Gene regulation in ulcerative colitis and uses thereof

Abstract

The present disclosure relates generally to methods and diagnostic applications for the treatment of ulcerative colitis. More particularly, the methods and diagnostic applications of the present invention relate to the expression profiles of specific gene transcripts in patients with ulcerative colitis and the utility of these gene transcript expression profiles for therapeutic and / or diagnostic uses in subgroups of patients with ulcerative colitis.

Description

[Technical Field]

[0001] (Reference to sequence listing) This application has been submitted with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled "30296_WO_000 sequence listing ST26," created on February 15, 2024, and is 5.2 kilobytes in size. The Sequence Listing information in ST.26 XML format is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention is in the field of pharmaceuticals. The present invention relates to methods and diagnostic applications for the treatment of ulcerative colitis. More particularly, the methods and diagnostic applications of the present invention relate to the identification of gene transcript expression profiles in patients with ulcerative colitis and the utility of gene transcript expression profiles for the prognosis of UC disease activity and / or the treatment of subgroups of patients with ulcerative colitis with anti-IL23p19 antibodies. [Background technology]

[0003] Ulcerative colitis (UC) is a chronic, relapsing, immune-mediated inflammatory bowel disease (IBD) characterized by mucosal inflammation of the colon. Substantial morbidity and reduced quality of life result from typical symptoms such as diarrhea, rectal bleeding, stool frequency, and urgency. Treatment goals include achieving symptom control and remission, suppressing intestinal inflammation to result in mucosal healing and remission (endoscopic remission), and maintaining bowel function.

[0004] Current treatment options for UC include 5-aminosalicylates, glucocorticoids, thiopurines, the Janus-associated kinase (JAK) inhibitors tofacitinib and upadacitinib, and biologics that antagonize TNFα, the p40 subunit of IL-12 / IL-23, and the a4β7 integrin. Although these treatments have shown efficacy in reducing symptoms for a subset of patients with UC, many patients remain unresponsive, experience a loss of response, experience an inadequate response, or are intolerant to currently available treatments, or have been reported to have potentially serious adverse effects, such as with certain anti-TNF therapies.

[0005] Interleukin-23 (IL-23), a member of the interleukin-12 (IL-12) family of cytokines, is a heterodimeric protein composed of two subunits: the p40 subunit shared by IL-12 and the p19 subunit specific to IL-23. Engagement of the IL-23 receptor results in activation of JAKs (mainly TYK2 and JAK2) and signal transducer and activator of transcription factors 3 and 4 (STAT3 and STAT4), inducing the transcription of downstream target genes. IL-23 promotes the differentiation, maintenance, and stabilization of pathogenic T cell lineages, including populations that simultaneously produce multiple proinflammatory cytokines (e.g., interferon-γ, IL-17A, IL-17F, and IL-22), as well as the activation and induction of effector functions of enterocolitis-inducing innate lymphoid cells. Therapeutic blockade of p40 has been found to be effective in treating UC, and drugs targeting p19 are being investigated for the treatment of UC. To date, there are no approved anti-IL23p19 antibodies for the treatment of UC.

[0006] The complex interplay of immune cell landscapes, molecular pathways, and gene transcript signatures has been investigated to provide insight into the pathogenesis of UC disease and potential mechanistic reasons why certain patients do not respond to certain therapies. Various genes that play a role in UC disease activity have been reported, such as in International Publication No. 2022251623. Furthermore, potential genes that play a role in resistance to existing therapies in UC, such as anti-TNF therapy, have been reported, for example, in Smillie et al. (Smillie CS; et al. "Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis." Cell. vol. 175, no. 3. Jul. 2019, pp. 714-730. e22. doi:10.1016 / j.cell.2019.06.029). Data demonstrate the complexity of treating patients with UC, particularly those who are non-responsive, experience loss of response, have an inadequate response, or are intolerant to specific treatments for UC. Thus, there remains a need to identify gene signatures or subsets of gene signatures to assess and inform clinical management of UC and / or UC subpopulations with specific therapies. Thus, there remains a need for alternative compounds, pharmaceutical compositions, and methods useful as therapeutics for the treatment of UC and / or in diagnostic applications related to the treatment of UC. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure generally relates to methods and diagnostic uses for the treatment of ulcerative colitis. More specifically, the methods and diagnostic uses of the present invention relate to expression profiles of specific gene transcripts in patients with ulcerative colitis and the utility of these gene transcript expression profiles for treatment and / or diagnostic use in subgroups of patients with ulcerative colitis. The present invention further provides specific gene transcripts that can be used as biomarkers for the treatment and / or diagnosis of ulcerative colitis, ulcerative colitis-associated bowel frequency, and / or ulcerative colitis-associated symptoms of ulcerative colitis, such as bowel urgency. The present invention further provides specific gene transcripts, the expression profile of which of a specific subset of the gene transcripts can prognose ulcerative colitis disease activity in a patient. Furthermore, the gene transcripts of the present invention can be used to determine whether a patient or subpopulation of patients with ulcerative colitis will respond to treatment with an anti-IL23p19 antibody. Certain subsets of gene transcripts of the present invention may also be useful as biomarkers to track response to treatment with anti-IL-23p19 antibodies, for example, in patients who are non-responsive to existing therapies, or who have experienced an inadequate response, lost response, or are intolerant to previous and / or conventional therapies such as biologic agents, or to determine whether a particular subpopulation of patients will respond to treatment with anti-IL23p19 antibodies.

[0008] Thus, the present invention provides specific gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1. In a further embodiment, the present invention provides specific gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B. In yet a further embodiment, the present invention provides specific gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A. In yet a further embodiment, the present invention provides specific gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, and SLC26A2. In yet other embodiments, the present invention provides specific gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, and IL1B. In such embodiments, the specific gene transcripts provided herein are prognostic for ulcerative colitis.

[0009] In some embodiments, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0010] In some embodiments, the invention provides anti-IL23p19 antibodies for use in treating moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

[0011] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

[0012] In another embodiment, the present invention provides a method of treating fecal urgency in a patient with moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0013] In some embodiments, the invention provides an anti-IL23p19 antibody for use in treating fecal urgency in a patient with moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

[0014] In some embodiments, the invention provides an anti-IL23p19 antibody for the manufacture of or use in a medicament for the treatment of fecal urgency in a patient with moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

[0015] In some embodiments, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has had an inadequate response, lost response, or is intolerant to at least one prior treatment for ulcerative colitis, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts. In certain such embodiments, the previous treatment is a biologic, and the biologic is an anti-TNFα therapeutic and / or an anti-α4β7 integrin therapeutic. In certain embodiments, the previous treatment is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. In certain embodiments, the previous treatment is one or more of an anti-TNFα therapeutic, an anti-α4β7 integrin therapeutic, a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0016] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has had an inadequate response, lost response, or is intolerant to at least one prior ulcerative colitis treatment, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts. In certain such embodiments, the prior treatment is a biologic, and the biologic is an anti-TNFα therapeutic and / or an anti-α4β7 integrin therapeutic. In certain embodiments, the prior treatment is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. In certain embodiments, the previous treatment is one or more of an anti-TNFα therapeutic agent, an anti-α4β7 integrin therapeutic agent, a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0017] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has had an inadequate response, lost response, or is intolerant to at least one prior ulcerative colitis treatment, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts. In certain such embodiments, the prior treatment is a biologic, and the biologic is an anti-TNFα therapeutic and / or an anti-α4β7 integrin therapeutic. In certain embodiments, the prior treatment is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. In certain embodiments, the previous treatment is one or more of an anti-TNFα therapeutic agent, an anti-α4β7 integrin therapeutic agent, a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0018] In a further embodiment, the invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, has lost response, or is intolerant to an anti-TNFα antibody, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts. In certain such embodiments, the anti-TNFα antibody can be adalimumab, infliximab, golimumab, or certolizumab.

[0019] In some embodiments, the invention provides anti-IL23p19 antibodies for use in treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, has lost response, or is intolerant to anti-TNFα therapeutics, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts. In certain such embodiments, the anti-TNFα antibody can be adalimumab, infliximab, golimumab, or certolizumab.

[0020] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, has lost response, or is intolerant to anti-TNFα therapeutics, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts. In certain such embodiments, the anti-TNFα antibody can be adalimumab, infliximab, golimumab, or certolizumab.

[0021] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, has lost response, or is intolerant to an anti-α4β7 therapeutic agent, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts. In certain such embodiments, the anti-α4β7 integrin therapeutic agent is vedolizumab.

[0022] In some embodiments, the invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, has lost response, or is intolerant to an anti-α4β7 integrin therapeutic agent, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts. In certain such embodiments, the anti-α4β7 integrin therapeutic agent is vedolizumab.

[0023] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, has lost response, or is intolerant to an anti-α4β7 therapeutic agent, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts. In certain such embodiments, the anti-α4β7 integrin therapeutic agent is vedolizumab.

[0024] In some embodiments, the present invention provides a method of treating bowel frequency in a patient with moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0025] In some embodiments, the invention provides anti-IL23p19 antibodies for use in treating bowel frequency in a patient in need thereof, having moderate to severe ulcerative colitis who is non-responsive, has had an inadequate response, lost response, or is intolerant to at least one prior treatment for ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, when compared to baseline values ​​for the particular gene transcripts.

[0026] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating bowel movement frequency in a patient with moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

[0027] In some embodiments, the present invention provides a method for prognosticating response in a patient with moderate to severe ulcerative colitis, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4AA, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; determining whether the expression levels of three or more gene transcripts selected from ABI1, HNF4AA, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts, thereby determining ulcerative colitis disease activity in the patient.

[0028] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are prognostic of ulcerative colitis disease activity in the patient when the patient has differentially regulated expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 compared to reference values ​​for the particular gene transcripts.

[0029] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are prognostic of ulcerative colitis disease activity in the patient when the patient has differentially regulated expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 compared to reference values ​​for the particular gene transcripts.

[0030] In another embodiment, the present invention provides a method for predicting the suitability of a patient in need of treatment for moderate to severe ulcerative colitis for treatment with an anti-IL23p19 antibody, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0031] In some embodiments, the invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient's differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, when compared to reference values ​​for the particular gene transcripts, is predictive of suitability for treatment with the anti-IL23p19 antibody.

[0032] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient's differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, when compared to reference values ​​for the particular gene transcripts, is predictive of suitability for treatment with the anti-IL23p19 antibody.

[0033] In another embodiment, the present invention provides a method of treating symptoms of moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts. In such embodiments, the symptom can be, for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.

[0034] In some embodiments, the invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis symptoms in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, when compared to reference values ​​for the particular gene transcripts. In such embodiments, the symptoms can be, for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.

[0035] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis symptoms in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1, when compared to reference values ​​for the particular gene transcripts. In such embodiments, the symptoms can be, for example, diarrhea, stool frequency, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.

