in CHO cells and purified by affinity chromatography to obtain the IL-23p19 antibody sample used in the present invention. The IL-23p19 antibody sample used in the present invention was purified by cation exchange chromatography to obtain the IL-23p19 antibody sample used in the present invention.

[0252] Example 2. Preparation of formulation

[0253] 2.1 Experimental steps

[0254] The formulation of the antibody preparation of the present invention was investigated according to PCT application number PCT / CN2021 / 093219. Specifically, 20 mM sodium citrate and 150 mM sodium chloride were prepared, and the pH was adjusted with hydrochloric acid. The purified IL-23p19 antibody from Example 1 was then ultrafiltered into the aforementioned buffers at different pH values, adjusting the protein content to 50 mg / ml. The vials were then filtered and dispensed into vials, stoppered, and capped.

[0255] The established formulation for the antibody injection is: 100 mg / ml recombinant anti-interleukin-23p19 subunit antibody, 0.76 mg / ml histidine, 1.08 mg / ml histidine hydrochloride, 50.00 mg / ml sorbitol, 0.50 mg / ml polysorbate 80, pH 6.0±0.3. The antibody injection formulation of the present invention was prepared according to this formulation, with a dosage of 100 mg (1 mL) per vial and packaged in a vial. The product is a clear to slightly opalescent, colorless to slightly yellowish liquid, free of foreign matter. This injection formulation was used in Example 3.

[0256] Corresponding placebo: Injection solution, 1 mL / vial. Excipients include: 0.76 mg / mL histidine, 1.08 mg / mL histidine hydrochloride, 50.00 mg / mL sorbitol, 0.5 mg / mL polysorbate 80, pH 6.0. The product is packaged in a vial and is a clear to slightly opalescent, colorless to slightly yellowish liquid free of foreign matter. This injection formulation was used as the placebo in Example 3.

[0257] Example 3. Clinical study

[0258] The anti-IL-23p19 antibody of the present invention demonstrated good safety and tolerability in a Phase I clinical study in healthy volunteers. No grade 3 or higher adverse events (TRAEs) occurred during the treatment period. TRAEs with an incidence of ≥5% were injection site erythema (20.0%), upper respiratory tract infection (14.3%), and runny nose (11.1%), which are generally consistent with the results of existing studies of drugs with the same target, and no new safety risks were identified. These results support further clinical efficacy and safety studies of the anti-IL-23p19 antibody.

[0259] 3.1 Research Objectives

[0260] Main Purpose:

[0261] To evaluate the effectiveness of anti-IL-23p19 antibodies in inducing clinical remission in patients with moderately to severely active ulcerative colitis (UC).

[0262] Secondary objectives:

[0263] To evaluate the effectiveness of anti-IL-23p19 antibody induction therapy in achieving clinical response, symptom relief, endoscopic remission, and mucosal healing in patients with moderately to severely active ulcerative colitis.

[0264] To evaluate the effectiveness of anti-IL-23p19 antibody maintenance therapy in achieving clinical remission, clinical response, symptom relief, endoscopic remission, and mucosal healing in patients with moderately to severely active ulcerative colitis.

[0265] To evaluate the effects of induction and maintenance treatment with anti-IL-23p19 antibodies on health-related quality of life in patients with moderately to severely active ulcerative colitis.

[0266] To evaluate the safety of anti-IL-23p19 antibody induction and maintenance therapy in patients with moderately to severely active ulcerative colitis;

[0267] To evaluate the pharmacokinetics of anti-IL-23p19 antibodies in patients with moderately to severely active ulcerative colitis;

[0268] -To evaluate the immunogenicity of anti-IL-23p19 antibodies in patients with moderately to severely active ulcerative colitis.

[0269] 3.2 Research Design Principles

[0270] 3.2.1. Basis for dose selection

[0271] Taking into account the disease characteristics of UC indications and the mechanism of action of the IL-23 molecular pathway, combined with clinical safety, efficacy and ease of operation, it is recommended that the intravenous infusion dose during the induction treatment period be: 200mg Q4W and 600mg Q4W, and the subcutaneous injection dose during the maintenance treatment period be: 200mg Q4W and 200mg Q8W dosing regimen for Phase II research.

[0272] 3.3 Research design

[0273] This multicenter, randomized, double-blind, placebo-controlled, Phase II study evaluated the efficacy and safety of an anti-IL-23p19 antibody as induction therapy and maintenance therapy in patients with moderately to severely active ulcerative colitis (modified Mayo score 4-9, including an endoscopic score ≥2). Approximately 150 subjects will be randomized, of whom approximately 30% to 50% must have previously received at least one biologic therapy, and approximately 50% to 70% will be biologic-naive. After screening no more than six weeks after enrollment, patients with moderately to severely active ulcerative colitis who meet the study eligibility criteria will be randomly assigned in a 1:1:1 ratio to one of three induction therapy groups, with prior biologic therapy as a stratification factor.

