TW202448503A - Regulation of genes in ulcerative colitis - Google Patents

Abstract

The present disclosure generally 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 expression profiles of certain gene transcripts in ulcerative colitis patients and the usefulness of the expression profiles of these gene transcripts for the treatment, and/ or diagnostic use in a subgroup of patients having ulcerative colitis.

Description

Genetic regulation of ulcerative colitis

The present invention belongs to the field of medicine. The present invention relates to methods and diagnostic applications for treating ulcerative colitis. More specifically, 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 use of the gene transcript expression profiles for the prognosis of UC disease activity, and/or the use of anti-IL23p19 antibodies to treat subgroups of patients with ulcerative colitis.

Ulcerative colitis (UC) is a chronic, relapsing, immune-mediated inflammatory bowel disease (IBD) characterized by inflammation of the colonic mucosa. Typical symptoms such as diarrhea, rectal bleeding, frequent bowel movements, and bowel urgency lead to considerable morbidity and compromised quality of life. Treatment goals include achieving symptom control and relief, inhibiting intestinal inflammation to achieve mucosal healing and relief (endoscopic relief), and preserving intestinal function.

Current UC treatment options include 5-aminosalicylate, glucocorticoids, thiopurines, Janus-associated kinase (JAK) inhibitors (tofacitinib and upadacitinib), and biologics that antagonize TNFα, the p40 subunit of IL-12/IL-23, and the α4β7 integrin. Although these treatments have demonstrated efficacy in reducing symptoms in a subset of UC patients, a significant number of patients remain unresponsive or lose response, have an inadequate response, or are intolerant to currently available treatments, or have reported potentially severe side effects, such as those seen with some anti-TNF therapies.

Interleukin-23 (IL-23), a member of the interleukin-12 (IL-12) family of interleukins, is a heterodimeric protein composed of two subunits: the p40 subunit shared by IL-12 and the p19 subunit specific to IL-23. IL-23 receptor engagement leads to the activation of JAKs (mainly TYK2 and JAK2) and signal transducers and activators of transcription 3 and 4 (STAT3 and STAT4), thereby triggering the transcription of downstream target genes. IL-23 promotes the differentiation, maintenance, and stabilization of the pathogenic T-cell lineage, including populations that co-produce a variety of pro-inflammatory interleukins (e.g., interferon-γ, IL-17A, IL-17F, and IL-22) and activate and induce effector functions of innate lymphoid cells that cause colitis. 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, no anti-IL23p19 antibodies have been approved for the treatment of UC.

The complex interactions of immune cell landscapes, molecular pathways, and transcript profiles are being studied to provide insights into UC disease pathogenesis and potential mechanistic reasons as to why some patients do not respond to certain therapies. Various genes that play a role in UC disease activity have been reported, for example, in WO2022251623. Furthermore, potential genes that play a role in resistance to existing treatments for UC, such as anti-TNF therapy, are 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. July 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 do not respond or have a loss of response, an inadequate response, or intolerance to certain treatments for UC. Therefore, there remains a need to identify gene signatures or subsets of gene signatures to assess and inform the clinical management of UC and/or UC subpopulations with a certain therapy. Therefore, there remains a need for alternative compounds, pharmaceutical compositions and methods that can be used as therapeutic agents for the treatment of UC and/or for diagnostic applications related to the treatment of UC.

The present disclosure generally relates to methods and diagnostic applications for treating ulcerative colitis. More specifically, the methods and diagnostic applications of the present invention relate to the expression profiles of certain gene transcripts in patients with ulcerative colitis, and the use of the expression profiles of these gene transcripts in subpopulations of patients with ulcerative colitis for treatment and/or diagnosis. The present invention further provides certain gene transcripts that can be used as biomarkers to treat and/or diagnose ulcerative colitis, symptoms of ulcerative colitis, such as frequent bowel movements associated with ulcerative colitis and/or bowel urgency associated with ulcerative colitis. The present invention further provides certain gene transcripts, wherein the expression amount of certain subsets of the gene transcripts of the present invention can be a prognostic factor for ulcerative colitis disease activity in a patient. The gene transcripts of the present invention can further be used to determine whether a patient or a subset of patients with ulcerative colitis will respond to treatment with an anti-IL23p19 antibody. Certain subsets of the gene transcripts of the present invention may also be used as biomarkers to track responses to treatment with anti-IL-23p19 antibodies, or to determine whether a particular patient subpopulation will respond to treatment with anti-IL23p19 antibodies, such as patients who have not responded to existing therapies or who have had an inadequate response, loss of response, or intolerance to previous therapies (e.g., biologics and/or conventional therapies).

Therefore, the present invention provides certain gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, CXCL1. In other embodiments, the present invention provides certain gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B. In even further embodiments, the present invention provides certain gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A. In yet other embodiments, the present invention provides certain gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B, PTPRC, SLC26A2. In yet other embodiments, the present invention provides certain gene transcripts associated with ulcerative colitis disease activity, including ABI1, HNF4A, IL1B. In these embodiments, certain gene transcripts provided herein are prognostic factors for ulcerative colitis disease activity.

In some embodiments, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of the specific gene transcript, then administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis, wherein 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 are differentially regulated compared to a reference value of the specific gene transcripts.

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

In other embodiments, the present invention provides a method for treating intestinal urgency in a patient with moderate to severe ulcerative colitis in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated relative to a reference value for the specific gene transcript, administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating intestinal urgency in patients with moderate to severe ulcerative colitis, wherein 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 are differentially regulated compared to a reference value for the specific gene transcripts.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating intestinal urgency in patients with moderate to severe ulcerative colitis, wherein the patient has the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 differentially regulated relative to a reference value of the specific gene transcript.

In some embodiments, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient is unresponsive, inadequately responsive, lost responsiveness, or intolerant to at least one previous ulcerative colitis treatment, the method comprising: Measuring the expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value for a specific gene transcript, then an anti-IL23p19 antibody is administered to the patient. In some of these embodiments, the previous treatment is a biologic, wherein the biologic is an anti-TNFα therapy and/or an anti-α4β7 integrin therapy. In some embodiments, the previous treatment is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. In certain embodiments, the prior treatment is one or more of an anti-TNFα therapy, an anti-α4β7 integrin therapy, a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has no response, inadequate response, loss of response, or intolerance to at least one prior ulcerative colitis treatment, wherein the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in the patient is differentially regulated relative to a reference value for a specific gene transcript. In certain of these embodiments, the prior treatment is a biologic, wherein the biologic is an anti-TNFα therapy and/or an anti-α4β7 integrin therapy. In certain embodiments, the prior treatment is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. In certain embodiments, the prior treatment is one or more of an anti-TNFα therapy, an anti-α4β7 integrin therapy, a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has no response, insufficient response, loss of response, or intolerance to at least one previous ulcerative colitis treatment, wherein 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 are differentially regulated relative to a reference value for the specific gene transcript. In certain of these embodiments, the prior treatment is a biologic, wherein 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 prior 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.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient is unresponsive, inadequately responsive, loses response or is intolerant to an anti-TNFα antibody, the method comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated relative to a reference value of a specific gene transcript, administering an anti-IL23p19 antibody to the patient. In certain of these embodiments, the anti-TNFα therapeutic agent may be adalimumab, infliximab, golimumab, or certolizumab.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, the patient being unresponsive, inadequately responsive, lost responsiveness or intolerant to an anti-TNFα therapy, wherein the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient is differentially regulated relative to a reference value for a specific gene transcript. In certain of these embodiments, the anti-TNFα therapy may be adalimumab, infliximab, golimumab or certolizumab.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, the patient being unresponsive, inadequately responsive, incapable of responding, or intolerant to an anti-TNFα therapy, wherein the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in the patient is differentially regulated relative to a reference value for a specific gene transcript. In certain of these embodiments, the anti-TNFα therapy may be adalimumab, infliximab, golimumab, or certolizumab.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient is unresponsive, inadequately responsive, loses response, or is intolerant to an anti-α4β7 therapeutic agent, the method comprising: Measuring the expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample is differentially regulated compared to a reference value for a specific gene transcript, an anti-IL23p19 antibody is administered to the patient. In certain of these embodiments, the anti-α4β7 integrin therapeutic agent is vedolizumab.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, the patient being unresponsive, inadequately responsive, ineffectively responsive, or intolerant to an anti-α4β7 therapy, wherein the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in the patient is differentially regulated relative to a reference value for the specific gene transcript. In certain of these embodiments, the anti-α4β7 integrin therapy is vedolizumab.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof who is unresponsive, inadequately responsive, lost responsiveness, or intolerant to an anti-α4β7 therapeutic, wherein the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3, and CXCL1 in the patient is differentially regulated relative to a reference value for a specific gene transcript. In certain of these embodiments, the anti-α4β7 integrin therapeutic is vedolizumab.