[0036] In another embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts; The method provides wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:2.

[0037] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference levels of the particular gene transcripts; The present invention provides an anti-IL23p19 antibody, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:2.

[0038] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference levels of the particular gene transcripts; The present invention provides an anti-IL23p19 antibody, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:2.

[0039] In certain embodiments, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; administering an anti-IL23p19 antibody to the patient if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts; measuring the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in the patient sample about 12 weeks to about 40 weeks after administration of the first dose of the anti-IL-23p19 antibody; and continuing to administer the anti-IL23p19 antibody to the patient if the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0040] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference levels of the particular gene transcripts; If the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to baseline values ​​for the particular gene transcripts about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody, the patient continues treatment with the anti-IL23p19 antibody.

[0041] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference levels of the particular gene transcripts; If the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to baseline values ​​for the particular gene transcripts about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody, the patient continues treatment with the anti-IL23p19 antibody.

[0042] In an even more particular embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0043] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B, when compared to reference values ​​for the particular gene transcripts.

[0044] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B when compared to reference values ​​for the particular gene transcripts.

[0045] In an even more particular embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0046] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A when compared to reference levels of the particular gene transcripts.

[0047] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A when compared to reference values ​​for the particular gene transcripts.

[0048] In an even more particular embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2; and administering an anti-IL23p19 antibody to the patient when the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0049] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2, when compared to reference levels of the particular gene transcripts.

[0050] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2 when compared to reference values ​​for the particular gene transcripts.

[0051] In yet a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression levels of gene transcripts ABI1, HNF4A, and IL1B in the patient sample; and administering an anti-IL23p19 antibody to the patient if the expression level of a gene transcript selected from ABI1, HNF4A, and IL1B is differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.

[0052] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of a gene transcript selected from ABI1, HNF4A, and IL1B, when compared to a reference value for the particular gene transcript.

[0053] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has a differentially regulated expression level of a gene transcript selected from ABI1, HNF4A, and IL1B when compared to a reference value for the particular gene transcript.

[0054] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; administering an anti-IL23p19 antibody to the patient when the expression level of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample, and / or the expression level of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for the particular gene transcripts.

[0055] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and / or decreased expression levels of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2, when compared to baseline levels of the particular gene transcripts.

[0056] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, IL23A, DEFB4B, MMP3, and CXCL1, and / or decreased expression levels of one or more gene transcripts selected from HNF4, PTPRC, SLC26A2, and OTOP2, when compared to baseline values ​​for the particular gene transcripts.

[0057] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; administering an anti-IL23p19 antibody to the patient when the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample, and when the expression level of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for the particular gene transcripts.

[0058] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and decreased expression levels of one or more gene transcripts selected from HNF4, SLC26A2, and OTOP2, when compared to baseline levels of the particular gene transcripts.

[0059] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and decreased expression levels of one or more gene transcripts selected from HNF4A, SLC26A2, and OTOP2, when compared to baseline values ​​for the particular gene transcripts.

[0060] In yet a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; administering an anti-IL23p19 antibody to the patient when the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample, and when the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference levels of the particular gene transcripts; The method provides wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:2.

[0061] In some embodiments, the invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and decreased expression levels of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, relative to baseline levels of the particular gene transcripts; The present invention provides an anti-IL23p19 antibody, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:2.

[0062] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and decreased expression levels of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, relative to baseline levels of the particular gene transcripts; The present invention provides an anti-IL23p19 antibody, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:2.

[0063] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B; administering an anti-IL23p19 antibody to the patient when the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, and DEFB4B is elevated in the patient sample, and when the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for the particular gene transcripts.

[0064] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, and DEFB4B, and decreased expression levels of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to baseline values ​​for the particular gene transcripts.

[0065] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, and DEFB4B, and decreased expression levels of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to baseline values ​​for the particular gene transcripts.

[0066] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A; administering an anti-IL23p19 antibody to the patient when the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, and IL23A is elevated in the patient sample, and when the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for the particular gene transcripts.

[0067] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, and IL23A, and decreased expression levels of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to baseline values ​​for the particular gene transcripts.

[0068] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, and IL23A, and decreased expression levels of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to baseline values ​​for the particular gene transcripts.

[0069] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in the patient sample of one or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2; administering an anti-IL23p19 antibody to the patient when the expression level of one or more gene transcripts selected from AbI1, IL1B, and PTPRC is elevated in the patient sample, and when the expression level of one or more gene transcripts selected from HFN4A and SLC26A2 is decreased in the patient sample, when compared to reference values ​​for the particular gene transcripts.

[0070] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, and PTPRC, and decreased expression levels of one or more gene transcripts selected from HFN4A and SLC26A2, when compared to baseline levels of the particular gene transcripts.

[0071] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, and PTPRC, and decreased expression levels of one or more gene transcripts selected from HFN4A and SLC26A2, when compared to baseline values ​​for the particular gene transcripts.

[0072] In a further embodiment, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression level in the patient sample of a gene transcript selected from ABI1, HNF4A, and IL1B; administering an anti-IL23p19 antibody to the patient when the expression level of a gene transcript selected from AbI1 and IL1B is elevated in the patient sample, and when the expression level of the gene transcript HFN4A is decreased in the patient sample, when compared to reference values ​​for the particular gene transcripts.

[0073] In some embodiments, the present invention provides an anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of gene transcripts selected from AbI1 and IL1B, and decreased expression levels of the gene transcript HFN4A, when compared to baseline values ​​for the particular gene transcripts.

[0074] In some embodiments, the invention provides an anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has elevated expression levels of gene transcripts selected from AbI1 and IL1B and decreased expression levels of the gene transcript HFN4A, when compared to baseline values ​​for the particular gene transcripts.

[0075] In certain embodiments of the invention, the methods, treatments and uses of anti-IL23p19 antibodies may be used to treat symptoms of UC, such as diarrhea, stool frequency, rectal bleeding, urgency, fatigue, or other symptoms known to be associated with UC.

[0076] In certain embodiments of the invention, the methods, treatments, and uses of anti-IL23p19 antibodies result in increased expression levels of at least one, at least two, or three gene transcripts selected from HNF4A, OTOP2, and SLC26A2 following treatment with the anti-IL23p19 antibody. In such embodiments, increased expression negatively correlates with increased disease activity as measured by a clinical score, such as the Mayo score, the endoscopy-based UCEIS score, and / or a histology-based score, such as the Geboes or RHI. In still further embodiments, if the expression levels of at least one, at least two, or three gene transcripts selected from HNF4A, OTOP2, and SLC26A2 decrease following treatment with the anti-IL23p19 antibody, the patient is continued on treatment with the anti-IL23p19 antibody.

[0077] In certain embodiments of the invention, the methods, treatments and uses of anti-IL23p19 antibodies result in a decrease in the expression levels of at least one, at least two or at least three, at least four, or at least five, at least six, or seven gene transcripts selected from ABI1, DEFB4B, PTPRC, IL23A, IL1B, MMP3, and CXCL1 following treatment with the anti-IL23p19 antibody. In such embodiments, the decrease in expression is positively correlated with disease activity as measured by clinical scores such as the Mayo score, the endoscopy-based UCEIS score, and / or histology-based scores such as the Geboes or RHI. In still further embodiments, if the expression levels of at least one, at least two, or at least three, at least four, at least five, at least six, or seven of the gene transcripts selected from ABI1, DEFB4B, PTPRC, IL23A, IL1B, MMP3, and CXCL1 decrease after treatment with an anti-IL23p19 antibody, the patient is continued on treatment with an anti-IL23p19 antibody.

[0078] In further embodiments of the methods and uses of the invention, a patient receiving an anti-IL23p19 antibody achieves at least one or more of the following therapeutic benefits within about 2 to about 12 weeks of treatment with the anti-IL23p19 antibody: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, and improvement in fatigue. In such embodiments, the patient achieves a therapeutic benefit within about 2, 4, 8, or 12 weeks of treatment with the anti-IL23p19 antibody. In still further embodiments, the patient achieves at least one or more sustained therapeutic benefits of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, and improvement in fatigue for up to at least about 12 weeks to about 104 weeks of treatment with the anti-IL23p19 antibody. In further embodiments, the patient sustains one or more of the therapeutic benefits for up to about 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, or 104 weeks of treatment with the anti-IL23p19 antibody.

[0079] In certain embodiments, the invention provides methods or uses for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein expression levels of at least three, at least five, at least seven, at least eight, or more gene transcripts of the invention are prognostic for at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, and improvement in fatigue. In further embodiments, treatment with an IL23p19 antibody achieves one or more of the following therapeutic effects: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, and improvement in fatigue.

[0080] In certain embodiments, the invention provides methods of treating moderate to severe ulcerative colitis in a patient in need thereof, wherein expression levels of at least three, at least five, at least seven, at least eight, or more gene transcripts of the invention are predictive of at least one of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, and improvement in fatigue with treatment with an anti-IL23p19 antibody.

[0081] In certain embodiments of the methods, treatments and uses of the invention, expression levels of at least 3, at least 5, at least 7, at least 8, or 10 or more gene transcripts of the invention are predictive of at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, improvement in fatigue with treatment with an anti-IL23p19 antibody.

[0082] In certain embodiments of the methods, treatments and uses of the present invention, the expression level of a gene transcript in a patient sample selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample when compared to a reference value for the particular gene transcript, and / or the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample when compared to a reference value for the particular gene transcript. In certain such embodiments, the expression levels of at least one, at least two, at least three, at least four, at least five, or at least six of the gene transcripts in the patient sample selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 are elevated in the patient sample when compared to reference values ​​for the particular gene transcripts, and / or the expression levels of at least one, at least two, at least three, or four of the gene transcripts in the patient sample selected from HFN4A, SLC26A2, and OTOP2 are decreased in the patient sample when compared to reference values ​​for the particular gene transcripts.

[0083] In certain embodiments of the methods, treatments and uses of the invention, the method, treatment or use comprises measuring the expression levels in a patient sample of at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or ten gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1, before and after administration of an anti-IL23p19 antibody, if appropriate.

[0084] In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels of at least three of the gene transcripts of the invention in patient samples, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels of at least four of the gene transcripts of the invention in patient samples, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels of at least five of the gene transcripts of the invention in patient samples, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels of at least six of the gene transcripts of the invention in patient samples, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels in patient samples of at least seven of the gene transcripts of the invention, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels in patient samples of at least eight of the gene transcripts of the invention, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels in patient samples of at least nine of the gene transcripts of the invention, where appropriate, before and after administration of an anti-IL23p19 antibody. In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise measuring the expression levels in patient samples of ten of the gene transcripts of the invention, where appropriate, before and after administration of an anti-IL23p19 antibody.

[0085] In certain embodiments of the methods, treatments and uses of the invention, the methods, treatments or uses comprise analyzing clinical metrics including modified Mayo Score (MMS), total Mayo score, Mayo endoscopic subscore, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) total score, Geboes score, Roberts Histopathology Index (RHI), and combinations thereof.