[0274] Induction Phase: The 12-week induction phase evaluated the efficacy and safety of intravenous infusions of anti-IL-23p19 antibodies in induction therapy of target patients. Participants were randomly assigned to receive placebo, 200 mg of anti-IL-23p19 antibody, or 600 mg of anti-IL-23p19 antibody via intravenous infusion at weeks 0, 4, and 8. The response to study drug was assessed at week 12.

[0275] Maintenance Phase: This phase will evaluate the efficacy and safety of subcutaneous anti-IL-23p19 antibody maintenance therapy in target patients. Subjects who achieve a clinical response at Week 12 will continue in the maintenance phase. Subjects who received placebo during the induction phase will continue receiving placebo subcutaneously every four weeks during the maintenance phase. Subjects who received anti-IL-23p19 antibody during the induction phase will be re-randomized in a 1:1 ratio to receive either 200 mg of anti-IL-23p19 antibody subcutaneously every four weeks or 200 mg of anti-IL-23p19 antibody subcutaneously every eight weeks, continuing through Week 44. Safety follow-up will continue through Week 52. Subjects who received 200 mg of anti-IL-23p19 antibody subcutaneously every eight weeks during the maintenance phase will receive placebo subcutaneously at Weeks 16, 24, 32, and 40 to maintain blinding.

[0276] Extension Phase: Subjects who do not achieve a clinical response at Week 12 may elect to enter the Extension Phase. All subjects who enter this Phase will receive 600 mg of anti-IL-23p19 antibody intravenous infusion starting at Week 12, Week 16, and Week 20, regardless of whether they received placebo or anti-IL-23p19 antibody during the induction phase. The efficacy response of these subjects to the anti-IL-23p19 antibody will be evaluated at Week 24. Subjects who achieve a clinical response will begin receiving 200 mg of anti-IL-23p19 antibody subcutaneously every 4 weeks, continuing through Week 56. Safety follow-up will continue through Week 64. Subjects who fail to achieve a clinical response will terminate the study.

[0277] The subjects and researchers remained blinded during the induction and maintenance treatment phases until the end of the study; the extension phase was an open-label study phase, in which no blinding was performed. The antibody injection formulation prepared as in Example 2 and placebo were used in this study.

[0278] 3.4 Study population

[0279] Inclusion criteria

[0280] Potential subjects must meet all the following criteria to be included in this study.

[0281] (1) Male or female aged 18 years or younger than 75 years;

[0282] (2) diagnosed with ulcerative colitis for at least 3 months, including endoscopic evidence supporting UC and histopathological evidence supporting the diagnosis of UC;

[0283] (3) had moderate to severe ulcerative colitis, defined as a modified Mayo score ≥4 and an endoscopic score ≥2;

[0284] (4) The subject must have received at least one biologic treatment before or be using a biologic for the first time:

[0285] 4a. Patients who have previously received at least one biologic agent include those who have received anti-tumor necrosis factor-α (TNF-α) antagonists such as adalimumab and infliximab, anti-integrin antibodies such as vedolizumab, or other experimental biologic therapies and have had a poor response, failed response, or are intolerant to these therapies;

[0286] - Inadequate treatment: Symptoms or signs of persistent active disease persist despite induction therapy using the induction dosing regimen recommended in the drug instructions (in the case of investigational therapy, the recommended trial dose is used for induction therapy);

[0287] - Loss of response: Symptoms or signs of active disease appear during maintenance dosing after previously achieving clinical benefit;

[0288] - Intolerance: Adverse reactions related to the above-mentioned drugs lead to dosage reduction or discontinuation of treatment.

[0289] 4b. Subjects using biologics for the first time must meet at least one of the following:

[0290] - Inadequate treatment with, or lack of response to, or intolerance of, oral 5-aminosalicylic acid (5-AMSA); defined as persistent signs or symptoms of active disease after at least two weeks of induction therapy with mesalamine at a dose of at least 2 g / day (or equivalent), or the development of signs or symptoms of active disease during maintenance therapy, or intolerance due to adverse effects of the drug.

[0291] - Inadequate treatment with or intolerance to oral glucocorticoids; defined as persistent active disease signs or symptoms despite treatment with at least 30 mg / day of oral prednisone (or equivalent) for at least two weeks; or intolerance due to glucocorticoid-related adverse effects.

[0292] -Corticosteroid dependence; defined as the inability to reduce the glucocorticoid dose to less than 10 mg / day of prednisone (or equivalent) without symptoms or signs of active disease within three months of starting glucocorticoid therapy; or relapse within three months of completing a course of glucocorticoid therapy.

[0293] - Inadequate treatment with or intolerance to immunomodulatory agents (6-mercaptopurine or azathioprine); defined as persistent signs or symptoms of active disease despite treatment with at least 0.75 mg / kg / day of 6-mercaptopurine or at least 1 mg / kg / day of azathioprine for at least three months; or intolerance due to drug-related adverse effects.