In some embodiments, the present invention provides a method for treating frequent stools in a patient with moderate to severe ulcerative colitis in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value for the specific gene transcript, administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating frequent stools in a patient with moderate to severe ulcerative colitis in need thereof, wherein the patient has no response, insufficient response, loss of response, or intolerance to at least one previous ulcerative colitis treatment, wherein 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 are differentially regulated compared to a reference value for the specific gene transcripts.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating frequent stools in patients with moderate to severe ulcerative colitis, wherein 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 are differentially regulated compared to a reference value of the specific gene transcript.

In some embodiments, the present invention provides a method for predicting a response in a patient with moderate to severe ulcerative colitis, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4AA, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and Determining whether the expression of three or more gene transcripts selected from ABI1, HNF4AA, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 is differentially regulated in the patient sample relative to a reference value of the specific gene transcript to determine the disease activity of ulcerative colitis in the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein if 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 are differentially regulated compared to a reference value for the specific gene transcript, then the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 are prognostic factors for ulcerative colitis disease activity in the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein if 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 are differentially regulated compared to a reference value of the specific gene transcript, then the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 are prognostic factors for the disease activity of ulcerative colitis in the patient.

In other embodiments, the present invention provides a method for predicting the suitability of treating moderate to severe ulcerative colitis with an anti-IL23p19 antibody in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value for the specific gene transcript, administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein if 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 are differentially regulated compared to a reference value for the specific gene transcript, then the expression levels can predict the suitability of treatment with the anti-IL23p19 antibody.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein if 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 are differentially regulated relative to a reference value for the specific gene transcript, then the expression levels can predict the suitability of treatment with the anti-IL23p19 antibody.

In other embodiments, the present invention provides a method for treating symptoms of moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value for the specific gene transcript, administering an anti-IL23p19 antibody to the patient. In these embodiments, the symptoms may be, for example, diarrhea, frequent bowel movements, rectal bleeding, bowel urgency, fatigue, or other symptoms known to be associated with UC.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating symptoms of 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 in the patient are differentially regulated relative to a reference value for the specific gene transcript. In these embodiments, the symptoms may be, for example, diarrhea, frequent stools, rectal bleeding, intestinal urgency, fatigue, or other symptoms known to be associated with UC.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating symptoms of 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 in the patient are differentially regulated relative to a reference value for the specific gene transcript. In these embodiments, the symptoms may be, for example, diarrhea, frequent stools, rectal bleeding, intestinal urgency, fatigue, or other symptoms known to be associated with UC.

In other embodiments, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of a specific gene transcript, then administering an anti-IL23p19 antibody to the patient, wherein the anti-IL23p19 antibody comprises a polypeptide having SEQ ID NO: A variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

In some embodiments, the present invention provides an anti-IL23p19 antibody for 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 in the patient are differentially regulated relative to a reference value of the specific gene transcript, wherein the anti-IL23p19 antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

In some embodiments, the present invention provides an anti-IL23p19 antibody for the manufacture of a medicament for 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 in the patient are differentially regulated relative to a reference value of the specific gene transcript, wherein the anti-IL23p19 antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

In a specific embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of a specific gene transcript, administering an anti-IL23p19 antibody to the patient; Measuring the expression of 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 the first dose of the anti-IL-23p19 antibody is administered; and If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value for the specific gene transcript, then continuing to administer the anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for 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 in the patient are differentially regulated relative to a reference value of a specific gene transcript, Wherein if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of the specific gene transcript, the patient continues to be treated with the anti-IL23p19 antibody at about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for 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 in the patient are differentially regulated relative to a reference value of a specific gene transcript, Wherein if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of the specific gene transcript, the patient continues to be treated with the anti-IL23p19 antibody at about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody.

In an even more specific embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B in the patient sample is differentially regulated relative to a reference value for the specific gene transcript.

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

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for 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 and DEFB4B in the patient are differentially regulated compared to a reference value of the specific gene transcripts.

In an even more specific embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A in the patient sample is differentially regulated relative to a reference value for the specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for 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 and IL23A in the patient are differentially regulated compared to a reference value of the specific gene transcripts.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for 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 and IL23A in the patient are differentially regulated compared to a reference value of the specific gene transcript.

In an even more specific embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 in a patient sample; If the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 in the patient sample is differentially regulated compared to a reference value for the specific gene transcript, administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for 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 and SLC26A2 in the patient are differentially regulated compared to a reference value of the specific gene transcripts.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for 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 and SLC26A2 in the patient are differentially regulated compared to a reference value of the specific gene transcripts.

In even another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of gene transcripts ABI1, HNF4A and IL1B in a patient sample; If the expression of a gene transcript selected from ABI1, HNF4A and IL1B in the patient sample is differentially regulated compared to a reference value for a specific gene transcript, administering an anti-IL23p19 antibody to the patient.

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

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

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 is increased in the patient sample and/or the expression of one or more gene transcripts selected from HNF4, SLC26A2, OTOP2 is decreased in the patient sample compared to a reference value of the specific gene transcript, then administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 is increased in the patient, and/or the expression level of one or more gene transcripts selected from HNF4, SLC26A2 and OTOP2 is decreased compared to a reference value of a specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, IL23A, DEFB4B, MMP3 and CXCL1 in the patient is increased compared to a reference value of a specific gene transcript, and/or the expression level of one or more gene transcripts selected from HNF4, PTPRC, SLC26A2 and OTOP2 is decreased.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 is increased in the patient sample and the expression of one or more gene transcripts selected from HNF4, SLC26A2 and OTOP2 is decreased in the patient sample compared to a reference value of the specific gene transcript, then administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 is increased in the patient, and the expression level of one or more gene transcripts selected from HNF4, SLC26A2 and OTOP2 is decreased compared to a reference value of a specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 is increased in the patient, and the expression level of one or more gene transcripts selected from HNF4A, SLC26A2 and OTOP2 is decreased compared to a reference value of a specific gene transcript.

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

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

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, 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 a decreased expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2, relative to a reference value of a specific gene transcript, wherein the anti-IL23p19 antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B in a patient sample; and If the expression of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A and DEFB4B is increased in the patient sample and if the expression of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 is decreased in the patient sample, administering an anti-IL23p19 antibody to the patient, relative to a reference value of the specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A and DEFB4B is increased in the patient, and the expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 is decreased compared to a reference value of a specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC, IL23A and DEFB4B in the patient is increased, and the expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 is decreased compared to a reference value of a specific gene transcript.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A in a patient sample; and If the expression of one or more gene transcripts selected from ABI1, IL1B, PTPRC and IL23A is increased in the patient sample and the expression of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 is decreased in the patient sample compared to a reference value of the specific gene transcript, then administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC and IL23A is increased, and the expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 is decreased in the patient compared to a reference value of a specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B, PTPRC and IL23A in the patient is increased, and the expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 is decreased compared to a reference value of a specific gene transcript.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: Measuring the expression level of one or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 in a patient sample; and If the expression level of one or more gene transcripts selected from ABI1, IL1B and PTPRC is increased in the patient sample and the expression level of one or more gene transcripts selected from HFN4A and SLC26A2 is decreased in the patient sample compared to a reference value of the specific gene transcript, then administering an anti-IL23p19 antibody to the patient.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B and PTPRC is increased and the expression level of one or more gene transcripts selected from HFN4A and SLC26A2 is decreased in the patient compared to a reference value of a specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of one or more gene transcripts selected from AbI1, IL1B and PTPRC is increased, and the expression level of one or more gene transcripts selected from HFN4A and SLC26A2 is decreased in the patient compared to a reference value of a specific gene transcript.

In another embodiment, the present invention provides a method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression of a gene transcript selected from ABI1, HNF4A and IL1B in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of a gene transcript selected from ABI1 and IL1B is increased in the patient sample and the expression of a gene transcript HFN4A is decreased in the patient sample relative to a reference value of the specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has increased expression of a gene transcript selected from AbI1 and IL1B and decreased expression of a gene transcript HFN4A compared to a reference value of a specific gene transcript.

In some embodiments, the present invention provides an anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of a gene transcript selected from AbI1 and IL1B is increased and the expression level of the gene transcript HFN4A is decreased in the patient compared to a reference value of a specific gene transcript.

In certain embodiments of the invention, methods, treatments and uses of anti-IL23p19 antibodies can be used to treat symptoms of UC. These symptoms can be, for example, diarrhea, frequent bowel movements, rectal bleeding, bowel urgency, fatigue or other symptoms known to be associated with UC.