[0086] In some embodiments, the anti-IL23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.

[0087] In a still further preferred embodiment of the methods, treatments and uses of the present invention, the anti-IL-23p19 antibody is mirikizumab.

[0088] Preferably, the method, treatment or use comprises: i. administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose being 300 mg of mirikizumab; ii. administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose, and each maintenance dose being 200 mg of mirikizumab.

[0089] In some embodiments, the first maintenance dose of mirikizumab is administered 4 weeks after the last induction dose. In further embodiments, the maintenance doses are administered at 4-week intervals. In still further embodiments, the maintenance doses are administered at 4-week intervals for at least about 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, or up to 104 weeks.

[0090] In some embodiments of the invention, the patient is biologic naive. In some embodiments, the patient is a biologic failure. In some embodiments, the patient is a conventional drug failure. In some embodiments, the patient is resistant to anti-TNF therapy. In some embodiments, the patient is a JAK inhibitor failure. In some embodiments, the patient is an anti-integrin therapy failure. In some embodiments, the patient is an S1P receptor modulator failure. In some embodiments, the patient is a biologic failure and a conventional drug failure. In some embodiments, the patient is non-responsive, has an inadequate response, has lost response, or is intolerant to conventional therapy or a biologic.

[0091] In some embodiments of the present invention, the expression levels of gene transcripts of the present invention are measured by a method of gene expression profiling. In further embodiments, the method is a PCR-based method. In other embodiments, the method is an RNA sequencing method. In some embodiments, the method is an in situ hybridization-based method. In some embodiments, the method is immunohistochemistry. In some embodiments, the method is a proteomics technique. In certain embodiments, the expression levels of gene transcripts of the present invention are normalized to the expression levels of one or more reference genes or their expression products. In certain embodiments, measuring the expression levels of the gene transcripts is performed using an analyzer unit, and comparing the determined expression levels of one or more gene transcripts to the reference values ​​for the particular gene transcripts is performed using a computing device.

[0092] In some embodiments of the invention, the sample is derived from a colon tissue biopsy or a rectal tissue biopsy. In further embodiments of the invention, the colon tissue biopsy is derived from a tissue selected from the group consisting of the terminal ileum, the ascending colon, the descending colon, and the sigmoid colon. In some embodiments, the colon tissue biopsy is derived from a non-inflamed region of the colon. In other embodiments, the colon tissue biopsy is derived from an inflamed region of the colon. DETAILED DESCRIPTION OF THE INVENTION

[0093] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, the preferred methods and materials are described below.

[0094] UC is a form of colitis, an inflammatory disease of the intestine, usually the colon, that contains characteristic ulcers. Symptoms of active disease include diarrhea, usually bloody, usually accompanied by abdominal pain that can range in severity from mild discomfort to severe cramping. Fecal urgency is also a common and disruptive symptom of ulcerative colitis (UC), and is distinct from stool frequency (SF) and rectal bleeding (RB).

[0095] There are several methods for assessing disease severity / clinical indicators, including the Mayo score, modified Mayo score (MMS), Ulcerative Colitis Disease Activity Index (UCDAI), total Mayo score, Mayo endoscopic subscore, Ulcerative Colitis Endoscopic Severity Index (UCEIS) total score, Geboes score, Roberts Histopathology Index (RHI), and combinations thereof.

[0096] The Mayo score is a composite measure consisting of four subscores: i. Bowel Frequency (SF): The SF subscore is a patient-reported measure. This item reports the number of bowel movements in a 24-hour period on a 4-point scale compared to the patient's normal number of bowel movements for the same period. A bowel movement is defined as going to the toilet either when the patient has a bowel movement or when they pass blood only, blood and mucus, or mucus only. The total number of bowel movements passed within a 24-hour period is recorded by the patient. The patient's reference "normal" SF is typically recorded at the beginning of the study or observation period. The patient's normal SF is the SF reported when the patient was in remission or, if the patient has never achieved remission, the SF reported before the first onset of UC signs and symptoms.

[0097] [Table 1] ii. Rectal Bleeding: The RB subscore is a patient-reported measure. This item reports the most significant amount of blood passed rectally on a given day on a 4-point scale.

[0098] [Table 2] iii. Endoscopic Subscore (ES): ES is a physician-reported measure of the worst appearance of the mucosa during flexible sigmoidoscopy or colonoscopy on a 4-point scale. Consistent with current clinical practice, fragility is excluded from the definition of an ES of 1.

[0099] [Table 3] iv. Physician's Global Assessment (PGA): The PGA is a physician-reported measure that summarizes the patient's assessment of UC disease activity on a 4-point scale.

[0100] [Table 4]

[0101] Each subscore is scored on a 4-point scale ranging from 0 to 3, resulting in a maximum Mayo score of 12.

[0102] The MMS is a modification of the original Mayo Index reference (Schroeder et al., New Eng J Med, 317(26):1625-1629, 1987) and includes three of the four subscores of the Mayo score. Physician Global Assessment is not included. The MMS assesses three subscores, each on a scale of 0 to 3, with a maximum total score of 9. Patients with a Mayo score of 6 to 12 or an MMS of 4 to 9, each with an ES of 2 or greater, are defined as having moderately to severely active ulcerative colitis.

[0103] The Mayo score ranges from 0 to 12, with higher scores indicating greater severity. The partial Mayo score excludes endoscopic examination and ranges from 0 to 9, whereas the modified Mayo score excludes physician global assessment and also ranges from 0 to 9. The original description of the Mayo score included friability in the definition of an endoscopic subscore of 1.

[0104] As used herein, "clinical remission" using the MMS is defined as a RB subscore of 0 and a SF subscore of 0 or 1 ( 3A "clinical response" using the MMS is defined as achieving a 2-point or greater reduction in a 9-point MMS subscore and a 30-35% or greater reduction from baseline, with a RB subscore of 1 or greater or an RB subscore of either 0 or 1. As used herein, "endoscopic remission" using the MMS is defined as achieving a Mayo ES of 0. As used herein, "endoscopic healing" using the MMS is defined as achieving a Mayo ES of 0 or 1. "Improvement of endoscopic histological inflammation" (mucosal healing) is defined as an endoscopic subscore of 0 or 1 and histological resolution (defined as a Geboes histological subscore of 0 for neutrophils in the lamina propria, neutrophils in the epithelium, and erosion or ulceration parameters, or defined as an RHI score) of 0 or 1.

[0105] As used herein, "symptomatic remission" using the MMS is defined as achieving SF=0 or SF=1 and RB=0, with a reduction of 1 or more points from baseline. As used herein, "symptomatic response" is defined as at least a 30% reduction from baseline in the composite SF and RB. As used herein, "loss of response" using the MMS is defined as (a) a 2 or more point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) score, (b) a combined SF and RB score of 4 or greater on two consecutive visits 7 or more days apart, accompanied by a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. "Corticosteroid-free remission" without surgery is defined as clinical remission and absence of corticosteroid use for 12 or more weeks prior to evaluation.

[0106] Bowel urgency is measured by the Uniform Numeric Rating Score (UNRS) to assess the mean change in the severity of bowel urgency. Urgency, the sudden or immediate need to defecate, is a common and bothersome symptom for patients with ulcerative colitis. The UNRS is a patient-reported measure of bowel urgency over the past 24 hours using an 11-point scale ranging from 0 (no urgency) to 10 (worst possible urgency). The UNRS score is recorded daily by patients in an eDiary. The change in UNRS from baseline is measured over 12, 28, 52, or up to approximately 104 weeks of treatment. A clinically meaningful "improvement in bowel urgency" or a clinically meaningful change in the severity of bowel urgency is defined as the proportion of patients achieving both a clinical response based on a 3-point or greater improvement from baseline in the MMS and UNRS scores. "Faecal urgency remission" is defined as minimal to no fecal urgency assessed at weeks 12, 28, and subsequent time points (maintenance) in patients with a baseline UNRS of 3 or greater: UNRS [0, 1].

[0107] The Geboes score, as used herein, consists of seven categories (or grades), each of which describes a histological feature, including "architectural (architectural changes)" (grade 0), "chronic inflammatory infiltrate" (grade 1), "lamina propria eosinophils" (grade 2A), "lamina propria neutrophils" (grade 2B), "neutrophils in the epithelium" (grade 3), "crypt destruction" (grade 4), and "surface epithelial damage" (grade 5). Each grade includes a subscore indicating the degree of abnormality seen for that histological feature, with a subscore of 0 indicating a normal appearance and higher subscores indicating increasing abnormal appearance. The RHI uses weighted results from the four Geboes score categories ("chronic inflammatory infiltrate," "lamina propria neutrophils," "neutrophils in the epithelium," and "surface epithelial damage") to derive a continuous score ranging from 0 (no disease activity) to 33 (severe disease activity). The RHI was developed as a response measure to detect treatment effects in early drug development.

[0108] As so used herein, "therapeutic effect" or response to treatment can be any one or more of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, improvement in fatigue.

[0109] As used herein, "sustained response" is the percentage of patients who achieve clinical remission at week 52 among those who achieve clinical remission at week 12.

[0110] As used herein, the term "biomarker" refers to any molecule or group of molecules found in a biological sample that can be used to characterize the biological sample or the subject from which the biological sample was obtained. For example, a biomarker may be a molecule or group of molecules whose presence, absence, or relative abundance indicates a characteristic of a particular cell or tissue type or condition, and / or a characteristic of a particular pathological state or condition, and / or the severity of a pathological state, the likelihood of progression or regression of a pathological state, and / or the likelihood that a pathological state will respond to a particular treatment. For example, a biomarker, as used herein, may be a gene expression product corresponding to a particular gene, e.g., an RNA transcript (gene transcript) expressed by a particular gene. The biomarkers provided herein may be predictive biomarkers that can be used to predict or identify individuals or groups of individuals more likely to respond to anti-IL-23p19 antibody treatment. The biomarkers provided herein may also be prognostic biomarkers for identifying ulcerative colitis disease activity. The biomarkers provided herein may be diagnostic biomarkers that can be used to detect and / or confirm the presence of ulcerative colitis. The biomarkers provided herein can also be monitoring biomarkers that can be analyzed continuously to assess the state of ulcerative colitis and / or track the response / effectiveness of a patient to treatment with an anti-IL-23p19 antibody. The biomarkers provided herein can also be pharmacodynamic biomarkers that can be used to determine a patient's response to anti-IL-23p19 antibody treatment. The biomarkers provided herein can also be prevalence / risk biomarkers that can indicate the likelihood that an individual who has not been diagnosed with ulcerative colitis will develop ulcerative colitis. The biomarkers provided herein can also be surrogate biomarkers that describe clinical outcomes after anti-IL-23p19 antibody treatment.