[0294] - Insufficient or intolerant treatment with JAK (Janus Kinase) inhibitors / investigational therapy. This is defined as persistent active disease signs or symptoms after at least 2 months of treatment with the JAK inhibitor label dose or investigational dose; or intolerance due to drug-related adverse reactions.

[0295] (5) Before the first use of the study drug, UC-related therapeutic drugs must meet the following requirements:

[0296] - TNF-α antagonists have been discontinued for at least 8 weeks;

[0297] - The anti-integrin antibody vedolizumab has been discontinued for at least 12 weeks;

[0298] - Other investigational biologics have been discontinued for at least 8 weeks;

[0299] - If receiving an oral aminosalicylic acid preparation (sulfasalazine or other 5-aminosalicylic acid), the patient must be stable on the prescribed dose for at least 2 weeks; if discontinued, the patient must have discontinued the medication for at least 2 weeks;

[0300] - If receiving oral glucocorticoids, they have been stable at the prescribed dose for at least 2 weeks; if discontinued, they have been discontinued for at least 2 weeks;

[0301] - If receiving a traditional immunomodulator (6-mercaptopurine, azathioprine, or methotrexate), they should have received it for at least 12 weeks and been stable at the prescribed dose for at least 4 weeks; if discontinued, they should have been off the drug for at least 4 weeks;

[0302] - Cyclosporine, tacrolimus, picolimus, 6-mercaptoguanine, thalidomide, mycophenolate mofetil, JAK inhibitors / investigational therapy have been discontinued for at least 4 weeks;

[0303] - Rectal glucocorticoids (administered via foam, enema, or suppository into the rectum or sigmoid colon) and injected glucocorticoids have not been used for at least 2 weeks;

[0304] - Rectal aminosalicylic acid (administered as a foam, enema, or suppository into the rectum or sigmoid colon) should be discontinued for at least 2 weeks;

[0305] - Stop taking Chinese herbal medicines (oral or enema) for at least 2 weeks;

[0306] - Parenteral nutrition has been discontinued for at least 2 weeks;

[0307] - Antibiotic treatment for ulcerative colitis has been discontinued for at least 2 weeks;

[0308] - Selective leukoadsorption therapy has been discontinued for at least 2 weeks;

[0309] - Other investigational treatments should be discontinued for at least 4 weeks.

[0310] (6) Have a full understanding of the purpose of the trial, and a basic understanding of the pharmacological effects of the trial drugs and possible adverse reactions; voluntarily sign the informed consent form in accordance with the spirit of the Declaration of Helsinki.

[0311] Exclusion criteria

[0312] Potential subjects must not meet any of the following criteria to be included in this study.

[0313] (1) Previous treatment with biological agents targeting IL-12 / 23 and / or IL-23;

[0314] (2) diagnosed as ischemic colitis, infectious colitis, radiation colitis, microscopic colitis, indeterminate colitis, etc. or suggesting Crohn's disease;

[0315] (3) UC lesions are limited to the rectum or involve the colon <15 cm;

[0316] (4) evidence of toxic megacolon was found during screening;

[0317] (5) history or evidence of atypical colon hyperplasia, adenomatous polyps (not removed before study entry), or gastrointestinal tumors;

[0318] (6) previous extensive colectomy, subtotal colectomy, or total colectomy, ileostomy, or colostomy for ulcerative colitis;

[0319] (7) Subjects who require surgery for ulcerative colitis or plan to undergo elective surgery during the study period;

[0320] (8) Had surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, intestinal stenosis, abdominal abscess or pancreatic abscess within 2 months before screening, or had the above conditions requiring surgery 2 weeks before screening;

[0321] (9) There is evidence that the subject suffers from severe, progressive or uncontrollable cardiovascular disease, blood disease, endocrine disease, kidney disease, liver disease, respiratory disease, neurological or psychiatric disease;

[0322] (10) Suffering from severe opportunistic infections within 6 months before screening, such as severe or recurrent herpes zoster, active cytomegalovirus infection, Pneumocystis carinii, Histoplasma capsulatum, Aspergillus, Mycobacterium, etc.;

[0323] (11) Patients who tested positive for Clostridium difficile during the screening period or 4 months before the first dose, with negative results in repeated tests and no symptoms of persistent infection with the pathogen (if time permits, treatment and repeated testing can be performed during the screening period);

[0324] (12) A history of recurrent or chronic infection, including but not limited to chronic kidney infection, chronic chest infection, recurrent urinary tract infection, etc.;

[0325] (13) A history of severe infection (such as sepsis, severe pneumonia, pyelonephritis, etc.), or hospitalization or intravenous antibiotic treatment due to infection within 1 month before screening (minor upper respiratory tract infection, simple urinary tract infection, etc. may be excluded at the discretion of the researcher);

[0326] (14) Known to have or have had lymphoproliferative diseases, including lymphoma, or symptoms or signs that may be lymphoproliferative diseases, such as lymphadenopathy and / or splenomegaly, within 5 years before screening;