In certain embodiments of the invention, methods, treatments and uses of anti-IL23p19 antibodies result in increased expression of at least one, at least two and three gene transcripts selected from HNF4A, OTOP2 and SLC26A2 following treatment with anti-IL23p19 antibodies. In these embodiments, increased expression is negatively correlated with increased disease activity as measured by clinical scores (such as Mayo scores), endoscopically based UCEIS scores and/or histologically based scores (such as Geboes or RHI). In even further embodiments, if after treatment with the anti-IL23p19 antibody, the expression level of at least one, at least two, and three gene transcripts selected from HNF4A, OTOP2, and SLC26A2 is reduced, the patient continues treatment with the anti-IL23p19 antibody.

In certain embodiments of the invention, the methods, treatments and uses of anti-IL23p19 antibodies reduce the expression 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 after treatment with anti-IL23p19 antibodies. In these embodiments, the increase or decrease is positively correlated with disease activity as measured by clinical scores (such as Mayo scores), endoscopically based UCEIS scores and/or histologically based scores (such as Geboes or RHI). In an even further embodiment, if following treatment with the anti-IL23p19 antibody, the expression level of at least one, at least two, or at least three, at least four, at least five, at least six, or seven gene transcripts selected from ABI1, DEFB4B, PTPRC, IL23A, IL1B, MMP3, and CXCL1 is reduced, the patient continues treatment with the anti-IL23p19 antibody.

In other embodiments of the methods and uses of the present invention, the patient administered the anti-IL23p19 antibody 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 relief, improvement of endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement of bowel urgency, relief of bowel frequency, improvement of bowel frequency, improvement of fatigue. In these embodiments, the patient achieves a therapeutic effect within about 2 weeks, 4 weeks, 8 weeks, or 12 weeks of treatment with the anti-IL23p19 antibody. In even further embodiments, the patient achieves a sustained therapeutic effect of at least one or more of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of stool frequency, improvement in stool frequency, improvement in fatigue, for at least about 12 weeks to about 104 weeks of treatment with the anti-IL23p19 antibody. In further embodiments, the patient continues one or more treatment effects for up to about 24 weeks, 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 of treatment with the anti-IL23p19 antibody.

In certain embodiments, the present invention provides a method or use for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of at least three, at least five, at least seven, at least eight, or more gene transcripts of the present invention is a prognostic factor for at least one or more of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement in intestinal urgency, relief of bowel frequency, improvement in bowel frequency, and improvement in fatigue. In other embodiments, treatment with an IL23p19 antibody achieves one or more of the following therapeutic effects: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of bowel frequency, improvement in bowel frequency, improvement in fatigue.

In certain embodiments, the present invention provides a method of treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the expression level of at least three, at least five, at least seven, at least eight, or more gene transcripts of the present invention is predictive of at least one or more of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of stool frequency, improvement in stool frequency, improvement in fatigue under treatment with an anti-IL23p19 antibody.

In certain embodiments of the methods, treatments, and uses of the invention, in the case of treatment with an anti-IL23p19 antibody, the expression levels of at least three, at least five, at least seven, at least eight, or ten or more gene transcripts of the invention are predictive of at least one or more of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of stool frequency, improvement in stool frequency.

In certain embodiments of the methods, treatments and uses of the present invention, the expression level of a gene transcript selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample is increased in the patient sample relative to a reference value of a specific 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 relative to a reference value of a specific gene transcript. In some of these embodiments, the expression levels of at least one, at least two, at least three, at least four, at least five, or at least six gene transcripts selected from AbI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3, and CXCL1 in the patient sample are increased in the patient sample relative to a reference value for the specific gene transcript, and/or the expression levels of at least one, at least two, at least three, or four gene transcripts selected from HFN4A, SLC26A2, and OTOP2 in the patient sample are decreased in the patient sample relative to a reference value for the specific gene transcript.

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, 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 in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate.

In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least three gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least four gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least five gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least six gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least seven gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least eight gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of at least nine gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate. In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses comprise measuring the expression of 10 gene transcripts of the present invention in a patient sample before and after administration of an anti-IL23p19 antibody, as appropriate.

In certain embodiments of the methods, treatments and uses of the present invention, the methods, treatments or uses include analyzing clinical indicators including modified Mayo score (MMS), Mayo total score, Mayo endoscopic examination score, ulcerative colitis endoscopic examination severity index (UCEIS) total score, Geboes score, Robarts histopathological index (RHI) and combinations thereof.

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

In another preferred embodiment of the methods, treatments and uses of the present invention, the anti-IL-23p19 antibody is migizizumab.

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

In some embodiments, the first maintenance dose of migizone is administered 4 weeks after the last induction dose is administered. In other embodiments, the maintenance dose is administered at 4 week intervals. In even further embodiments, the maintenance dose is 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 104 weeks.

In some embodiments of the invention, the patient is biologic treatment naive. In some embodiments, the patient has failed biologic treatment. In some embodiments, the patient has failed a known treatment. In some embodiments, the patient is resistant to anti-TNF therapy. In some embodiments, the patient has failed JAK inhibitor therapy. In some embodiments, the patient has failed anti-integrin therapy. In some embodiments, the patient has failed S1P receptor modulator therapy. In some embodiments, the patient has failed biologic therapy and has failed known treatment. In some embodiments, the patient is unresponsive, inadequately responsive, has lost response, or is intolerant to known or biologic therapy.

In some embodiments of the present invention, the expression amount of the gene transcript of the present invention is measured by a gene expression analysis method. In other embodiments, the method is a PCR-based method. In other embodiments, the method is an RNA sequencing method. In some embodiments, the method is a method based on in situ hybridization. In some embodiments, the method is an immunohistochemistry method. In some embodiments, the method is a proteomics technique. In certain embodiments, the expression amount of the gene transcript of the present invention is standardized relative to the expression amount of one or more reference genes or their expression products. In certain embodiments, the expression amount of the gene transcript is measured with an analyzer unit, and a comparison of the measured expression amount of one or more gene transcripts with a reference value of a specific gene transcript is performed with a computing device.

In some embodiments of the present invention, the sample is from a colon tissue biopsy or a rectal tissue biopsy. In other embodiments of the present invention, the colon tissue biopsy is from a tissue selected from the group consisting of the terminal ileum, ascending colon, descending colon, and sigmoid colon. In some embodiments, the colon tissue biopsy is from a non-inflamed colon region. In other embodiments, the colon tissue biopsy is from an inflamed colon region.

This application claims the benefit of U.S. Provisional Application Serial No. 63/486,342, filed February 22, 2023, and U.S. Provisional Application Serial No. 63/486,551, filed February 23, 2023, pursuant to 35 USC §119(e); the disclosures of those applications are incorporated herein by reference .

This application is filed with a sequence listing in ST.26 XML format. The sequence listing is provided in the form of a file named "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.

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

UC is a form of colitis, an inflammatory disease of the intestinal tract, usually the colon, including characteristic ulcers. Symptoms of active disease usually include diarrhea mixed with blood, often accompanied by varying degrees of abdominal pain, ranging from mild discomfort to severe painful cramps. Bowel urgency is also a common and destructive symptom of ulcerative colitis (UC) and is distinct from frequent stools (SF) and rectal bleeding (RB).

There are many methods for assessing disease severity/clinical indicators, including the Mayo score, modified Mayo score (MMS), Ulcerative Colitis Disease Activity Index (UCDAI), Mayo total score, Mayo endoscopic score, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) total score, Geboes score, Robarts histopathological index (RHI), and their combinations.

The Mayo score is a composite instrument that includes the following 4 subscores: i. Stool frequency (SF): The SF subscore is a patient-reported measure. It reports the number of stools in a 24-hour period on a 4-point scale relative to the patient's normal number of stools in the same period. Stool is defined as a stool with either blood only, blood and mucus only, or mucus only when the patient goes to the toilet. The patient records the total number of stools in the 24-hour period. A reference "normal" SF is usually recorded for that patient at the beginning of the study or observation period. The patient's normal SF is the SF reported by the patient when he or she is in remission, or before the first onset of signs and symptoms of UC if the patient never achieves remission. The Stool Frequency subscore rates the individual's normal number of bowel movements per day. 0 1 to 2 more bowel movements per day than normal 1 3 to 4 more bowel movements per day than normal 2 5 to more bowel movements per day than normal 3 ii. Rectal Bleeding: The RB subscore is a patient-reported measure. This item reports the maximum amount of blood that passes through the rectum on a given day on a 4-point scale. Rectal Bleeding Subscore No blood seen 0 Blood in stool less than half the time 1 Significant bleeding (more than just blood ) or blood in stool most of the time 2 Excessive blood 3 iii. Endoscopy Subscore (ES): ES is a physician-reported measure that reports the worst appearance of the mucosa on flexible sigmoidoscopy or colonoscopy on a 4-point scale. Consistent with current clinical practice, friability does not include an ES of 1 in the definition. Endoscopic subscore Normal or inactive disease 0 Mild disease (erythema, decreased vascular pattern) 1 Moderate disease (prominent erythema, lack of vascular pattern, friability, erosion) 2 Severe disease (spontaneous bleeding, ulcers) 3 iv. Physician's Global Assessment (PGA): PGA is a physician-reported measure that summarizes the patient's assessment of UC disease activity on a 4-point scale. Physician's Global Assessment score Normal 0 Mild disease 1 Moderate disease 2 Severe disease 3

Each sub-score is scored on a 4-point scale ranging from 0 to 3, with a maximum Mayo score of 12.