[0111] As used herein, the term "gene transcript" or "gene transcript biomarker" refers to a gene expression product corresponding to a particular gene, e.g., an RNA transcript expressed by a particular gene. Gene transcripts may be used more generally as biomarkers, as described above with respect to biomarkers. The gene transcripts provided herein may be prognostic biomarkers for identifying disease activity, progression, and / or recurrence of ulcerative colitis. The gene transcripts provided herein may also be predictive biomarkers that can be used to predict or identify individuals or populations more likely to respond to treatment with an anti-IL-23p19 antibody therapy. The gene transcripts provided herein may be diagnostic gene transcripts that can be used to detect and / or confirm the presence and / or severity of ulcerative colitis. The gene transcripts provided herein may also be monitoring biomarkers that can be serially analyzed to assess the status of ulcerative colitis. The gene transcripts provided herein may also be pharmacodynamic biomarkers that can be used to determine a patient's response to anti-IL-23p19 antibody therapy. The gene transcripts provided herein may also be prevalence / risk biomarkers that may indicate the likelihood that an individual who has not been diagnosed with ulcerative colitis will develop ulcerative colitis. The gene transcripts provided herein may also be surrogate biomarkers that explain clinical outcomes following anti-IL-23p19 antibody treatment. The terms "biomarker" and "gene transcript biomarker" and "gene transcript" are used interchangeably herein.

[0112] As used herein, "gene transcript expression level" or "gene transcript biomarker" refers to the process by which a gene product is synthesized from a gene encoding a biomarker, as is well known to those of skill in the art. Gene products can be, for example, ribonucleic acid (RNA) and protein. Expression levels can be quantitatively measured by methods known to those of skill in the art, such as polymerase chain reaction (PCR), microarray analysis, tag-based technologies (e.g., serial analysis of gene expression and next-generation sequencing such as whole-transcriptome shotgun sequencing or RNA-Seq), in situ hybridization techniques, immunoassays including Northern blot, Southern blot, in situ hybridization, Western blotting, enzyme-linked immunosorbent assay (ELISA), enzyme-linked fluorescence assay (ELFA), immunoprecipitation, immunohistochemistry, and combinations thereof.

[0113] As used herein, a "reference value" or "reference expression level" of a gene transcript or biomarker may refer to an established expression level of a gene transcript for subjects without ulcerative colitis, as determined by a medical professional and / or research professional using the established methods described herein, and / or a known expression level of a gene transcript obtained from the literature. A reference value may be an absolute or relative value of the gene transcript, a range of expression levels, or a minimum, average, and / or median expression level. A reference value may also serve as a baseline expression level of a gene transcript to which values ​​obtained from patient samples are compared. A reference expression level of a gene transcript may also refer to an established expression level of a biomarker for any combination of subjects, such as subjects without ulcerative colitis, the expression level of a gene transcript in normal / healthy subjects without ulcerative colitis, and the expression level of a gene transcript for a subject who does not have ulcerative colitis at the time the sample is obtained from the subject but who later develops ulcerative colitis. A reference expression level of a gene transcript may also refer to the expression level of a gene transcript obtained from a subject to which the method is applied. Thus, changes within a subject from visit to visit may indicate an increased or decreased risk of ulcerative colitis. For example, multiple expression levels of a gene transcript can be obtained from multiple samples obtained from the same subject, which can be used to identify differences between the multiple expression levels in each sample. Thus, in some embodiments, two or more samples obtained from the same subject can provide an expression level of a gene transcript and a baseline expression level of the gene transcript. The baseline expression level may also refer to the expression level of a gene transcript in a "placebo responder." As used herein, a "placebo responder" is a subject who has ulcerative colitis and shows clinical improvement, but has not been administered an anti-IL-23p19 antibody, as determined by a medical professional and / or research professional using the established methods described herein. The baseline value may be a predetermined threshold value arrived at from any one or more of the above-mentioned methods.

[0114] As used herein, the terms "differentially regulated" and / or "differentially expressed" refer to the difference in expression levels of a particular gene transcript in patients with UC as compared to a reference value as defined herein for that particular gene transcript. Differentially regulated can mean that a patient has elevated (increased, higher, upregulated) or decreased (decreased, lower, downregulated) expression levels of a particular gene transcript as compared to a reference value as defined herein.

[0115] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Antibody embodiments include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, bispecific or multispecific antibodies, or conjugated antibodies. The antibody may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0116] An exemplary antibody of the present disclosure is an immunoglobulin G (IgG) antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) cross-linked via interchain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains contains a variable region of about 100 to 125 amino acids or more primarily responsible for antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is composed of a light chain variable region (VL) and a light chain constant region. IgG isotypes may be further divided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

[0117] The VH and VL regions can be further subdivided into hypervariable regions, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). The CDRs are exposed on the surface of the protein and are critical regions of the antibody for antigen-binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Herein, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." The CDRs contain most of the residues that form specific interactions with the antigen.The assignment of amino acid residues to CDRs can be performed using the methods of Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987), Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics (Lefranc et al., Nucleic Acids Res. 1999;27:209-212, database available at www.imgt.org) The assignment of amino acid residues to CDRs can be performed according to a combination of the above schemes.

[0118] Embodiments of the present disclosure also include antibody fragments or antigen-binding fragments, as used herein, that comprise at least a portion of an antibody that retains the ability to specifically interact with an antigen or an epitope of an antigen, such as Fab, Fab', F(ab')2, Fv fragment, scFv antibody fragment, scFab, disulfide-linked Fv (sdFv), Fd fragment, etc.

[0119] As used herein, "anti-IL-23p19 antibody" refers to an antibody that binds to the p19 subunit of human IL-23 but does not bind to the p40 subunit of human IL-23. Thus, an anti-IL-23p19 antibody binds to human IL-23 but does not bind to human IL-12. Examples of anti-IL23p19 antibodies that may be used in the methods, treatments and uses of the present invention include mirikizumab, guselkumab, tildrakizumab, risankizumab, and brazikumab.

[0120] Guselkumab, CAS Registry Number 1350289-85-8, is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of human IL-23. This antibody and methods for making it are described in U.S. Patent No. 7,935,344.

[0121] Tildrakizumab, CAS Registry Number 1326244-10-3, is a humanized IgG1 kappa (κ) monoclonal antibody that targets the p19 subunit of human IL-23. This antibody and methods for making it are described in U.S. Patent No. 8,293,883.

[0122] Risankizumab, CAS Registry Number 1612838-76-2, is a humanized IgG1 kappa (κ) monoclonal antibody that targets the p19 subunit of human IL-23. This antibody and methods for making it are described in U.S. Patent No. 8,778,346.

[0123] Mirikizumab, CAS Registry Number 1884201-71-1, is a humanized IgG4 kappa (κ) monoclonal antibody that targets the p19 subunit of human IL-23. This antibody and methods for making it are described in U.S. Patent No. 9,023,358. Mirikizumab contains the following heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain (HC), and light chain (LC) amino acid sequences: HCVR-SEQ ID NO:1 LCVR-SEQ ID NO:2 HC-SEQ ID NO:3 LC-SEQ ID NO:4 Mirikizumab is particularly suitable for use in many aspects of the present invention.

[0124] Suitable anti-IL-23p19 antibody induction dosages include about 50 mg to about 600 mg. A particularly suitable dosage is a 300 mg induction dose of anti-IL-23p19 antibody. The anti-IL-23p19 antibody induction dose is preferably administered intravenously. Suitably, an induction dose of 50 mg to 600 mg, preferably 300 mg, is administered to the patient every four weeks for 12 weeks. The induction dose may be followed by at least one maintenance dose of anti-IL-23p19 antibody in the range of about 150 mg to about 400 mg, preferably 200 mg. A particularly suitable dosage is a 200 mg maintenance dose of anti-IL-23p19 antibody. Preferably, a maintenance dose of 150 mg to 400 mg is administered to the patient every four weeks or every 12 weeks. Administration of at least one induction dose of an anti-IL-23p19 antibody to a patient in need thereof during an induction period is intended to induce a desired therapeutic effect, the desired therapeutic effect being clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, or improvement in fatigue. If the patient achieves the desired therapeutic effect at the end of the induction period, the patient is then administered at least one maintenance dose to maintain at least one of the therapeutic effects achieved during the induction period, the therapeutic effect being clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, or improvement in fatigue. Although there is no minimum or maximum duration of the induction period, it is typically 4, 8, or 12 weeks in duration, and the end of the induction period is typically an end-of-induction evaluation, which occurs 4 or 8 weeks after the last induction dose is administered. If a patient does not achieve a clinical response at the end of the initial induction period, administration of the induction dose may be extended, referred to as an "extended induction dose," to distinguish it from the initial induction dose.If a patient achieves a clinical response at the end of the extended induction period, at least one maintenance dose of an anti-IL-23p19 antibody is administered to maintain the clinical response or other desired therapeutic effect, such as clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, or improvement in fatigue. The first maintenance dose is administered 4 to 12 weeks after the patient's last extended induction dose. The 4- to 12-week period corresponds to the variability in the time between the administration of the last extended induction dose and the end-of-extension induction assessment. Maintenance doses are administered at 4-week, 8-week, or 12-week intervals after the first maintenance dose. Maintenance doses may be administered by subcutaneous injection. If a patient experiences a loss of response during the maintenance period, one, two, or three extra boost doses of the anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4 to 12 weeks after the last extra boost dose, one or more additional maintenance doses of the anti-IL-23p19 antibody are administered to the patient, where "loss of response" is defined as (a) a greater than 2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of greater than 4 on two consecutive visits greater than 7 days apart, accompanied by a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3, and a clinical response is defined as achieving a greater than 2-point reduction and greater than 30-35% reduction from baseline in a 9-point modified Mayo score (MMS) subscore, accompanied by either a greater than 1 reduction in the rectal bleeding (RB) subscore, or an RB subscore of 0 or 1.

[0125] The methods disclosed herein can further include obtaining three or more samples from the patient. It is particularly preferred to obtain multiple samples from the patient, reference subjects, and placebo responders for analysis of the samples to determine whether expression levels of gene transcripts change, remain changed over time, are maintained over time, etc.

[0126] Suitable samples include tissue biopsies, fecal samples, whole blood, plasma, serum, and combinations thereof. Particularly suitable tissue biopsies include colonic tissue biopsies or rectal tissue biopsies. Colonic tissue biopsies are derived from tissues selected from the group consisting of the terminal ileum, ascending colon, descending colon, and sigmoid colon. Colonic tissue biopsies can be derived from non-inflamed or inflamed colonic areas. Biopsies can be obtained from the edge of an ulcer, the edge of an erosion, or at intervals throughout the affected mucosa, or a combination thereof.