[0327] (15) Known history of malignant tumors or malignant tumors (except for basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix that has been successfully excised and treated with no evidence of recurrence or metastasis 5 years before screening);

[0328] (16) Patients with untreated latent or active tuberculosis evidence / symptoms or a history of active tuberculosis at the time of screening; patients without active tuberculosis evidence / symptoms but with a positive QuantiFERON-TB test [if there is no QuantiFERON-TB test, a positive tuberculosis T-cell spot test (T-SPOT)] are exempted from receiving appropriate anti-latent tuberculosis treatment before the first medication;

[0329] (17) Laboratory test results during screening meet any of the following criteria;

[0330] - Hemoglobin <80 g / L; or any of the white blood cell, neutrophil, or platelet indicators < the lower limit of normal value (LLN), and the abnormality is judged by the investigator to be clinically significant;

[0331] - Alanine transaminase (ALT), aspartate aminotransferase (AST), or total bilirubin (TBIL) > 2 times the upper limit of normal value (ULN);

[0332] - Creatinine (Cr) > ULN;

[0333] (18) Virological examination results during screening meet any of the following conditions:

[0334] - Positive for human immunodeficiency virus (HIV) antibodies;

[0335] - Hepatitis C virus (HCV) antibody positive with no history of successful treatment, where successful treatment is defined as completion of antiviral therapy for at least 24 weeks with negative HCV RNA;

[0336] - Hepatitis B virus (HBV) screening should include at least hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (HbsAb), and hepatitis B core antibody (HbcAb). If the test result is: HBsAg positive; or if only HbcAb is positive when HBsAg is negative, HBV DNA testing is required and the test result is positive;

[0337] (19) Participated in other clinical studies within 4 weeks before screening and received the study drug or is still within 5 half-lives of the study drug, or plans to participate in other clinical studies during the study;

[0338] (20) BCG vaccination within 12 months before the first use of study drug, or plan to receive BCG vaccination during the study or within 12 months after the last study treatment;

[0339] (21) Received a live vaccine or bacterial vaccine within 3 months before the first use of the study drug, or planned to receive a live vaccine or bacterial vaccine during the study or within 3 months after the last study treatment;

[0340] (22) Those who are suspected or confirmed to have allergic constitution or have had severe drug or food allergic reactions in the past, and / or those who are allergic to the test drug or its ingredients;

[0341] (23) history of alcohol and drug abuse within 12 months before screening;

[0342] (24) Female subjects are pregnant or lactating, or female subjects of childbearing age have a positive pregnancy test before screening and administration;

[0343] (25) Those who have plans to have children during the study period and within 6 months after the administration of the study drug, or those who are unwilling to take contraceptive measures (such as condoms, etc.) deemed appropriate by the doctor during the trial;

[0344] (26) Those who the researcher considers are not suitable to participate in this clinical trial due to various reasons.

[0345] 3.5. Definition of study end

[0346] A subject is considered to have completed the study if they complete the final study visit. Premature termination of treatment / study for any reason before study completion is considered incomplete. Study completion is defined as the last subject completing the final follow-up visit.

[0347] 3.5.1 Clinical criteria for study discontinuation

[0348] If there are sufficient justifiable reasons, this study may be temporarily suspended or terminated early. The party suspending or terminating the study should provide written notice to the subjects, investigators, funding agencies, and regulatory agencies, and record the reasons for the suspension or termination of the study. If the study is terminated or suspended early, the principal investigator should promptly notify the subjects and the Ethics Committee (EC) and provide the reasons for the termination or suspension of the study. If applicable, the investigator will contact the subjects and inform them of changes to the visit schedule.

[0349] Circumstances that may require termination or suspension include, but are not limited to:

[0350] Determination of unexpected, significant, or unacceptable risks to subjects;

[0351] The basis for effectiveness should be termination / suspension of the study;

[0352] Failure to meet protocol compliance requirements;

[0353] Data are incomplete and / or insufficient for evaluation;

[0354] Plans to change or discontinue development of an investigational drug.

[0355] The study may continue only when issues related to safety, protocol compliance, and data quality are resolved and meet the requirements of the EC and / or National Medical Products Administration.

[0356] If the sponsor decides to no longer provide study drug, sufficient notice will be provided to allow appropriate adjustments to the subject's treatment.

[0357] 3.6 Efficacy-related evaluation

[0358] 3.6.1. Mayo Clinic Score

[0359] The "modified Mayo score" is derived from the Mayo scoring system for the severity and activity of ulcerative colitis. It is based on the recommendation of the U.S. Food and Drug Administration (FDA) not to use the physician's global assessment. It consists of three items: frequency of bowel movements, blood in the stool, and endoscopic findings, with scores ranging from 0 to 9.