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 3 of the 4 subscores of the Mayo score. It does not include the physician's overall assessment. The MMS assesses three subscores, each with a grade 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 with each ES ≥ 2 are defined as having moderate to severe active ulcerative colitis.

The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. The partial Mayo score excludes endoscopy and ranges from 0 to 9, while the modified Mayo score excludes the physician's overall assessment and also ranges from 0 to 9. The original description of the Mayo score included fragility in the definition with an endoscopy score of 1.

Using the MMS, as used herein, "clinical remission" is defined as a RB subscore of 0, a SF subscore of 0 or 1 (a decrease of ≥1 point from baseline), and an ES of 0 or 1 (excluding fragility). Using the MMS, as used herein, a "clinical response" is defined as achieving a decrease of ≥2 points and ≥30% to 35% from baseline in the 9-point MMS subscore, with a decrease of ≥1 in the RB subscore or a RB subscore of 0 or 1. Using the MMS, as used herein, "endoscopic remission" is defined as achieving a Mayo ES of 0. Using the MMS, as used herein, "endoscopic cure" is defined as having achieved a Mayo ES of 0 or 1. "Improvement of endoscopic and histological inflammation" (mucosal healing) was defined as an endoscopic subscore of 0 or 1 and histological resolution (defined as a Geboes histological subscore of 0 for lamina propria neutrophils, epithelial neutrophils, and erosion or ulcer parameters or as an RHI score).

Using MMS, as used herein, "symptomatic relief" is defined as having achieved SF = 0 or SF = 1, with a decrease of ≥ 1 point from baseline, and RB = 0. As used herein, "symptomatic response" is defined as a decrease of at least 30% from baseline in the combined SF and RB. Using MMS, as used herein, "loss response" is defined as: (a) an increase of ≥ 2 points from baseline in the combined score of frequent stools (SF) and rectal bleeding (RB); (b) a combined score of SF and RB of ≥ 4, with an interval of ≥ 7 days between 2 consecutive visits, a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. “Corticosteroid-free remission” without surgery was defined as clinical remission and no use of corticosteroids for ≥12 weeks before assessment.

Bowel urgency was measured by the Unified Numerical Rating Scale (UNRS) to assess mean change in severity of bowel urgency. Bowel urgency, the sudden or immediate need to have a bowel movement, is a common and distressing symptom in 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 (the worst possible urgency). UNRS scores were recorded daily by patients in an electronic diary. Change from baseline in the UNRS was measured at Week 12, Week 28, Week 52, or up to approximately Week 104 of treatment. Clinically significant "improvement in bowel urgency" or clinically significant change in severity of bowel urgency was defined as the proportion of patients achieving both clinical responses based on an improvement of ≥3 points from baseline on both the MMS and UNRS scores. "Relief of bowel urgency" was defined as minimal to no bowel urgency: UNRS [0,1], assessed at Week 12, Week 28, and thereafter (maintenance) in patients with a baseline UNRS ≥3.

As used herein, the Geboes score consists of seven categories (or grades), each of which describes a histological item, including "architecture (architectural changes)" (grade 0), "chronic inflammatory infiltrate" (grade 1), "lamina propria eosinophils" (grade 2A), "lamina propria neutrophils" (grade 2B), "epithelial neutrophils" (grade 3), "crypt destruction" (grade 4), and "surface epithelial damage" (grade 5). Each grade includes a subscore indicating the degree of abnormality found in the histological feature, where a subscore of 0 indicates normal morphology, and higher subscores indicate increasingly abnormal morphology. The RHI uses weighted results from 4 Geboes scoring categories ("chronic inflammatory infiltrate," "lamina propria neutrophils," "epithelial neutrophils," and "surface epithelial damage") to produce a continuous score ranging from 0 (no disease activity) to 33 (severe disease activity). The RHI was developed as a response tool to detect therapeutic effects in early drug development.

Thus, as used herein, a "therapeutic effect" or response to a treatment can be any one or more of the following: clinical response, clinical relief, endoscopic relief, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free relief, relief of bowel urgency, improvement in bowel urgency, relief in stool frequency, improvement in stool frequency, improvement in fatigue.

As used herein, "sustained response" is the percentage of patients who achieved clinical remission at Week 12 who achieved clinical remission at Week 52.

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 individual from which the biological sample was obtained. For example, a biomarker can be a molecule or group of molecules whose presence, absence, or relative abundance is: characteristic of a particular cell or tissue type or state; and/or characteristic of a particular pathological condition or state; and/or indicates the severity of a pathological condition, the likelihood that a pathological condition will progress or regress, and/or the likelihood that a pathological condition will respond to a particular treatment. For example, a biomarker as used herein can be a gene expression product corresponding to a particular gene, such as an RNA transcript (gene transcript) expressed by a particular gene. The biomarkers provided herein can be predictive biomarkers that can be used to predict or identify individuals or groups of individuals who are more likely to respond to anti-IL-23p19 antibody treatment. The biomarkers provided herein can also be prognostic biomarkers used to identify ulcerative colitis disease activity. The biomarkers provided herein can 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 continuously analyzed to assess the status of ulcerative colitis and/or track the response/efficacy of patients to anti-IL23p19 antibody treatment. The biomarkers provided herein may also be pharmacodynamic biomarkers that can be used to determine a patient's response to anti-IL-23p19 antibody treatment. The biomarkers provided herein may also be susceptibility/risk biomarkers that can indicate the likelihood of developing ulcerative colitis in an individual who has not yet been diagnosed with ulcerative colitis. The biomarkers provided herein may also be surrogate biomarkers that explain clinical outcomes following anti-IL-23p19 antibody treatment.

As used herein, the term "gene transcript" or "gene transcript biomarker" refers to a gene expression product corresponding to a specific gene, such as an RNA transcript expressed by a specific gene. Gene transcripts can be used as biomarkers, as described above with respect to more general biomarkers. The gene transcripts provided herein can be prognostic biomarkers for identifying disease activity, progression and/or recurrence of ulcerative colitis. The gene transcripts provided herein can also be predictive biomarkers that can be used to predict or identify individuals or groups of individuals who are more likely to respond to anti-IL-23p19 antibody treatment. The gene transcripts provided herein can be diagnostic gene transcripts, which can be used to detect and/or confirm the presence and/or severity of ulcerative colitis. The gene transcripts provided herein can also be monitoring biomarkers, which can be continuously analyzed to assess the status of ulcerative colitis. The gene transcripts provided herein can also be pharmacodynamic biomarkers, which can be used to determine the patient's response to anti-IL-23p19 antibody treatment. The gene transcripts provided herein can also be susceptibility/risk biomarkers, which can indicate the possibility of developing ulcerative colitis in an individual who has not yet been diagnosed with ulcerative colitis. The gene transcripts provided herein may also be surrogate biomarkers for explaining clinical outcomes after anti-IL-23p19 antibody treatment. The terms "biomarker" and "gene transcript biomarker" and "gene transcript" are used interchangeably herein.

As used herein, "transcript expression" or "transcript biomarker" refers to the process of synthesizing a gene product from a gene encoding a biomarker known to those skilled in the art. Gene products can be, for example, RNA (ribonucleic acid) and protein. Expression can be quantitatively measured by methods known to those skilled in the art, such as polymerase chain reaction (PCR), microarray analysis, tag-based techniques (e.g., gene expression serial analysis and next generation sequencing, such as whole transcriptome bird shot sequencing or RNA-Seq), in situ hybridization, Northern blotting, Southern blotting, in situ hybridization, immunoassay (including Western blotting), enzyme-linked immunosorbent assay (ELISA), enzyme-linked fluorescent assay (ELFA), immunoprecipitation, immunohistochemistry, and combinations thereof.

As used herein, a "reference value" or "reference expression level" of a gene transcript or biomarker may refer to an expression level of a gene transcript determined for individuals without ulcerative colitis (determined by a medical professional and/or a research professional using 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, a range of expression levels, or a minimum expression level, an average expression level, and/or a median expression level of a gene transcript. A reference value may also be used as a baseline for the expression level of a gene transcript to which a value obtained from a patient sample is compared. A reference expression level of a gene transcript may also refer to the expression level of any combination of biomarkers determined for an individual (e.g., an individual without ulcerative colitis), the expression level of a gene transcript in a normal/healthy individual without ulcerative colitis, and the expression level of a gene transcript in an individual who did not have ulcerative colitis when the sample was obtained from the individual but later developed ulcerative colitis. A reference expression level of a gene transcript may also refer to the expression level of a gene transcript obtained from an individual to whom the method is applied. Thus, changes in an individual's visit to a clinic 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 individual and used to identify the difference between multiple expression levels in each sample. Therefore, in some embodiments, two or more samples obtained from the same individual can provide one or more expression levels of a gene transcript and one or more reference expression levels of a gene transcript. The reference expression level can also refer to the expression level of a gene transcript in a "placebo responder". As used herein, a "placebo responder" is an individual with ulcerative colitis determined by a medical professional and/or research professional using the established methods described herein, who shows clinical improvement but is not administered an anti-IL-23p19 antibody. The reference value can be a predetermined critical value derived from any one or more methods described above.