[0127] For embodiments in which the patient is administered an anti-IL-23p19 antibody, the first sample is taken prior to or concurrently with administration of the anti-IL-23p19 antibody, and further taken at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 30 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks, or up to at least 104 weeks after the first administration of the anti-IL-23p19 antibody. Alternatively, the sample can be obtained about 4 weeks after administration of the anti-IL-23p19 antibody, about 12 weeks after administration of the anti-IL-23p19 antibody, about 52 weeks after administration of the anti-IL-23p19 antibody, and combinations thereof. The sample can also be obtained 52 weeks after administration of the anti-IL-23p19 antibody. Samples may also be obtained at other intervals, including daily, weekly, monthly, and yearly.

[0128] As used herein, the term "biologic-naive" refers to a patient who has not received a biologic, such as an anti-IL23 antibody, an anti-TNF-α antibody, an anti-integrin antibody, a JAK inhibitor, a TYK2 inhibitor, or an S1P receptor modulator, for the treatment of UC, particularly for the treatment of moderate to severe UC. Such a patient may or may not be receiving a conventional drug for the treatment of UC.

[0129] As used herein, the term "biologic-experienced" refers to a patient who has received at least one conventional biologic, such as an anti-TNFα (e.g., adalimumab, golimumab, infliximab), an anti-integrin (e.g., vedolizumab), a JAK inhibitor (e.g., tofacitinib, upadacitinib), a TYK2 inhibitor, or an S1P receptor modulator (e.g., ozanimod), for the treatment of UC, particularly moderate to severe UC. Such patients may or may not have received conventional medications for the treatment of UC.

[0130] As used herein, the term "biologic failure patient" refers to a patient who has received at least one conventional biologic, e.g., an anti-TNF-α antibody, an anti-integrin antibody, a JAK inhibitor, a TYK2 inhibitor, or an S1P receptor modulator, for the treatment of UC, particularly for the treatment of moderate to severe UC. Such patients may or may not have received conventional therapy for the treatment of UC. Such patients have had an inadequate response, lost response, or are intolerant to biologic therapy for UC (e.g., an anti-TNF-α antibody, an anti-integrin antibody, a JAK inhibitor, a TYK2 inhibitor, or an S1P receptor modulator). In terms of the term "biologic failure patient," an inadequate response means exhibiting signs and symptoms of persistent active disease despite induction treatment with an approved induction medication indicated in the product label at the time of use. In the context of the term "biologic failure," loss of response is defined as a recurrence of signs and symptoms of active disease while on approved maintenance medication following previous clinical benefit (discontinuation despite clinical benefit is not evidence of failure or intolerance to UC biologic therapy). In the context of the term "biologic failure," intolerance means a history of intolerance to, for example, anti-TNF-α antibodies, anti-integrin antibodies, JAK inhibitors, TYK2 inhibitors, S1P receptor modulators, including infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, tofacitinib, upadacitinib, deuclavacitinib, ozanimod, or other approved therapies including JAK inhibitors, TYK2 inhibitors, and S1P receptor modulators.

[0131] As used herein, the term "conventional drug failure" refers to a patient who has an inadequate response, loss of response, or intolerance to at least one of the following medications: Corticosteroids Corticosteroid-refractory colitis is defined as the presence of signs or symptoms of active UC despite taking oral prednisone or an equivalent oral corticosteroid at a dose of 30 mg / day or more for at least 2 weeks. Corticosteroid-dependent colitis is defined as (a) the inability to taper or reduce the corticosteroid dose to less than 10 mg prednisone equivalent per day within 3 months of initiating corticosteroids without recurrence of signs or symptoms of active UC, or (b) recurrence within 3 months of completing a course of corticosteroids. History of corticosteroid intolerance including, but not limited to, cataracts, Cushing's syndrome, hyperglycemia, hypertension, osteopenia / osteoporosis, or neuropsychiatric side effects including insomnia. Immunomodulators: - Have signs and / or symptoms of persistent active disease despite 3 months or more of treatment with one of the following: ■ Oral AZA (≥1.5 mg / kg / day) or 6-MP (≥0.75 mg / kg / day) Oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or Thiopurine and allopurinol combinations within the therapeutic range as determined by thioguanine metabolite testing History of intolerance to at least one immunomodulatory agent, including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia Patients who were conventional drug failures had failed or demonstrated intolerance to biologics (anti-TNF antibodies or anti-integrin antibodies) or JAK, S1P, or TYK2 inhibitors indicated for the treatment of UC.

[0132] As used herein, "treatment" or "treating" refers to any process that may slow, control, retard, or halt the progression of a disorder or disease disclosed herein, or alleviate the symptoms of the disorder or disease, but does not necessarily indicate the complete disappearance of all disorder or disease symptoms. Treatment includes the administration of a protein or nucleic acid or vector or composition for the treatment of a disease or condition in a patient, particularly a human. [Example]

[0133] Example 1 - I6T-MC-AMAC Clinical Trial - Induction Period Study design and participants Clinical trial I6T-MC-AMAC was a multicenter, randomized, double-blind, parallel, placebo-controlled study of mirikizumab in subjects with moderate to severe ulcerative colitis. The study was registered with ClinicalTrials.gov, number NCT02589665.

[0134] Procedures and Results Patients were randomized 1:1:1:1 to placebo IV Q4W (N=63), mirikizumab 50 mg IV Q4W (N=63), mirikizumab 200 mg IV Q4W (N=62) (with potential dose escalation based on exposure), and mirikizumab 600 mg IV Q4W (N=61). Endoscopic findings were scored by one of two blinded central readers. Histologic disease activity was assessed by the central reader using two biopsy samples obtained during endoscopy at baseline and study week 12. All biopsies were taken at least 30 cm from the anal verge.

[0135] If a discrete lesion was present, biopsies were obtained preferentially from the edge of the ulcer, or, if no ulcer was present, from the edge of the erosion. If gross disease was present but no discrete lesion was present, biopsies were obtained at intervals throughout the affected mucosa. If no gross disease was present, biopsies were obtained from the entire section.

[0136] histopathology Two endoscopic biopsy samples for histopathological evaluation were obtained from the most affected area at least 30 cm from the anal verge at each endoscopy. One of two blinded pathologists assessed histopathological disease activity for each sample using the Geboes score and the Roberts Histopathology Index (RHI).

[0137] The endpoints in this study were endoscopic improvement (endoscopic subscore of 0 or 1) and histologic resolution (defined as a Geboes histologic subscore of 0 for neutrophils in the lamina propria, neutrophils in the epithelium, and erosion or ulceration parameters). Mucosal healing was determined by the presence of both histologic resolution and endoscopic improvement. There is no consensus on what constitutes increased lamina propria eosinophils, and given the lack of reproducibility and insufficient prospective data, successfully reducing eosinophils was not included in the primary definition of histologic resolution. The Robarts Histopathology Index (RHI) score was determined simultaneously with the Geboes score.

[0138] RNA Extraction and Gene Array Methodology Gene expression was measured in 553 colon tissue biopsies from I6T-MC-AMAC using the Affymetrix WT protocol on GeneChip HT A2.0 arrays. Biopsies from the same subject for each time point were pooled together to obtain a total of 277 biopsy RNA samples. These were subjected to quality control (QC) checkpoints (e.g., RNA sample quality / quantity and amplification) and then advanced to HTA2.0 processing.

[0139] RNA sample preparation and quality control Colon tissue samples were placed in two tubes per subject per time point. To ensure sufficient mass was available for transcriptome analysis, an extraction pilot was performed by pooling colon biopsies from 20 subjects. RNA extraction was performed according to the manufacturer's recommended protocol. Briefly, extracted RNA QC included both BioAnalyzer (BA) QC and quantification. BA system QC indicators were the 28S / 18S ratio (0.75-3.0) and RNA Integrity Number (RIN) score (≥6). RNA concentration was measured using the RIBOGREEN® fluorescent dye assay. Samples with concentrations below 5 ng / μL were excluded from subsequent profiling steps. Samples were run on an Agilent 2100 Bioanalyzer to assess RNA quality. All samples had sufficient mass for the assay and proceeded to HTA2 processing.

[0140] RNA samples that passed CGL QC metrics were aliquoted into 96-well plates (100 ng input). Two samples were removed after one patient discontinued, and four biopsies from week 12 were not collected from subjects who left the study after the week 0 biopsy was collected, leaving a dataset of 224 week 0 and 220 week 12 time points that passed array QC.

[0141] gene chip array Probe-level data from the HTA2 platform were preprocessed with background correction and quantile normalization using standard RMA methods and aggregated to the level of probe sets defined by the Affymetrix NETAFFX™ NA35 / GRCh37 human reference genome release. Data were then aggregated to the level of "exon groups," data-defined clusters of highly correlated exon-based probe sets, as follows: A correlation matrix between probe set expression was calculated, and the distance metric between pairs of probe sets was defined as 1 minus the pairwise correlation. Hierarchical clustering was performed using the Rhclust function, and exon groups were formed by cutting the dendrogram at a distance of 0.8. Once exon groups were defined, aggregated expression for samples was obtained from the sample effect in a two-way ANOVA model. Probe and sample effects were estimated using robust regression implemented by the rlm function in the R MASS package applied to the probe-level data within that exon group.

[0142] Differential expression statistical analysis The exon clusters generated from the above procedure were filtered according to two criteria: 1) exon clusters with a log2 expression SD less than 0.286 (corresponding to a CV of approximately 20%), and 2) exon clusters whose mean log2 expression was less than the 75th percentile of the median log2 expression for negative control (normal gene->intron) probe sets. If a gene contained multiple exon clusters, the feature with the greatest number of probe sets was selected to represent the gene's expression as a whole, and the link was broken by the feature with the highest mean expression level. In all models, a multiplicity correction was applied to the resulting p-values ​​to account for the number of comparisons made across treatment groups as well as across all tested exon clusters using the Benjamini-Hochberg method.

[0143] A mixed-effect repeated-measures model (MRMM) was fitted separately to each filtered exon group to calculate the fold change between week 0 and week 12 using age, sex, batch, baseline BMI, previous biologic therapy, and baseline modified Mayo score (MMS) as covariates. A cross-timepoint contrast model compared the differential expression of each exon group in the treatment group with its differential expression in the placebo group. Exon groups with a fold change of more than 0.5 log2 units (approximately 1.41 × change) and a false discovery rate (FDR)-adjusted q value of less than 0.05 were classified as differentially expressed.

[0144] Correlation statistical analysis Pearson correlation coefficients were calculated between cross-time differential expression of exon groups and changes in clinical metrics between weeks 0 and 12, using age, sex, and array chip batch as covariates. Clinical metrics included MMS, total Mayo score, Mayo endoscopic subscore, Ulcerative Colitis Endoscopic Severity Index (UCEIS) total score, Geboes score, and Roberts Histopathology Index (RHI). Laboratory outcomes included fecal calprotectin and peripheral blood titers of IL-17A, IL-22, and CRP.