[0360] The data on the number of bowel movements and blood in stool should be collected for three consecutive days within one week before the scoring follow-up. The average value of the three-day period will be used as the score for the number of bowel movements and blood in stool during the scoring follow-up. Days that meet the following conditions will be excluded from the calculation:

[0361] a. Use of medications for constipation or diarrhea;

[0362] b. Procedures or bowel preparation days that affect bowel movement frequency and / or blood in stool (e.g., enemas, liquid diets, and laxatives);

[0363] c. 2 days after the use of gastrointestinal motility inhibitors (such as diphenoxylate hydrochloride, atropine, loperamide or other opioids);

[0364] d. 2 days after colonoscopy.

[0365] The "Symptom Mayo Score" refers to the modified Mayo score that does not include endoscopic findings, with a score of 0 to 6.

[0366] The "partial Mayo score" refers to the Mayo score that excludes endoscopic findings, namely, the score that includes bowel movements, blood in stool, and the physician's global assessment. It is used only to assess clinical recurrence and is not an indicator of efficacy.

[0367] The primary endpoint of the study was clinical remission, defined as a modified Mayo score of 0 for hematochezia, 1 for bowel movement frequency, and 1 for endoscopic findings.

[0368] "Clinical response" refers to a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score relative to the baseline value, and a decrease of ≥1 point in the hematochezia score relative to the baseline value or a score of 0 or 1 point in this sub-item.

[0369] “Symptom relief” was defined as a bowel movement frequency score of 0 or 1 and a blood in stool score of 0.

[0370] Endoscopic remission refers to an endoscopic score of 0 or 1 in the modified Mayo Clinic Pathology Scale (MCSA). An endoscopic score of 0 is considered complete endoscopic remission.

[0371] "Mucosal healing" refers to endoscopic remission and histopathological remission of the Geboes index (Geboes, K., Riddell, R., Ost, A., Jensfelt, B., Persson, T. & Lofberg, R. 2000. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut, 47, 404-9).

[0372] 3.6.2. Endoscopy / colon histopathology

[0373] Endoscopy was performed according to the study protocol, and biopsy specimens were obtained from the inflammatory site of UC during endoscopic examination. To ensure data quality and standardization and reduce evaluation bias, endoscopic scores and histopathological scores were evaluated by a central laboratory.

[0374] Complete video recordings of the endoscopic examination and endoscopic images were transmitted to the central laboratory, where trained gastrointestinal endoscopists performed central review according to the review protocol. Endoscopic scores based on the modified Mayo scale were obtained from the central reviewers in the clinical study.

[0375] Colon histopathology scoring was performed by a central laboratory. Trained pathologists in the central laboratory read the films according to the film reading charter and used the Geboes index to perform histopathology scoring on biopsy samples.

[0376] Two biopsy specimens are collected from a representative area 15 to 20 cm from the anal verge. If this area is not representative of mucosal inflammation, biopsy specimens can be collected from other representative areas. The maximum number of biopsy specimens collected at one time is 6. Fresh biopsy specimens will be submitted to the central laboratory.

[0377] "Geboes index remission" means that grade 0 ≤ 0.3, grade 1 ≤ 1.1, grade 2A ≤ 2A.3, and grades 2B, 3, 4, and 5 are all 0.

[0378] 3.6.3. Inflammatory Bowel Disease Quality of Life Questionnaire

[0379] The Inflammatory Bowel Disease Questionnaire (IBDQ) is a validated patient-reported outcome (PRO) tool used to assess health-related quality of life in patients with inflammatory bowel disease, including ulcerative colitis (Guyatt 1989). The questionnaire consists of 32 questions that assess four areas of patients' lives: intestinal symptoms, systemic symptoms, emotional functioning, and social functioning. Scores range from 32 to 224, with higher scores indicating better quality of life.

[0380] 3.6.4 Health Status Survey Brief

[0381] The SF-36, also known as the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), is a subject-completed quality of life assessment tool that has been widely used to assess health-related quality of life (Ware and Sherbourne, 1992). It provides a brief, multi-faceted assessment of a subject's health. The SF-36 consists of 36 items covering eight domains: physical functioning, physical role, bodily pain, general health, energy, social functioning, emotional role, and mental health. Scores range from 0 to 100, with higher scores indicating better physical functioning and / or health.

[0382] 3.6.5 Clinical relapse

[0383] During maintenance therapy or the subcutaneous administration phase of the extension phase, subjects who meet the following criteria will be considered to have clinical relapse:

[0384] An increase of at least 2 points in the partial Mayo score compared to the maintenance treatment baseline (at the time of the first subcutaneous dose of the extension phase), and an absolute partial Mayo score of 4 points or more; or

[0385] Some subjects with absolute Mayo score ≥ 7. Rescue treatment may be given to subjects with clinical relapse.

[0386] 3.7 Safety Assessment

[0387] Laboratory tests: including blood routine, blood biochemistry, urine routine, viral serology, tuberculosis, pregnancy test, Clostridium difficile test, etc.

[0388] Clinical examination: including physical examination, vital signs examination, 12-lead electrocardiogram (ECG), severe allergic reactions, infusion reactions, injection reactions, cardiovascular events, mental-related events, etc.