As used herein, the term "differentially regulated" and/or "differentially expressed" refers to the difference between the expression amount of a specific gene transcript in a UC patient and the reference value of the specific gene transcript defined herein. Differential regulation may mean that the expression amount of a specific gene transcript in a patient is increased (increased, higher, up-regulated) or decreased (decreased, lower, down-regulated) compared to the reference value defined herein.

The term "antibody" as used herein refers to an immunoglobulin molecule that binds to an antigen. Examples of antibodies include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, bispecific or multispecific antibodies, or conjugate antibodies. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

The exemplary antibodies disclosed herein are immunoglobulin G (IgG) type antibodies composed of the following four polypeptide chains: two heavy chains (HC) and two light chains (LC) cross-linked by interchain disulfide bonds. The amino terminal portion of each of the four polypeptide chains includes a variable region having about 100 to 125 or more amino acids that is primarily responsible for antigen recognition. The carboxyl terminal portion of each of the four polypeptide chains contains a constant region that is 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 can be further divided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). CDRs are exposed on the surface of the protein and are important regions for the antigen binding specificity of the antibody. Each VH and VL is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this article, 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". CDRs contain most of the residues that form specific interactions with antigens. Assignment of amino acid residues to CDRs can be performed according to well-known schemes, including those described in 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 ImMunoGeneTic database can be found at www.imgt.org ; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212.) Assignment of amino acid residues to CDRs can be performed according to a combination of the schemes described above.

The embodiments of the present disclosure also include antibody fragments or antigen-binding fragments used herein, which include at least a portion of an antibody that retains the ability to specifically interact with an antigen or an antigenic determinant of an antigen, such as Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, scFab, disulfide-linked Fvs (sdFv), and Fd fragments.

As used herein, "anti-IL-23p19 antibody" refers to an antibody that binds to the p19 subunit of human IL-23 but not to the p40 subunit of human IL-23. Anti-IL-23p19 antibodies thus bind to human IL-23 but not to human IL-12. Examples of anti-IL23p19 antibodies that can be used in the methods, treatments, and uses of the invention include migizone, guselkumab, tirazumab, risakizumab, and brezumab.

Guselkumab, CAS registration number 1350289-85-8, is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of human IL-23. The antibody and its preparation method are described in U.S. Patent No. 7,935,344.

Tilatuzumab, CAS registration number 1326244-10-3, is a humanized IgG1 κ monoclonal antibody targeting the p19 subunit of human IL-23. The antibody and its preparation method are described in U.S. Patent No. 8,293,883.

Risanizumab, CAS injection number 1612838-76-2, is a humanized IgG1 κ monoclonal antibody targeting the p19 subunit of human IL-23. The antibody and its preparation method are described in U.S. Patent No. 8,778,346.

Migidizumab, CAS registration number 1884201-71-1, is a humanized IgG4-κ monoclonal antibody targeting the p19 subunit of human IL-23. The antibody and its preparation method are described in U.S. Patent No. 9,023,358. Migidizumab comprises 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 Migidizumab is particularly suitable for many aspects of the present invention.

Suitable inducing doses of anti-IL-23p19 antibodies include about 50 mg to about 600 mg. A particularly suitable dose is a 300 mg inducing dose of anti-IL-23p19 antibody. The inducing dose of anti-IL-23p19 antibody is preferably administered intravenously. Suitably, the patient is administered an inducing dose of 50 mg to 600 mg, preferably 300 mg, every 4 weeks for 12 weeks. The inducing dose(s) may be followed by at least one maintenance dose ranging from about 150 mg to about 400 mg, preferably 200 mg of anti-IL-23p19 antibody. A particularly suitable dose is a 200 mg maintenance dose of anti-IL-23p19 antibody. Suitably, a maintenance dose of 150 mg to 400 mg is administered to the patient every 4 weeks or every 12 weeks. Administration of at least one induction dose of anti-IL-23p19 antibody to a patient in need during the induction period is intended to induce a desired therapeutic effect, wherein the desired therapeutic effect is clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of stool frequency, improvement in stool frequency, and 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 therapeutic effect obtained during the induction period, wherein the therapeutic effect is clinical response, clinical relief, endoscopic relief, endoscopic cure, symptom relief, improvement of endoscopic histological inflammation, corticosteroid-free relief, relief of intestinal urgency, improvement of intestinal urgency, relief of stool frequency, improvement of stool frequency, and improvement of fatigue. There is no minimum or maximum duration for the induction phase, but it usually lasts 4, 8, or 12 weeks, and ends with an end-of-induction assessment, which usually occurs 4 or 8 weeks after the last induction dose. If the patient does not achieve a clinical response at the end of the initial induction phase, the induction dose may be extended, called an "extended induction dose" to distinguish it from the initial induction dose. If the patient achieves a clinical response at the end of the extended induction period, at least one maintenance dose of 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 relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief in stool frequency, improvement in stool frequency, improvement in fatigue. The first maintenance dose is administered 4 to 12 weeks after the last extended induction dose is administered to the patient. The 4 to 12 week period accommodates the variation in the period between administration of the last extended induction dose and the end of the extended induction assessment. After administration of the first maintenance dose, the maintenance dose(s) are administered at intervals of 4, 8, or 12 weeks. The maintenance dose(s) may be administered by subcutaneous injection. If a patient develops a loss reaction during the maintenance period, the patient is administered one, two, or three rescue doses of anti-IL-23p19 antibody, wherein if the patient achieves a clinical response 4 to 12 weeks after the last rescue dose, the patient is administered one or more additional maintenance doses of anti-IL-23p19 antibody, wherein "loss reaction" is defined as: (a) an increase of >2 points from baseline in the combined score of frequent stool (SF) and rectal bleeding (RB); (b) SF and RB combined score >4, 2 consecutive visits >7 days apart, confirmed negative Clostridium difficile test, and (c) endoscopic subscore (ES) of 2 or 3, with clinical response defined as a decrease of >2 points on the 9-point modified Mayo scale (MMS) and >30-35% from baseline, a decrease of >1 in the rectal bleeding (RB) subscore or a RB subscore of 0 or 1.

The methods disclosed herein may further include obtaining three or more samples from the patient. It is particularly suitable to obtain multiple samples from the patient, reference individuals and/or placebo responders for analyzing the samples to determine whether the expression level of the gene transcript changes, changes over time, remains unchanged over time, etc.

Suitable samples include tissue biopsy, stool sample, whole blood, plasma, serum and combinations thereof. Particularly suitable tissue biopsy samples include colonic tissue biopsy samples or rectal tissue biopsy samples. The colonic tissue biopsy is from a tissue selected from the group consisting of the terminal ileum, ascending colon, descending colon and sigmoid colon. The colonic tissue biopsy may be from a non-inflamed colon area or from an inflamed colon area. The biopsy may be obtained from the edge of an ulcer, from the edge of an erosion, throughout the affected mucosal compartment, and combinations thereof.

For embodiments wherein an anti-IL23p19 antibody is administered to the patient, the first sample is collected prior to or concurrently with administration of the anti-IL-23p19 antibody, and additionally is collected at least two weeks, at least four weeks, at least eight weeks, at least twelve weeks, at least sixteen weeks, at least twenty weeks, at least twenty-four weeks, at least twenty-eight weeks, at least thirty weeks, at least thirty-two weeks, at least thirty-six weeks, at least forty weeks, at least forty-four weeks, at least forty-eight weeks, or at least fifty-two weeks, or up to at least 104 weeks after the first administration of the anti-IL-23p19 antibody. Alternatively, the sample may be obtained at 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 may be further obtained after 52 weeks after administration of the anti-IL-23p19 antibody. The sample may be further obtained at other time intervals, including daily, weekly, monthly, and yearly.

As used herein, the term "biologic-naïve" refers to patients who have not been administered biologics, such as anti-IL23 antibodies, anti-TNF-α antibodies, anti-integrin antibodies, JAK inhibitors, TYK2 inhibitors, S1P receptor modulators, for the treatment of UC, particularly for the treatment of moderate to severe UC. These patients may or may not have been administered known drugs for the treatment of UC.