[0145] result Patients, study details and biological samples In this study, 358 patients were screened for eligibility and 249 were randomized. Of these, 224 patients underwent baseline biopsies and 220 underwent week 12 biopsies. Of these 220 patients, over 63% had received prior biologic therapy, and 47.3% were using corticosteroids at baseline. Baseline disease characteristics were well balanced across treatment groups, with similar disease activity (modified Mayo score) and mucosal inflammation (Mayo endoscopy subscore) between treatment groups. Histologic measures (Geboes index and RHI) were lower in the placebo group but similar between the mirikizumab treatment groups (Table 1).

[0146] [Table 5]

[0147] Mirikizumab-mediated changes in transcripts in ulcerative colitis at 12 weeks In addition to demonstrating the greatest efficacy at week 12 compared with placebo in all three treatment groups, the 200 mg mirikizumab treatment group also had the highest number of differentially expressed colon biopsy genes between baseline and week 12. To better distinguish the effects of mirikizumab treatment from the effects of standard treatment, changes in gene expression were assessed between baseline and week 12 in the 200 mg mirikizumab group both with and without normalization to placebo. Normalization to placebo provided greater confidence in the reduction in the number of differentially regulated transcripts. Table 2 shows the transcripts with the greatest changes at week 12 after normalizing for changes in the placebo group.

[0148] [Table 6]

[0149] Further analysis of the gene transcripts in Table 2 indicated that changes in individual transcripts shown in Table 2 correlated with changes in disease activity as defined by MMS, Geboes, or RHI (data not shown). Several transcripts identified in Table 2 exhibit the strongest changes in regulation induced by mirikizumab treatment, which correlate with changes in disease activity. All transcripts positively correlated with disease were uniformly and consistently downregulated by mirikizumab. In contrast, all transcripts negatively associated with disease were upregulated by mirikizumab treatment. This is consistent with the observation that changes in mirikizumab-regulated transcripts reflect a profile of disease attenuation, suggesting preliminary evidence of molecular cure as early as 12 weeks after initiation of mirikizumab treatment.

[0150] Example 2 - I6T-MC-AMAC Clinical Trial - Maintenance Period method: At Week 12, mirikizumab-treated patients who achieved a clinical response (≥2-point reduction in the 9-point Mayo subscore [reduction in rectal bleeding, stool frequency, and endoscopy] with either a RB subscore reduction of ≥1 or an RB subscore of 0 or 1, and a ≥35% or better reduction from baseline [BL]) were re-randomized to receive mirikizumab 200 mg subcutaneously (SQ) every 4 weeks or every 12 weeks through Week 52. Patients who received placebo (PBO) in induction who achieved a clinical response continued on PBO in the maintenance period. Patients (n=272) who did not respond to mirikizumab (miri) 300 mg intravenous (IV) every 4 weeks (Q4W) at W12 were randomized to receive open-label 300 mg IV miri. Patients received an extended 12-week induction treatment Q4W with three additional doses. Patients (n=144) who responded at W24 of continuous IV treatment entered open-label maintenance and received 200 mg miri subcutaneously (SC) Q4W until W52. Additionally, patients who experienced loss or response during the maintenance period received an extended induction dose and, if they achieved a clinical response, returned to maintenance dosing.

[0151] Colon biopsies were obtained from the most affected area at least 30 cm from the anal verge (mirikizumab N=31, PBO N=7) at weeks 0, 12, and 52. Using the Bayesian Limma R package, transcript changes from baseline to week 12 in the PBO and mirikizumab arms were clustered into differentially expressed genes (DEGs). Among these DEGs, similarly expressed genes (SEGs) were identified as those that maintained their week 12 expression levels through week 52. Specifically, DEGs were identified using standard Limma analysis (fold change (FC) >2 and p-value <0.05), and SEGs were identified using the two one-sided test (TOST) version of Limma analysis (Q). log2FC ±0.26 and TOST p-value <0.05).

[0152] result: Baseline demographics and disease characteristics of patients in the maintenance phase At week 12, a significantly (p<0.001) greater proportion of mirikizumab-treated patients achieved clinical remission (24.2% vs. 13.3%) and clinical response (63.5% vs. 42.2%) compared with placebo. Among patients who failed to achieve a clinical response after 12 weeks of induction therapy, 54% had failed prior biologic therapy, the mean disease duration was 7.6 years, 56.6% had a modified Mayo score of 7 or greater, and 72.4% had an endoscopic Mayo subscore of 3, indicating severe disease at baseline. Three additional mirikizumab IV induction doses induced a clinical response in 54% of these patients who initially did not respond to induction therapy at week 12 (delayed responders).

[0153] Of these 144 responders at 24 weeks who entered the open-label maintenance study, approximately 72% achieved a clinical response, approximately 36% achieved clinical remission at week 52, approximately 43% achieved endoscopic remission, and approximately 42% of patients achieved histologic improvement at week 52. Furthermore, for these patients, there was a 3.8 (±2.7) point reduction from baseline in bowel urgency (BU) severity, and 58.8% achieved a clinically meaningful improvement in BU. These results highlight the potential benefit of long-term induction therapy and the feasibility of treating patients with mirikizumab who have failed previous biologic therapy.

[0154] Mirikizumab-mediated changes in transcripts in ulcerative colitis at 52 weeks Analysis of transcript changes at week 52 in responders at week 12 who maintained disease remission identified a profile of DEGs and SEGs in responders. Of these genes, 63 (70.8%) were present only in mirikizumab responders, 5 (5.6%) were present only in PBO responders, and 21 (23.6%) were present in both groups. The magnitude of transcript changes was greater at week 12 and more consistent through week 52 in mirikizumab responders compared with PBO responders. At week 52 after mirikizumab treatment, genes that were upregulated at baseline remained downregulated, and genes that were downregulated at baseline remained upregulated. These results demonstrate that the gene expression changes induced by mirikizumab during induction were maintained over time to week 52 (the data collection endpoint). These results also demonstrate that mirikizumab-treated responders have differentially expressed transcripts that are quantitatively different in both fold change and significance from transcripts in the PBO responder group.

[0155] In this sample of PBO and mirikizumab responders at week 12, mirikizumab responders demonstrated broader, larger, and more sustained changes in magnitude at week 52 compared with PBO responders. Qualitative description of transcripts identified only in mirikizumab responders and in both placebo and mirikizumab responders indicated distinct molecular healing pathways associated with mirikizumab treatment compared with the spontaneous healing that occurred in PBO responders. These included genes related to the interferon-gamma response, the complement system, TNFα / NFκB, allograft rejection, and mTORC1 signaling and apoptosis. Response to mirikizumab was also associated with increased expression of genes related to epithelial transporters, chemokines, and drivers of stromal epitheliitis.

[0156] Example 3 - 10-gene prognostic XGBoost model for disease outcome in ulcerative colitis method: We developed a prognostic gene model using an XGBoost model that utilizes multiple gene datasets. XGBoost models have been widely applied in medical and research machine learning (Chang, W. et al., "A Machine-Learning-Based Predicition Method for Hypertension Outcomes Based on Medical Data." Cell, vol. 9, no. 4, Nov 2019, 178, DOI: 10.3390 / diagnostics9040178; Leong, S. et al., "Cross-validation of existing signatures and derivation of a novel 29-gene transcriptomic signature predictive of progression to TB in a Brazilian cohort of household contacts of pulmonary TB." Tuberculosis, vol. 120, Jan 2020, 101898, DOI: 10.1016 / j.tube.2020.101898; Lam, K.H.B. et al., "Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intratumoral "Heterogeneity." Nat.Commun.,vol.13 no.1,Jan 2022,116,DOI:10.1038 / s41467-021-27667-w).

[0157] The first gene dataset, identified from the I6T-MC-AMAC study (see Example 2), consisted of a set of 84 genes identified in mirikizumab responders that changed significantly from baseline to week 12 and then stably expressed from week 12 to week 52, including 63 genes present only in mirikizumab responders and 21 genes present in both mirikizumab and placebo responders. The second gene dataset included a set of 57 genes from Smillie et al., which were found to be associated with anti-TNF treatment resistance based on single-cell transcriptomes. Finally, because mirikizumab is a monoclonal antibody targeting the p19 subunit of IL-23, the IL-23 gene, IL23A, was also considered in the analyzed gene set.

[0158] To account for any systematic bias in the analysis, gene features were normalized by taking their relative rank to other gene features, such that the highest expressed gene was ranked 10 and the lowest expressed gene was ranked 1. An XGBoost model was used to predict response at week 12 from baseline gene expression. The XGBoost model had a maximum tree depth of 10 nodes, a binary:logistic objective function, and was trained for 100 rounds. An XGBoost model (using genes as features and clinical outcomes as responses) was trained on the PROTECT study data (see Hyams JS, et al. Lancet Gastroenterol Hepatol. 2017;2(12):855-868), and the results were used to predict outcomes in the I6T-MC-AMAC dataset and two publicly available datasets: NCBI Gene Expression Omnibus accession numbers GSE12251 and GSE23597.

[0159] XGBoost model results The results of the XGBoost Model identified 10 genes as prognostic predictors of response in ulcerative colitis (see Table 3), and their accurate performance in each dataset was demonstrated by the area under the precision-recall curve (PR-AUC) as follows: PROTECT (training dataset) - 0.98PR-AUC I6T-MC-AMAC (test dataset) - 0.90PR-AUC GSE12251 (validation dataset) - 0.85PR-AUC · GSE23597 (validation dataset) - 0.77PR-AUC.

[0160] These PR-AUC metrics indicate that the XGBoost model was not only effective on the PROTECT data on which it was trained, but also demonstrated excellent precision-recall performance on the untrained ulcerative colitis gene expression dataset. Furthermore, Table 3 also demonstrates the correlation between changes in expression of each of the 10 genes identified from the XGBoost model and changes in clinical response using the modified Mayo score (MMS) in the 50 mg, 200 mg, 600 mg, and placebo groups from weeks 0 to 12 in the I6T-MC-AMAC study.

[0161] [Table 7] * P values ​​are adjusted for multiplicity

[0162] Further analysis from the XGBoost model identified subsets of 8, 7, 5, and 3 genes from the 10 genes (see Table 4). These gene subsets were also found to have predictive value in the PROTECT, I6T-MC-AMAC, GSE12251, and GSE23597 datasets (Table 5). The DEFB4B gene was treated as missing in the GSE12251 and GSE23597 datasets because these genes were only identified as DEFB4A / B genes in these datasets. The 7-gene signatures from the 3-gene sets did not include DEFB4B.

[0163] [Table 8]

[0164] [Table 9] * The evaluation index in the table is Precision-Recall-AUC (PR-AUC).