[0389] 3.8 Pharmacokinetic Analysis

[0390] 3.5 ml of whole blood was collected, serum was separated, and aliquots were frozen for PK analysis. The concentration of antibodies in the serum was determined by ELISA. Descriptive statistical analysis was performed on the PK parameters, including mean, standard deviation, maximum, minimum, median, etc., including but not limited to C max ,AUC,V,T 1 / 2 、CL.

[0391] 3.9 Immunogenicity Analysis

[0392] Approximately 5 ml of whole blood was collected, serum was separated, and aliquots were frozen for ADA and NAb analysis. If necessary, immunogenicity samples were used for antibody concentration testing. The positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) were calculated by treatment group.

[0393] 3.10 Research Results

[0394] To date, 141 subjects have been enrolled in this study. During the induction phase, 94 subjects received either 200 mg or 600 mg of the antibody, while 47 received placebo (the ratio of subjects in the 200 mg group: 600 mg group: placebo group was 1:1:1). At the end of the induction phase (week 12), 72 subjects achieved a clinical response and 19 subjects achieved clinical remission. No significant or unacceptable toxicities were observed in the enrolled subjects, and patient compliance was good.

[0395] The blinded data for this study were estimated based on the response rates in the placebo group of other products in the same population. Assuming a 29.9% clinical response rate in the placebo group, the number of subjects achieving a clinical response in the placebo group was 47 x 29.9% = 14. The number of subjects achieving a clinical response in the antibody-treated groups (including the 200 mg and 600 mg doses) was 72 minus 14 = 58 (i.e., the total number of subjects achieving a clinical response minus the number of subjects achieving a clinical response in the placebo group). Therefore, the proportion of subjects achieving a clinical response in the antibody-treated group was 58 / 72 = 61.7%. This proportion is similar to the clinical response rate at the end of the induction phase for guselkumab, another anti-IL-23p19 subunit antibody. Similarly, the proportion of subjects achieving clinical remission in the antibody-treated groups (including the 200 mg and 600 mg doses) was estimated to be 16.0%.

[0396] The blinded data of this study showed that the administration of IL-23p19 subunit antibody according to the dosage regimen of the present invention can produce a positive therapeutic effect on ulcerative colitis, especially moderate to severe ulcerative colitis, with good safety and good patient compliance.

[0397] While the exemplary embodiments of the present invention have been described above, it should be understood by those skilled in the art that these disclosures are merely exemplary and that various other substitutions, adaptations, and modifications may be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. A method for preventing or treating inflammatory bowel disease, preferably ulcerative colitis or Crohn's disease, the method comprising administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises: a) induction therapy phase: administering one or more induction doses of anti-IL-23p19 antibody to a patient in need thereof, wherein each of the induction doses is 100-1000 mg; and b) maintenance treatment phase: administering one or more maintenance doses of anti-IL-23p19 antibody to the patient, the first maintenance dose being administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg; The amino acid sequence of the antibody heavy chain CDR1 includes or consists of SEQ ID NO.1, the amino acid sequence of the heavy chain CDR2 includes or consists of SEQ ID NO.2, and the heavy chain The amino acid sequence of CDR3 includes or consists of SEQ ID NO.3; the amino acid sequence of the light chain CDR1 of the antibody includes or consists of SEQ ID NO.4, the amino acid sequence of the light chain CDR2 includes or consists of SEQ ID NO.5, and the amino acid sequence of the light chain CDR3 includes or consists of SEQ ID NO.

6.

2. The method of claim 1, wherein the induction dose is administered by intravenous injection, and / or the maintenance dose is administered by subcutaneous injection.

3. The method according to claim 1 or 2, wherein once administration of the induction dose produces a clinical response, the patient enters a maintenance treatment phase.

4. The method according to any one of claims 1 to 3, wherein the induction dose is administered 1 to 3 times, preferably 3 times.

5. The method according to any one of claims 1 to 4, wherein when multiple induction doses are administered, the induction doses are administered at intervals of 4 weeks; and / or when multiple maintenance doses are administered, the maintenance doses are administered at intervals of 4-8 weeks.

6. The method according to any one of claims 1 to 5, wherein the first maintenance dose is administered 2 to 8 weeks, preferably 4 weeks, after the administration of the last induction dose.

7. The method according to any one of claims 1 to 6, which is a method for preventing or treating ulcerative colitis (UC), the method comprising administering an anti-IL-23p19 antibody to a patient in need thereof, wherein the administration regimen comprises: a) Induction therapy phase: Administering 3 induction doses of anti-IL-23p19 antibody to patients in need at 4-week intervals, wherein each induction dose is 100-1000 mg; and b) Maintenance treatment phase: administering maintenance doses of anti-IL-23p19 antibody to the patient at intervals of 4-8 weeks, with the first maintenance dose administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg; The amino acid sequence of the antibody heavy chain CDR1 includes or consists of SEQ ID NO.1, the amino acid sequence of the heavy chain CDR2 includes or consists of SEQ ID NO.2, and the heavy chain The amino acid sequence of CDR3 includes or consists of SEQ ID NO.3; the amino acid sequence of the light chain CDR1 of the antibody includes or consists of SEQ ID NO.4, the amino acid sequence of the light chain CDR2 includes or consists of SEQ ID NO.5, and the amino acid sequence of the light chain CDR3 includes or consists of SEQ ID NO.