As used herein, the term "biologic experienced" refers to a patient who has been administered at least one prior biologic, such as anti-TNFα (e.g., adalimumab, golimumab, infliximab), anti-integrin (e.g., vedolizumab), JAK inhibitor (e.g., tofacitinib, upatinib), TYK2 inhibitor, S1P receptor modulator (e.g., ozanimod), for the treatment of UC, particularly for the treatment of moderate to severe UC. Such patients may or may not have been administered a known drug for the treatment of UC.

As used herein, the term "biologic-failed" refers to a patient who has been administered at least one previous biologic, e.g., an anti-TNF-α antibody, an anti-integrin antibody, a JAK inhibitor, a TYK2 inhibitor, an S1P receptor modulator, for the treatment of UC, particularly for the treatment of moderate to severe UC. These patients may or may not have been administered a known therapy for the treatment of UC. These patients have an inadequate response, loss of response, or intolerance to a biologic therapy for UC (e.g., an anti-TNF-α antibody, an anti-integrin antibody, a JAK inhibitor, a TYK2 inhibitor, an S1P receptor modulator). In the context of the term "biologic-failed," an inadequate response is defined as signs and symptoms of persistent active disease despite induction therapy at the approved induction dose as indicated in the product labeling at the time of use. In the context of the term "biologic-failed," a loss response is defined as the return of signs and symptoms of active disease while on an approved maintenance dose after prior clinical benefit (discontinuation of therapy despite clinical benefit is not considered failure or intolerance of biologic therapy for UC). In the context of the term "failure of biologic treatment", intolerance means a history of intolerance to, for example, anti-TNF-α antibodies, anti-integrin antibodies, JAK inhibitors, TYK2 inhibitors, S1P receptor modulators, examples of which include infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, tofacitinib, upatitinib, deucravacitinib, osmamod or other approved biologics, including JAK inhibitors, TYK2 inhibitors, S1P receptor modulators.

As used herein, the term "learned treatment failure" refers to a patient's inadequate response, loss of response, or intolerance to at least one of the following medications: Corticosteroids ●Corticosteroid-refractory colitis is defined as signs or symptoms of active UC, even when taking oral prednisone or an equivalent oral corticosteroid at a dose of ≥30 mg/day for ≥2 weeks. ● Corticosteroid-dependent colitis, defined as (a) inability to taper corticosteroids or to reduce corticosteroids to the equivalent of 10 mg/day of sedrin without recurrence of active UC signs or symptoms within 3 months after initiation of corticosteroid therapy, or (b) recurrence ≤ 3 months after completion of a course of corticosteroids. ● History of corticosteroid intolerance includes but is not limited to cataracts, Cushing's syndrome, hyperglycemia, hypertension, osteopenia/osteoporosis, or neuropsychiatric side effects, including insomnia. ● Immunomodulators: ○ Signs and/or symptoms of persistent active disease despite treatment with one of the following for ≥3 months: ■ Oral AZA (≥1.5 mg/kg/day) or 6-MP (≥0.75 mg/kg/day) ■ Oral AZA or 6-MP within therapeutic range as determined by thioguanine metabolite testing, or ■ Combination of thiopurine and allopurinol within therapeutic range as determined by thioguanine metabolite testing ○ History of intolerance to at least one immunomodulator including but not limited to nausea/vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia Patients with known treatment failure had neither failed nor demonstrated intolerance to biologics indicated for the treatment of UC (anti-TNF antibodies or anti-integrin antibodies) or JAK, S1P, or TYK2 inhibitors.

The term "treatment" or "treating" as used herein refers to all processes in which the progression of the disorders or diseases disclosed herein can be slowed, controlled, delayed or stopped, or the disorders or disease symptoms can be improved, but does not necessarily indicate that all disorders or disease symptoms are completely eliminated. Treatment includes the administration of proteins or nucleic acids or vectors or compositions for the treatment of diseases or conditions in patients, especially humans.

Examples

Examples 1 - I6T-MC-AMAC Clinical Research - Induction period

Study Design and Participants

Clinical Study I6T-MC-AMAC is a multicenter, randomized, double-blind, parallel, placebo-controlled study of migizone in individuals with moderate to severe ulcerative colitis. This study is registered with ClinicalTrials.gov, number NCT02589665.

Procedure and Results

Patients were randomized 1:1:1:1 to: placebo IV Q4W (N=63); migizone 50 mg IV Q4W (N=63); migizone 200 mg IV Q4W (N=62), with possible exposure-based dose escalation; migizone 600 mg IV Q4W (N=61). Endoscopic findings were scored by one of two blinded central readers. Histologic disease activity was assessed by a central reader using two biopsy specimens obtained during endoscopy at baseline and at study week 12. All biopsy specimens were obtained at least 30 cm from the anal verge.

When discrete lesions are present, biopsies are preferentially obtained at the edge of the ulcer, or from the edge of the erosion if no ulcer is present. When macroscopic disease is present but discrete lesions are absent, biopsies are obtained at intervals throughout the affected mucosa. In the absence of macroscopic disease, the entire segment is biopsied.

Histopathology

At each endoscopic examination, two endoscopic biopsy specimens for histopathological assessment were obtained from the most severely affected area at least 30 cm from the anal verge. One of two blinded pathologists assessed the histological disease activity of each specimen using the Geboes score and the Robarts histopathological index (RHI).

Endpoints for this study were endoscopic improvement (endoscopic subscore of 0 or 1) and histological remission (defined as a Geboes histological subscore of 0 for lamina propria neutrophils, epithelial neutrophils, and erosion or ulcer parameters). Mucosal healing was determined by the presence of histological remission and endoscopic improvement. Because there is no agreed definition of what constitutes an increase in lamina propria eosinophils and because of lack of reproducibility and predictive data, a reduction in eosinophils to normal was not included in the primary definition of histological remission. Robarts histopathology index (RHI) scores and Geboes scores were also determined.

RNA Extraction and gene array method

Gene expression in 553 colon tissue biopsies from I6T-MC-AMAC was measured on GeneChip HT A2.0 arrays using the Affymetrix WT protocol. Biopsies from the same individual at each time point were pooled together, yielding a total of 277 biopsy RNA samples. These samples were subjected to quality control ("QC") checkpoints (e.g., RNA sample quality/quantity and amplification) and HTA 2.0 processing.

RNA Sample preparation and quality control

Colonic tissue samples were collected from each individual at each time point in two tubes. Extraction trials were performed by pooling colonic biopsies from 20 individuals to ensure adequate quality for transcriptome analysis. RNA extraction was performed according to the manufacturer's recommended protocol. Briefly, extracted RNA QC included bioanalyzer (BA) QC and quantification. BA-based QC criteria were: 28S/18S ratio (0.75 to 3.0), 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 analysis steps. Samples were run on an Agilent 2100 bioanalyzer to assess RNA quality. All samples were of sufficient quality for analysis and continued to HTA2 processing.

RNA samples that passed CGL QC were aliquoted into 96-well plates (100 ng input). Two samples were removed after one patient dropped out, and four biopsies at Week 12 were not collected from individuals who left the trial after the Week 0 biopsy was collected, leaving 224 Week 0 timepoints and 220 Week 12 timepoints data sets that passed array QC.

Gene chip array

Probe-level data from the HTA2 platform were pre-processed for background correction and quantile normalization according to standard RMA methods and summarized to the probe set level defined by the Affymetrix NETAFFX™ NA35/GRCh37 human reference human reference genome release. The data were then aggregated to the "exome" level, i.e., data-defined clusters of highly correlated exon-based probe sets, as follows: A correlation matrix between probe set representations was calculated, and the distance metric between pairs of probe sets was defined as one minus the correlation of the pair. Exomes were formed by performing hierarchical clustering using the R hclust function and cutting the dendrogram at a distance of 0.8. Once the exome is defined, the summary performance of the sample can be obtained from the sample effects in the two-way ANOVA model. Probe and sample effects are estimated using robust regression implemented with the rlm function in the R MASS package applied to probe-level data within the exome.

Statistical analysis of differential performance

Exomes generated by the above procedure were filtered according to two criteria: 1) exomes with a SD of log2(expression) less than 0.286 (corresponding to approximately 20% CV), and 2) exomes whose log2(expression) means were less than 75% of the median log2 expression of the negative control (normgene -> intron) probe set. In cases where genes contained multiple exomes, the feature with the largest number of probe sets was selected to represent the overall gene expression, with the balance being broken by the feature with the highest mean expression. In all models, the resulting p-values were multiplicity corrected to account for the number of comparisons made between treatment groups and across all exomes tested using the Benjamini-Hochberg method. .

A mixed-effects repeated measures model (MRMM) was fit to each filtered exome separately to calculate the fold change between week 0 and week 12 time points using age, sex, batch, BMI at baseline, previous biologic treatment, and modified Mayo score (MMS) at baseline as covariates. A cross-time point comparison model compared the differential performance of each exome in the drug treatment group with its differential performance in the placebo group. Exomes with a fold change greater than 0.5 log2 units (approximately 1.41 fold change) and a false discovery rate (FDR) adjusted q value less than 0.05 were classified as differentially represented.