[0165] Overall, the results provided in Example 3 identify a distinct set of 10 genes that, using a rigorous training model, is prognostic of moderate-to-severe ulcerative colitis disease activity in patients. Furthermore, distinct gene sets such as those provided in Example 3 may be suitable for predicting response in patients with moderate-to-severe UC using treatment with anti-IL23p19 antibodies. Based on correlation analysis between the identified gene sets and disease activity defined by MMS (as shown in Example 3), the identified gene sets may be further suitable for tracking efficacy using measures of disease activity (e.g., MMS, RHI, Geboes, improvement / remission of bowel urgency) in patients with moderate-to-severe UC treated with anti-IL23p19 antibodies, as found with mirikizumab treatment of UC patients (see Example 2). Furthermore, based on the gene dataset used to identify the 10 gene sets and the pathway correlations of the identified gene sets, there are further potential opportunities to use the gene sets to predict response to anti-IL23p19 antibodies and / or to prognose disease activity and / or response to treatment with IL-23p19 antibodies in patients who have had an inadequate response, lost response, or are intolerant to at least one prior treatment for ulcerative colitis (e.g., anti-TNFα antibodies, anti-integrin antibodies, JAK inhibitors, or S1P receptor modulators). Additionally, the identified set of genes includes IL1b transcripts, which are known to mediate the inflammatory burden observed in patients who show an inadequate response to available therapies, such as anti-TNF treatments, anti-integrins such as vedolizumab, and Jak inhibitors.This is demonstrated in Example 2 (Table 2), where IL1b transcripts were robustly reduced by mirikizumab at the end of the 12-week induction period compared to baseline and remained reduced throughout the 52-week maintenance period, further demonstrating the potential for using gene sets to predict and / or prognose response to anti-IL23p19 antibodies in patients who have had an inadequate response, lost response, or are intolerant to at least one prior treatment for ulcerative colitis, such as an anti-TNFα antibody, an anti-integrin antibody, or a JAK inhibitor.

[0166] array SEQ ID NO: 1 Mirikizumab heavy chain variable region (HCVR) QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSS

[0167] SEQ ID NO: 2 Mirikizumab light chain variable region (LCVR) DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK

[0168] SEQ ID NO: 3 Mirikizumab heavy chain (HC) QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0169] SEQ ID NO: 4 Mirikizumab light chain (LC) DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

1. 1. A method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

2. 1. A method of treating fecal urgency in a patient with moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

3. 1. A method of treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has had an inadequate response, has lost response to, or is intolerant to, at least one prior treatment for ulcerative colitis, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

4. 1. A method of treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, or has lost response to anti-TNF therapy, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

5. 1. A method of treating moderate to severe ulcerative colitis in a patient in need thereof who is non-responsive, has an inadequate response, or has lost response to anti-a4β7 integrin therapy, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.

6. 1. A method of treating bowel frequency in a patient with moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

7. 1. A method for prognosticating response in a patient with moderate to severe ulcerative colitis, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and determining whether the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts, thereby determining disease activity of the patient.

8. 1. A method for predicting suitability of a patient in need of treatment for moderate to severe ulcerative colitis for treatment with an anti-IL23p19 antibody, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

9. 1. A method of treating moderate to severe symptoms of ulcerative colitis with an anti-IL23p19 antibody in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to reference values ​​for the particular gene transcripts.

10. 1. A method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to a reference value for the particular gene transcript, administering an anti-IL23p19 antibody to the patient; The method, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:

2.

11. 1. A method of treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; administering an anti-IL23p19 antibody to the patient if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to a reference value for the particular gene transcript; measuring the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in a patient sample from about 12 weeks to about 40 weeks after administration of a first dose of the anti-IL-23p19 antibody; and continuing to administer the anti-IL23p19 antibody to the patient if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample when compared to a reference value for the particular gene transcript.

12. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B; and administering the anti-IL23p19 antibody to the patient if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts.

13. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A; and administering the anti-IL23p19 antibody to the patient if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts.

14. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2; and administering to the patient an anti-IL23p19 antibody if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2 are differentially regulated in the patient sample compared to reference values ​​for the particular gene transcripts.

15. Measuring the expression levels of gene transcripts ABI1, HNF4A, and IL1B in the patient sample; and if the expression levels of gene transcripts ABI1, HNF4A, and IL1B are differentially regulated in the patient sample when compared to reference values ​​for particular gene transcripts, administering an anti-IL23p19 antibody to the patient.

16. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering to the patient an anti-IL23p19 antibody if the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample and / or the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample when compared to reference values ​​of specific gene transcripts.

17. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; and administering an anti-IL23p19 antibody to the patient if the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample, and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for those particular gene transcripts.

18. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1; administering an anti-IL23p19 antibody to the patient if the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 is elevated in the patient sample, and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference levels of specific gene transcripts; The method of any one of claims 1 to 11, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO:

2.

19. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B; and administering to the patient an anti-IL23p19 antibody if the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, and DEFB4B is elevated in the patient sample, and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for those particular gene transcripts.

20. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A; and administering to the patient an anti-IL23p19 antibody if the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, and IL23A is elevated in the patient sample, and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2 is decreased in the patient sample, when compared to reference values ​​for specific gene transcripts.

21. measuring the expression levels in the patient sample of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2; and administering an anti-IL23p19 antibody to the patient if the expression level of one or more gene transcripts selected from AbI1, IL1B, and PTPRC is elevated in the patient sample, and if the expression level of one or more gene transcripts selected from HFN4A and SLC26A2 is decreased in the patient sample, when compared to reference values ​​for those particular gene transcripts.

22. Measuring the expression levels of gene transcripts ABI1, HNF4A, and IL1B in the patient sample; and administering to the patient an anti-IL23p19 antibody if the expression level of one or more gene transcripts selected from ABI1 and IL1B is elevated in the patient sample, and if the expression level of gene transcript HFN4A is decreased in the patient sample, when compared to reference values ​​for specific gene transcripts.

23. 22. The method of any one of claims 1 to 14 or 16 to 21, wherein the method comprises measuring the expression levels of at least four of the gene transcripts of claims 1 to 12 or 14 to 19.

24. 22. The method of any one of claims 1 to 14 or 16 to 21, wherein the method comprises measuring the expression levels of at least five of the gene transcripts of claims 1 to 12 or 14 to 19.

25. 21. The method of any one of claims 1 to 13 or 16 to 20, wherein the method comprises measuring the expression levels of at least six of the gene transcripts of claims 1 to 11 or 14 to 18.

26. 21. The method of any one of claims 1 to 13 or 16 to 20, wherein the method comprises measuring the expression levels of at least seven of the gene transcripts of claims 1 to 11 or 14 to 18.

27. 20. The method of any one of claims 1 to 12 or 16 to 19, wherein the method comprises measuring the expression levels of at least eight of the gene transcripts of claims 1 to 10 or 14 to 17.

28. 19. The method of any one of claims 1 to 11 or 16 to 18, wherein the method comprises measuring the expression levels of at least 9 of the gene transcripts of claims 1 to 10 or 14 to 16.

29. 19. The method of any one of claims 1 to 11 or 16 to 18, wherein the method comprises measuring the expression levels of 10 of the gene transcripts of claims 1 to 10 or 14 to 16.

30. 30. The method of any one of claims 1 to 29, wherein the patient achieves at least one or more of the following therapeutic effects within about 2 weeks to about 12 weeks of treatment with the anti-IL23p19 antibody: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, and improvement in fatigue.

31. 31. The method of claim 30, wherein the at least one or more therapeutic effects are achieved within about 2 weeks, 4 weeks, 8 weeks, or about 12 weeks of treatment with the anti-IL23p19 antibody.

32. 32. The method of claim 30 or 31, wherein the patient exhibits at least one or more sustained therapeutic effects of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, and improvement in fatigue for up to at least about 12 weeks to about 104 weeks.

33. 33. The method of claim 32, wherein the therapeutic effect persists through approximately 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, or 104 weeks of treatment with the anti-IL23p19 antibody.

34. 30. The method of any one of claims 1-29, wherein the expression level of the gene transcript is prognostic for at least one of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, and improvement in fatigue.

35. 30. The method of any one of claims 1 to 29, wherein the expression level of the gene transcript is predictive of at least one of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, and improvement in fatigue upon treatment with the anti-IL23p19 antibody.

36. The method of any one of claims 1 to 35, wherein the anti-IL23p19 antibody is mirikizumab.

37. 36. The method of any one of claims 1-9, 11-17, or 19-35, wherein the anti-IL23p19 antibody is guselkumab, tildrakizumab, risankizumab, or brazikumab.

38. The method of any one of claims 1 to 37, wherein the patient is biologic naive.

39. The method of any one of claims 1 to 37, wherein the patient is a biologics failure patient.

40. The method of any one of claims 1 to 37, wherein the patient is a traditional drug failure patient.

41. The method according to any one of claims 1 to 37, wherein the patient is a biological agent failure patient and a conventional drug failure patient.

42. 42. The method of any one of claims 38 to 41, wherein the patient is resistant to TNF therapy.

43. 42. The method of any one of claims 38-41, wherein the patient is one or more of an anti-TNF therapy failure, an anti-α4β7 therapy failure, a JAK inhibitor failure, an S1P receptor modulator failure, or a TYK2 inhibitor failure.

44. a. administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose being 300 mg of mirikizumab; b. Administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4-weekly or 12-weekly intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose, and each maintenance dose is 200 mg of mirikizumab.

45. 45. The method of claim 44, wherein the first maintenance dose is administered 4 weeks after administration of the final induction dose.

46. 46. ​​The method of claim 44 or 45, wherein the maintenance doses are administered at four week intervals.

47. 47. The method of any one of claims 44-46, wherein the maintenance doses are administered at 4 week intervals for at least up to about 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, or 104 weeks.

48. 30. The method of any one of claims 1 to 29, wherein the expression levels of the three or more gene transcripts are measured by a method of gene expression profiling.

49. 49. The method of claim 48, wherein the method is a PCR-based method.

50. 49. The method of claim 48, wherein the method is an RNA sequencing method.

51. 49. The method of claim 48, wherein the method is an in situ hybridization technology-based method.

52. 49. The method of claim 48, wherein the method is immunohistochemistry.

53. 49. The method of claim 48, wherein the method is a proteomics technique.

54. 49. The method of claim 48, wherein the expression levels of the three or more gene transcripts are normalized to the expression levels of three or more reference genes or their expression products.

55. 30. The method of any one of claims 1 to 29, wherein measuring the expression levels of the three or more gene transcripts is performed using an analyzer unit, and comparing the determined expression levels of the three or more gene transcripts with reference values ​​for particular gene transcripts is performed using a computing device.

56. 30. The method of any one of claims 1 to 29, wherein the patient sample is derived from a colon or rectal tissue biopsy.

57. 57. The method of claim 56, wherein the colon tissue biopsy is from tissue selected from the group consisting of the terminal ileum, the ascending colon, the descending colon, and the sigmoid colon.

58. 58. The method of claim 57, wherein the colon tissue biopsy is from a non-inflamed area of ​​the colon.

59. 58. The method of claim 57, wherein the colon tissue biopsy is from an inflamed colon region.