6.

8. The method of claim 7, wherein the UC is moderate to severe ulcerative colitis.

9. The method according to claim 7 or 8, wherein the induction dose is administered by intravenous injection, and / or the maintenance dose is administered by subcutaneous injection.

10. The method according to any one of claims 1 to 9, wherein: During the induction treatment phase, 3 induction doses of anti-IL-23p19 antibody were administered to patients in need by intravenous infusion at 4-week intervals.

11. The method according to any one of claims 1 to 10, wherein: During the maintenance treatment phase, maintenance doses of anti-IL-23p19 antibodies are administered to patients in need by subcutaneous injection at 4-week or 8-week intervals.

12. The method according to any one of claims 1 to 11, wherein the induction dose administered is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or a range consisting of any two thereof.

13. The method according to any one of claims 1-11, wherein each induction dose is 200 mg.

14. The method according to any one of claims 1 to 11, wherein each induction dose is 600 mg.

15. The method according to any one of claims 1 to 14, wherein the maintenance dose is administered at intervals of 4 weeks or 8 weeks after administration of the first maintenance dose.

16. The method of any one of claims 1-15, wherein the first maintenance dose is administered 4 weeks after administration of the last induction dose.

17. The method according to any one of claims 1-16, wherein each maintenance dose is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or a range consisting of any two thereof.

18. The method of any one of claims 1-16, wherein each maintenance dose is 200 mg.

19. The method of any one of claims 1-18, wherein the dosing regimen comprises: a) Induction therapy phase: 3 induction doses of anti-IL-23p19 antibody, each 200 mg or 600 mg, are administered to patients in need by intravenous infusion at 4-week intervals; and b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 4 weeks after the last induction dose, each maintenance dose is 200 mg, and administration continues until the 44th week.

20. The method of any one of claims 1-9, wherein the dosing regimen comprises an extended induction phase followed by an induction therapy phase and preceded by a maintenance therapy phase: Extended induction phase: one or more extended induction doses of anti-IL-23p19 antibody are administered to the patient, wherein the extended induction dose is 100-1000 mg; preferably, once the administration of the extended induction dose produces a clinical response, the patient enters the maintenance treatment phase.

21. The method of claim 20, wherein the extended induction dose is administered by intravenous injection.

22. The method according to claim 20 or 21, wherein the extended induction dose is administered 1-3 times, preferably 3 times.

23. The method of any one of claims 20-22, wherein when multiple extended induction doses are administered, the extended induction doses are administered at 4-week intervals.

24. The method according to any one of claims 1-23, wherein the dosing regimen further comprises an extended induction phase: after administering 3 induction doses of anti-IL-23p19 antibody to a patient in need at intervals of 4 weeks, if the patient does not achieve a clinical response 2-8 weeks after the last induction dose, the patient is given 3 extended induction doses, each extended induction dose is 100-1000 mg; if the patient has a clinical response to the extended induction dose, the patient enters a maintenance treatment phase.

25. The method according to claim 24, wherein if the patient does not achieve clinical response 4 weeks after the last induction dose, the patient is given 3 extended induction doses, each extended induction dose is 100-1000 mg; if the patient has a clinical response to the extended induction dose, the patient enters the maintenance treatment stage.

26. The method of any one of claims 20-25, wherein the first extended induction dose is administered 4 weeks after administration of the last induction dose of the induction treatment phase.

27. The method of any one of claims 20-26, wherein each extended induction dose is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or a range consisting of any two thereof.

28. The method of claim 27, wherein each extended induction dose is 600 mg.

29. The method of any one of claims 20-28, wherein after the extended induction phase, the first maintenance dose is administered 2-8 weeks after the last extended induction dose.

30. The method of claim 29, wherein after the extended induction phase, the first maintenance dose is administered 4 weeks after the last extended induction dose.

31. The method according to any one of claims 20-30, wherein after the extended induction phase, maintenance doses of anti-IL-23p19 antibody are administered to the patient in need thereof by subcutaneous injection at 4-week intervals, wherein each maintenance dose is 100-1000 mg.

32. The method of any one of claims 20-31, wherein after the extended induction phase, the maintenance dose administered is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg, or a range consisting of any two thereof.