Related statistical analysis

Using age, sex, and array chip batch as covariates, Pearson correlation coefficients were calculated between cross-time differential expression of exomes and changes in clinical indicators between week 0 and week 12. Clinical indicators included MMS, Mayo total score, Mayo endoscopic examination subscore, ulcerative colitis endoscopic examination severity index (UCEIS) total score, Geboes score, and Robarts histopathology index (RHI). Laboratory results included fecal calcitonin and peripheral blood levels of IL-17A, IL-22, and CRP.

result

Patients, Study Overview, and Biospecimens

In this study, 358 patients were screened for eligibility and 249 were randomized. Of these, 224 patients underwent baseline biopsy and 220 patients underwent week 12 biopsy. Of those 220 patients, more than 63% had previously been treated with biologic agents and 47.3% were using corticosteroids at baseline. Baseline disease characteristics were well balanced across treatment groups, with similar disease activity (modified Mayo score), mucosal inflammation (Mayo endoscopic subscore). Histologic measures (Geboes index and RHI) were lower in the placebo group but similar in the migizone-treated groups (Table 1).

Table 1. Baseline demographics and disease characteristics of biopsy patients. Values are mean (SD) unless otherwise stated. Placebo IV Q4W (N=62) Migidizumab 50mg EB IV Q4W (N=63) Migidizumab 200mg EB IV Q4W (N=62) Migidizumab 600mg IV Q4W (N=60) Age, years 42.8 (13.5) 41.8 (14.1) 43.4 (14.8) 42.3 (13.4) Duration of disease, years 9.6 (9.7) 8.2 (7.2) 9.0 (9.0) 6.1 (5.7) Modified Mayo scorea ^​ 6.6 (1.2) 6.6 (1.4) 6.4 (1.4) 6.5 (1.3) Mayo endoscopic examination score 2.7 (0.4) 2.8 (0.4) 2.7 (0.5) 2.7 (0.5) Geboes index ^b 4.4 (1.2) 4.2 (1.3) 3.9 (1.7) 4.0 (1.4) Geboes level ^c n ( %) Level 0 Level 1 Level 2A Level 2B Level 3 Level 4 Level 5 1 (1.6) 3 (4.8) 26 (41.94) 4 (6.5) 4 (6.5) 36 (58.1) 19 (30.65) 2 (3.2) 3 (4.8) 23 (36.51) 4 (6.4) 5 (7.9) 36 (57.1) 22 (34.9) 4 (6.5) 8 (12.9) 24 (38.71) 9 (14.5) 10 (16.1) 35 (56.5) 26 (41.9) 3 (5.1) 7 (11.67) 32 (53.33) 5 (8.3) 5 (8.5) 35 (59.3) 25 (41.7) ^RHI 18.0 (7.8) 18.1 (9.1) 15.7 (9.3) 16.8 (9.1) Concomitant therapy - n (%) 5-ASA Corticosteroid Thiopurine 46 (74.2) 33 (53.2) 25 (40.3) 42 (66.7) 29 (46.0) 15 (23.8) 56 (90.3) 25 (40.3) 18 (29.0) 39 (65.0) 35 (58.3) 11 (18.3) Previous biologic use, n (%) 39 (62.9) 39 (61.9) 40 (64.5) 38 (63.3) Previous anti- TNF use, n (%) 36 (58.1) 35 (55.6) 37 (59.7) 35 (58.3) Fecal calcium-protein , mg/kg , median (SD) 1392 (3450) 1945 (3868) 1560 (2964) 1523 (6197) CRP, mg/L, mean (SD) 8.8 (13.5) 9.3 (12.9) 9.1 (12.9) 14.6 (25.9) The analysis population included patients who underwent biopsies at weeks 0 and 12; EB = exposure-based; ^a Modified Mayo score = subscores for rectal bleeding, frequent stools, and endoscopy ^b Geboes index = mean of all Geboes grades ^c Geboes grade (grade for each patient in which a certain degree of abnormality is found): 0 = architecture (architectural changes), 1 = chronic inflammatory infiltrate, 2A = eosinophils in lamina propria, 2B = neutrophils in lamina propria, 3 = neutrophils in epithelium, 4 = crypt destruction, 5 = erosion or ulcer, with a subscore of 0 indicating normal appearance and higher subscores indicating increasingly abnormal appearance. ^d RHI = Robarts histopathology index, with scores ranging from 0 (no disease activity) to 33 (high disease activity)

Ulcerative colitis 12 Week Semegizumab-mediated transcript changes

In addition to demonstrating the greatest efficacy at Week 12, the 200 mg migizone treatment group also had the greatest number of colon biopsy genes differentially expressed between baseline and Week 12 compared with placebo in all three treatment groups. To better discern the effect of migizone treatment from the effect of standard of care, changes in gene expression in the 200 mg migizone group were assessed between baseline and Week 12 without and normalized to placebo. Normalization to placebo provides greater confidence in a reduction in the number of differentially regulated transcripts. The transcripts with the greatest change at Week 12 after normalization for changes in the placebo group are shown in Table 2.

surface 2 : Placebo-adjusted 200 mg In the migizone group, 12 Genes with the largest expression fold change relative to baseline at week. The ^lowest drop Increase up to ^a REG1B ¯ ¯ ABCG2++ MMP3 ¯ ¯ HMGCS2++ REG3A ¯ ¯ AQP8++ DUOXA2 ¯ ¯ TMIGD1++ SLC6A14 ¯ ¯ GUCA2A++ DMBT1 ¯ ¯ SLC26A2++ MMP1 ¯ ¯ LOC101928405++ REG1P ¯ ¯ SLC26A3+ S100A8 ¯ ¯ MS4A12 + IL1B ¯ ¯ UGT2A3 + IGKV2D-40 ¯ ¯ TRPM6 + PI3 ¯ ¯ NXPE4+ TNIP3 ¯ SLC16A9+ REG1A ¯ ADH1C + IDO1 ¯ PCK1 + DUOX2 ¯ CDKN2B-AS1+ NOS2 ¯ TMEM236+ MMP10 ¯ CD177P1+ CXCL1 ¯ SLC17A4+ PTGS2 ¯ ZG16 + ^aGenes are ranked from largest to smallest fold change ¯ at least 0.5 log2 unit-fold less than PBO; ¯ ¯ at least 1 log2 unit-fold less than PBO; + at least 0.5 log2 unit-fold greater than PBO; ++ at least 1 log2 unit-fold greater than PBO.

Further analysis of the gene transcripts in Table 2 indicated that changes in the individual transcripts shown in Table 2 were associated with changes in disease activity as defined by MMS, Geboes, or RHI (data not shown). Several transcripts identified in Table 2 showed the strongest changes in regulation induced by migizone treatment associated with changes in disease activity. All transcripts positively associated with disease were consistently and consistently downregulated by migizone. In contrast, all transcripts negatively associated with disease were upregulated by migizone treatment. This is consistent with the observation that changes in migizone-regulated transcripts showed a profile of disease attenuation and suggested preliminary evidence of molecular healing as early as 12 weeks after the start of migizone treatment.

Examples 2 - I6T-MC-AMAC Clinical Research - Maintenance period

method:

Migidizumab-treated patients who achieved a clinical response or better at Week 12 (9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] reduction from baseline [BL] of ≥2 points and ≥35% and RB subscore reduction of ≥1 or RB subscore of 0 or 1) were re-randomized to receive migidizumab 200 mg subcutaneously (SQ) every 4 or 12 weeks until Week 52. Patients who received placebo (PBO) during the induction phase and achieved a clinical response continued on PBO during the maintenance phase. Patients (n=272) who did not respond to mirigetumab (miri) 300 mg intravenously (IV) every 4 weeks (Q4W) at Week 12 received an extended 12-week induction treatment of 3 additional doses of open-label 300 mg mirigetumab IV Q4W. Patients who responded at Week 24 of continuous IV treatment (n=144) entered open-label maintenance and received mirigetumab 200 mg Q4W subcutaneously (SC) until Week 52. In addition, patients who had losses or responses during the maintenance period received an extended induction dose and resumed the maintenance dose if they achieved clinical response.