60. An anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

61. An anti-IL23p19 antibody in the manufacture of a medicament for use in treating moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

62. An anti-IL23p19 antibody for use in treating fecal urgency in a patient with moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

63. An anti-IL23p19 antibody for the manufacture or use of a medicament for the treatment of fecal urgency in a patient with moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

64. An anti-IL23p19 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need of such treatment who is non-responsive, has had an inadequate response, has lost response to, or is intolerant to, at least one previous treatment for ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

65. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need of such treatment who is non-responsive, has had an inadequate response, has lost response, or is intolerant to at least one previous treatment for ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

66. An anti-IL23p19 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need of such treatment who is non-responsive, has an inadequate response, or has lost response to anti-TNF therapy, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

67. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need of such treatment who is non-responsive, has an inadequate response, or has lost response to anti-TNF therapy, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

68. An anti-IL23p19 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need of such treatment who is non-responsive, has an inadequate response, or has lost response to anti-a4β7 integrin therapy, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to baseline values ​​for the particular gene transcripts.

69. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need of such treatment who is non-responsive, has an inadequate response, or has lost response to anti-a4β7 integrin therapy, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

70. An anti-IL23p19 antibody in the manufacture of a medicament for use in treating bowel frequency in a patient with moderate to severe ulcerative colitis, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts.

71. 1. An anti-IL23p19 antibody for use in treating moderate to severe ulcerative colitis in a patient in need thereof, wherein when the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 compared to reference values ​​for the particular gene transcripts, the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are prognostic for disease activity of the ulcerative colitis in the patient.

72. 1. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: The anti-IL23p19 antibody wherein the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are prognostic for the disease activity of the ulcerative colitis in the patient, when the patient has differentially regulated expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 compared to reference values ​​for the particular gene transcripts.

73. 1. An anti-IL23p19 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: an anti-IL23p19 antibody, wherein if the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts, the expression levels of at least three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts is predictive of suitability for treatment with the anti-IL23p19 antibody.

74. 1. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: an anti-IL23p19 antibody, wherein if the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts, the expression levels of at least three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts is predictive of suitability for treatment with the anti-IL23p19 antibody.

75. 1. An anti-IL23p19 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts; An anti-IL23p19 antibody, comprising a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:

2.

76. 1. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts; An anti-IL23p19 antibody, comprising a variable heavy chain having the amino acid sequence of SEQ ID NO:1 and a variable light chain having the amino acid sequence of SEQ ID NO:

2.

77. 1. An anti-IL23p19 antibody for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts; and wherein if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to a baseline value for the particular gene transcripts about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody, the patient continues treatment with the anti-IL23p19 antibody.

78. 1. An anti-IL23p19 antibody in the manufacture of a medicament for use in the treatment of moderate to severe ulcerative colitis in a patient in need thereof, comprising: the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 when compared to reference values ​​for the particular gene transcripts; and wherein if the expression levels of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 are differentially regulated in the patient sample compared to a baseline value for the particular gene transcripts about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody, the patient continues treatment with the anti-IL23p19 antibody.

79. 79. The use of any one of claims 60 to 78, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, and DEFB4B when compared to reference values ​​for the particular gene transcripts.

80. 79. The use of any one of claims 60 to 78, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, and IL23A when compared to reference values ​​for the particular gene transcripts.

81. 79. The use of any one of claims 60 to 78, wherein the patient has differentially regulated expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, and SLC26A2 when compared to reference values ​​for the particular gene transcripts.

82. 79. The use of any one of claims 60 to 78, wherein the patient has differentially regulated expression levels of the gene transcripts ABI1, HNF4A, and IL1B when compared to reference values ​​for the particular gene transcripts.

83. 79. The use of any one of claims 60 to 78, wherein the patient has an increased expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and / or a decreased expression level of one or more gene transcripts selected from HFN4A, SLC26A2, and OTOP2, when compared to reference values ​​for the particular gene transcripts.

84. The use of any one of claims 60 to 78, wherein the patient has increased expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and decreased expression levels of one or more gene transcripts selected from HNF4A, SLC26A2, and OTOP2, when compared to reference values ​​for the particular gene transcripts.

85. the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1, and decreased expression levels of one or more gene transcripts selected from HNF4A, SLC26A2, and OTOP2, when compared to baseline values ​​of the particular gene transcripts; The use of any one of claims 60 to 78, wherein the anti-IL23p19 antibody comprises a variable heavy chain having the amino acid sequence of SEQ ID NO: 1 and a variable light chain having the amino acid sequence of SEQ ID NO:

2.

86. 86. The use of any one of claims 60 to 85, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC IL23A, and DEFB4B, and decreased expression levels of one or more gene transcripts selected from HNF4A, SLC26A2, and OTOP2, when compared to reference values ​​for the particular gene transcripts.

87. The use of any one of claims 60 to 85, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, PTPRC, and IL23A, and decreased expression levels of one or more gene transcripts selected from HNF4A, SLC26A2, and OTOP2, when compared to reference values ​​of the particular gene transcripts.

88. The use of any one of claims 60 to 85, wherein the patient has elevated expression levels of one or more gene transcripts selected from AbI1, IL1B, and PTPRC, and decreased expression levels of one or more gene transcripts selected from HNF4 and SLC26A2, when compared to baseline values ​​of the particular gene transcripts.

89. 86. The use of any one of claims 60 to 85, wherein the patient has an elevated expression level of one or more gene transcripts selected from ABI1 and IL1B, and a decreased expression level of the gene transcript HNF4, when compared to reference values ​​for the particular gene transcripts.

90. 89. The use of any one of claims 60 to 81 or 83 to 88, wherein the patient has differentially regulated expression levels of at least four of the gene transcripts of claims 60 to 81 or 83 to 88.

91. 89. The use of any one of claims 60 to 81 or 83 to 88, wherein the patient has differentially regulated expression levels of at least five of the gene transcripts of claims 60 to 81 or 83 to 88.

92. 88. The use of any one of claims 59 to 80 or 83 to 87, wherein the patient has differentially regulated expression levels of at least six of the gene transcripts of claims 60 to 80 or 83 to 87.

93. 88. The use of any one of claims 60 to 80 or 83 to 87, wherein the patient has differentially regulated expression levels of at least seven of the gene transcripts of claims 60 to 80 or 83 to 87.

94. 87. The use of any one of claims 60 to 79 or 83 to 86, wherein the patient has differentially regulated expression levels of at least eight of the gene transcripts of claims 60 to 79 or 83 to 86.

95. 86. The use of any one of claims 60 to 77 or 83 to 85, wherein the patient has differentially regulated expression levels of at least 9 of the gene transcripts of claims 60 to 77 or 83 to 85.

96. 86. The use of any one of claims 60 to 77 or 83 to 85, wherein the patient has differentially regulated expression levels of 10 of the gene transcripts of claims 60 to 77 or 83 to 85.

97. The use of any one of claims 60 to 96, wherein the patient achieves at least one or more of the following therapeutic effects within about 2 weeks to about 12 weeks of treatment with the anti-IL23p19 antibody: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, and improvement in fatigue.

98. 98. The use of claim 97, wherein the therapeutic effect is achieved within about 2 weeks, 4 weeks, 8 weeks, or about 12 weeks of treatment with the anti-IL23p19 antibody.

99. 99. The use of claim 97 or 98, wherein the patient exhibits at least one or more sustained therapeutic effects of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission of bowel frequency, improvement in bowel frequency, and improvement in fatigue for up to at least about 12 weeks to about 104 weeks.

100. 100. The use of claim 99, wherein the therapeutic effect lasts for up to about 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, or 104 weeks of treatment with the anti-IL23p19 antibody.

101. 97. The use of any one of claims 60 to 96, wherein the expression level of the gene transcript is prognostic for at least one of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, improvement in fatigue.

102. 97. The use of any one of claims 60 to 96, wherein the expression level of the gene transcript is predictive of at least one of clinical response, clinical remission, endoscopic remission, endoscopic cure, symptomatic remission, endoscopic histological improvement in inflammation, corticosteroid-free remission, remission of bowel urgency, improvement in bowel urgency, remission in bowel frequency, improvement in bowel frequency, improvement in fatigue upon treatment with the anti-IL23p19 antibody.

103. The use according to any one of claims 60 to 102, wherein the anti-IL23p19 antibody is mirikizumab.

104. 103. The use of any one of claims 60-74, 77-84, or 86-102, wherein the anti-IL23p19 antibody is guselkumab, tildrakizumab, risankizumab, or brazikumab.

105. The use according to any one of claims 60 to 96, wherein the patient is biologic naive.

106. The use according to any one of claims 60 to 96, wherein the patient is a biologics failure patient.

107. The use according to any one of claims 60 to 96, wherein the patient is a conventional drug failure patient.

108. The use according to any one of claims 60 to 96, wherein the patient is a biologics failure patient and a conventional drug failure patient.

109. 107. The use of claim 105 or 106, wherein the patient is resistant to TNF therapeutics.

110. The use of claim 105 or 106, wherein the patient is an anti-TNF therapeutic agent failure, an anti-α4β7 therapeutic agent failure, a JAK inhibitor failure, an S1P receptor modulator failure, or a TYK2 inhibitor failure.

111. a. administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose being 300 mg of mirikizumab; b. Administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4-weekly or 12-weekly intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose, and each maintenance dose is 200 mg of mirikizumab.

112. 112. The use of claim 111, wherein the first maintenance dose is administered 4 weeks after administration of the final induction dose.

113. 113. The use of claim 111 or 112, wherein the maintenance doses are administered at 4 week intervals.

114. 114. The use of any one of claims 111 to 113, wherein the maintenance doses are administered at 4 week intervals for at least up to about 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, or 104 weeks.

115. 97. The use according to any one of claims 60 to 96, wherein the expression level of the one or more gene transcripts is measured by a method of gene expression profiling.

116. 116. The use according to claim 115, wherein the method is a PCR-based method.

117. The use according to claim 115, wherein the method is an RNA sequencing method.

118. The use according to claim 115, wherein the method is an in situ hybridization technology-based method.

119. 116. The use according to claim 115, wherein the method is immunohistochemistry.

120. The use according to claim 115, wherein the method is a proteomics technique.

121. 116. The use of claim 115, wherein the expression levels of the one or more gene transcripts are normalized to the expression levels of one or more reference genes or their expression products.

122. 97. The use of any one of claims 60 to 96, wherein measuring the expression levels of the one or more gene transcripts is performed using an analyzer unit and comparing the determined expression levels of the one or more gene transcripts with reference values ​​for particular gene transcripts is performed using a computing device.

123. 97. The use according to any one of claims 60 to 96, wherein the patient sample is derived from a colon or rectal tissue biopsy.

124. 124. The use of claim 123, wherein the colon tissue biopsy is derived from tissue selected from the group consisting of the terminal ileum, the ascending colon, the descending colon, and the sigmoid colon.

125. 125. The use of claim 124, wherein the colon tissue biopsy is from a non-inflamed area of ​​the colon.

126. 125. The use of claim 124, wherein the colon tissue biopsy is from an inflamed colon area.

Images