33. The method of claim 32, wherein each maintenance dose is 200 mg.

34. The method of any one of claims 1-33, wherein the dosing regimen comprises: a) Induction therapy phase: 3 induction doses of anti-IL-23p19 antibody, each 200 mg or 600 mg, are administered to patients in need by intravenous infusion at 4-week intervals; and a1) Extended induction phase: Administer 3 extended induction doses of anti-IL-23p19 antibody to patients in need by intravenous infusion at 4-week intervals, each extended induction dose is 600 mg; and b) Maintenance treatment phase: The patient is administered a maintenance dose of anti-IL-23p19 antibody by subcutaneous injection at intervals of 4 or 8 weeks, with the first maintenance dose administered 4 weeks after the last extended induction dose, each maintenance dose is 200 mg, and administration continues until the 56th week.

35. The method of any one of claims 1-34, wherein the heavy chain of the anti-IL-23p19 antibody contains one N-glycosylation site located at asparagine 295 of the heavy chain.

36. The method of any one of claims 1-35, wherein the anti-IL-23p19 antibody comprises a heavy chain variable region, VH, comprising or consisting of the sequence of SEQ ID NO:7, or a sequence having at least 90%, 95%, 98% or 99% identity thereto, and a light chain variable region, VL, comprising or consisting of the sequence of SEQ ID NO:8, or a sequence having at least 90%, 95%, 98% or 99% identity thereto.

37. The method according to any one of claims 1 to 36, wherein the anti-IL-23p19 antibody is an IgG1 type antibody, preferably comprising a heavy chain and a light chain, the heavy chain comprising or consisting of SEQ ID NO: 9 or a sequence having at least 90%, 95%, 98% or 99% identity thereto, and the light chain comprising or consisting of SEQ ID NO: 10 or a sequence having at least 90%, 95%, 98% or 99% identity thereto.

38. The method according to any one of claims 1-37, wherein the anti-IL-23p19 antibody comprises a heavy chain as shown in SEQ ID NO:9 and a light chain as shown in SEQ ID NO:10; for example, the anti-IL-23p19 antibody comprises 2 heavy chains as shown in SEQ ID NO:9 and 2 light chains as shown in SEQ ID NO:10, or consists of 2 heavy chains as shown in SEQ ID NO:9 and 2 light chains as shown in SEQ ID NO:

10.

39. The method of any one of claims 1-38, wherein the anti-IL-23p19 antibody is recombinantly expressed in HEK 293 cells or CHO cells.

40. An anti-IL-23p19 antibody for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, wherein the amino acid sequence of the heavy chain CDR1 of the antibody comprises or consists of SEQ ID NO.1, the amino acid sequence of the heavy chain CDR2 comprises or consists of SEQ ID NO.2, and the heavy chain The amino acid sequence of CDR3 includes SEQ ID NO.3 or consists of it; the amino acid sequence of the light chain CDR1 of the antibody includes SEQ ID NO.4 or consists of it, the amino acid sequence of the light chain CDR2 includes SEQ ID NO.5 or consists of it, the amino acid sequence of the light chain CDR3 includes SEQ ID NO.6 or consists of it, and the administration regimen of the antibody includes: a) induction therapy phase: administering one or more induction doses of anti-IL-23p19 antibody to a patient in need thereof, wherein each of the induction doses is 100-1000 mg; and b) Maintenance treatment phase: the patient is administered one or more maintenance doses of anti-IL-23p19 antibody, the first maintenance dose is administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg.

41. An anti-IL-23p19 antibody for use according to claim 40, wherein the dosing regimen is as defined in any one of claims 2-7 and 9-34, and / or wherein the anti-IL-23p19 antibody is as defined in any one of claims 35-39.

42. Use of an anti-IL-23p19 antibody in the preparation of a medicament for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, wherein the amino acid sequence of the heavy chain CDR1 of the antibody comprises or consists of SEQ ID NO.1, the amino acid sequence of the heavy chain CDR2 comprises or consists of SEQ ID NO.2, and the heavy chain The amino acid sequence of CDR3 includes SEQ ID NO.3 or consists of it; the amino acid sequence of the light chain CDR1 of the antibody includes SEQ ID NO.4 or consists of it, the amino acid sequence of the light chain CDR2 includes SEQ ID NO.5 or consists of it, the amino acid sequence of the light chain CDR3 includes SEQ ID NO.6 or consists of it, and the administration regimen of the antibody or drug includes: a) Induction therapy phase: administering one or more induction doses of anti-IL-23p19 antibody to a patient in need, wherein each induction dose is 100-1000 mg; b) Maintenance treatment phase: the patient is administered one or more maintenance doses of anti-IL-23p19 antibody, the first maintenance dose is administered 2-8 weeks after the last induction dose, wherein each maintenance dose is 100-1000 mg.

43. The use according to claim 41, wherein the dosage regimen is as defined in any one of claims 2-7 and 9-34, and / or wherein the anti-IL-23p19 antibody is as defined in any one of claims 35-39.

44. A kit of parts comprising an effective amount of an anti-IL-23p19 antibody as defined in any one of claims 1 to 39; preferably, further comprising a package insert having instructions for using the anti-IL-23p19 antibody in preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, in an individual.

45. Use of the kit of parts according to claim 44 in the preparation of a medicament for preventing or treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

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