Colonic biopsies were obtained from the most severely affected area at least 30 cm from the anal verge at weeks 0, 12, and 52 (migizumab N=31, PBO N=7). Transcript changes at week 12 relative to baseline in the PBO and migizumab groups were clustered into differentially expressed genes (DEGs) using the Bayesian Limma R package. Among these DEGs, similarly expressed genes (SEGs) were identified as genes that maintained their expression levels from week 12 to week 52. Specifically, standard Limma analysis was used to identify DEGs (fold change (FC) > 2 and p-value < 0.05), and the two-sided one-sided test (TOST) version of Limma analysis was used to identify SEGs (Q _log2FC ± 0.26 and TOST p-value < 0.05).

result:

Baseline demographics and disease characteristics of patients in the maintenance phase

At week 12, significantly greater proportions of patients treated with migizone achieved clinical remission (24.2% vs. 13.3%) and clinical response (63.5% vs. 42.2%) compared with placebo. Among patients who did not 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 ≥7, and 72.4% had an endoscopic Mayo score of 3, indicating severe disease, at baseline. The three additional migizone IV induction doses induced clinical responses in 54% of these patients who initially did not respond to induction therapy at 12 weeks (delayed responders).

Of these 144 responders at 24 weeks entering the open-label maintenance study, approximately 72% achieved a clinical response at Week 52, approximately 36% achieved clinical remission, and approximately 43% achieved endoscopic remission at Week 52, with approximately 42% of patients achieving histologic improvement. Additionally, these patients experienced a 3.8 (±2.7) point decrease in bowel urgency (BU) severity relative to baseline, and 58.8% achieved a clinically meaningful improvement in BU. These results highlight the potential benefit of extended induction therapy and the potential of migizone to treat patients who have failed prior biologic therapy.

Ulcerative colitis 52 Week Semegizumab-mediated transcript changes

Analysis of transcript changes at week 52 in week 12 responders who maintained disease remission identified the profile of DEG-SEGs in responders. Of these genes, 63 (70.8%) were present only in migidizumab responders, 5 (5.6%) were present only in PBO responders, and 21 (23.6%) were present in both groups. The magnitude of transcript changes in the migidizumab responder group was greater at week 12 and more consistent at week 52 compared with PBO responders. Genes that were upregulated at baseline remained downregulated and genes that were downregulated at baseline remained upregulated at week 52 after migidizumab treatment. These results suggest that gene expression changes induced by migidizumab during the induction period are maintained up to week 52 (end point of data collection). These results also indicate that responders treated with migizone have differentially expressed transcripts that are quantitatively different in fold change and significance from those in the PBO responder group.

In this sample of PBO and migizone responders at Week 12, migizone responders demonstrated more extensive, greater, and more sustained changes at Week 52 compared with PBO responders. Qualitative characterization of transcripts identified only in migizone responders and in placebo and migizone responders indicated unique molecular healing pathways associated with migizone treatment compared with spontaneous healing occurring in PBO responders. These included genes associated with interferon gamma response, complement system, TNFα/NFκB, allograft rejection, and mTORC1 signaling and apoptosis. Response to migizone was also associated with the expression of genes involved in epithelial transporters, interleukins, and stromal-epithelial inflammatory drivers.

Examples 3 - Ulcerative colitis 10 Genetic prognosis XGBoost Model

method:

Develop a prognostic gene model using XGBoost model and multiple gene datasets. XGBoost models are widely used in medicine 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, November 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, January 2020, 101898, DOI: 10.1016/j.tube.2020.101898; Lam, KHB et al. "Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity." Nat. Commun. , Vol. 13, No. 1, January 2022, 116, DOI: 10.1038/s41467-021-27667-w).

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

To account for any systematic bias in the analysis, gene signatures were normalized by ranking them relative to other gene signatures such that the highest performing gene would be ranked 10 and the lowest performing gene would be ranked 1. XGBoost models were used to predict response at week 12 based on baseline gene performance. XGBoost models had a maximum tree depth of 10 nodes, binary: logical object function, and were trained for 100 epochs. XGBoost models (using genes as features and clinical outcomes as responses) were trained on the PROTECT study data (see Hyams JS et al., Lancet Gastroenterol Hepatol. 2017;2(12):855-868), and their results were used to predict results on the I6T-MC-AMAC dataset and the following two publicly available datasets: NCBI Gene Expression Public Depository Nos. GSE12251 and GSE23597.

XGBoost Model Results

The results of the XGBoost model confirmed ten genes (see Table 3) as the prognostic model for ulcerative colitis response, which has accurate performance in each dataset as shown by the area under the precision-recall curve (PR-AUC), as follows: ● PROTECT (training dataset) - 0.98 PR-AUC ● I6T-MC-AMAC (test dataset) - 0.90 PR-AUC ● GSE12251 (validation dataset) - 0.85 PR-AUC ● GSE23597 (validation dataset) - 0.77 PR-AUC.

These PR-AUC indicators indicate that the XGBoost model is not only effective on the PROTECT data on which it was trained, but also exhibits excellent precision-recall performance on the ulcerative colitis gene expression dataset on which it was not trained. In addition, Table 3 also shows the correlation between the expression changes of each of the 10 genes identified by the XGBoost model and the changes in clinical response using the modified Mayo score (MMS) in the 50 mg, 200 mg, 600 mg and placebo groups from week 0 to week 12 in the I6T-MC-AMAC study.

Table 3. Ten-gene XGBoost prognostic model for ulcerative colitis disease outcome Gene symbol Gene name MMS correlation R value (P value*) ABI1 Abelson-interacting factor 1 1.52E-02 (8.27E-01) HNF4A Hepatocyte nuclear factor 4 alpha -2.64E-01 (1.16E-04) IL1B Interleukin 1β 3.32E-01 (9.31E-07) PTPRC Protein tyrosine phosphatase receptor type C 3.97E-01 (2.99E-09) SLC26A2 Solute carrier family 26 member 2 -3.35E-01 (7.80E-07) OTOP2 Otopetrin 2 -3.81E-01 (1.38E-08) IL23A IL-23α 3.31E-01 (1.07E-06) DEFB4B Defensin β 4B 2.22E-01 (1.25E-03) MMP3 Matrix metallopeptidase 3 3.53E-01 (1.75E-07) CXCL1 CXC motif interleukin ligand 1 3.58E-01 (1.07E-07) * P values adjusted for multiplicity

By further analysis of the XGBoost model, subsets of 8 genes, 7 genes, 5 genes, and 3 genes were identified 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 considered missing in the GSE12251 and GSE23597 datasets because the gene was only identified as the DEFB4A/B gene in these datasets. The 3-gene set to the 7-gene set signature did not include DEFB4B.

surface 4. Ulcerative colitis 10- Gene XGBoost Gene subsets for prognostic models Gene Subset XGBoost Model Gene list Eight-gene model ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B Seven-gene model ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A Five gene model ABI1, HNF4A, IL1B, PTPRC, SLC26A2 Three-gene model ABI1, HNF4A, IL1B

Table 5. Gene subsets with predictive value when used to train XGBoost models. PR-AUC* Dataset 3- Gene 5- Gene 7- Gene 8- Gene PROTECT ( Training) 0.58 0.72 0.79 0.89 I6T-MC-AMAC ( Test) 0.93 0.95 0.88 0.96 GSE12251 ( verification) 0.86 0.94 0.95 0.90 GSE23597 ( verification) 0.78 0.80 0.81 0.77 * The evaluation indicators in the table are precision - recall -AUC (PR-AUC) .

In summary, the results provided in Example 3 identified a different set of ten genes that are prognostic factors for moderate to severe ulcerative colitis disease activity in patients using a rigorously trained model. In addition, the different gene sets provided in Example 3 may be suitable for predicting the response of moderate to severe UC patients to treatment with anti-IL23p19 antibodies. Based on the correlation analysis of the identified gene sets with MMS-defined disease activity (as shown in Example 3), the identified gene sets may be further suitable for tracking the efficacy of disease activity measures (e.g., MMS, RHI, Geboes, bowel urgency improvement/relief) in moderate to severe UC patients who are receiving anti-IL23p19 antibody treatment, as found in UC patients treated with migizone (see Example 2). Additionally, based on the gene dataset used to identify the 10 gene sets and the pathway relevance of the identified gene sets, there is further potential to use the gene sets to predict response to anti-IL23p19 antibodies and/or to anticipate disease activity and/or response to IL-23p19 antibody treatment in patients who have had an inadequate response, loss of response, or intolerance to at least one prior ulcerative colitis treatment, such as an anti-TNFα antibody, an anti-integrin antibody, a JAK inhibitor, or an S1P receptor modulator. Additionally, the gene set identified included the IL1b transcript, which is known to mediate the inflammatory burden observed in patients with an inadequate response to existing therapies such as anti-TNF therapy, anti-integrins such as Vedolizumab, and Jak inhibitors. This is demonstrated in Example 2 (Table 2), where IL1b transcripts were robustly reduced by migizone compared to baseline at the end of the 12-week induction period and remained reduced during the 52-week maintenance period, further demonstrating the potential ability to use the gene set to predict response to anti-IL23p19 antibodies and/or to anticipate response in patients who have had an inadequate response, loss of response, or intolerance to at least one prior ulcerative colitis therapy (e.g., anti-TNFα antibodies, anti-integrin antibodies, or JAK inhibitors).

sequence

SEQ ID NO: 1 Migidizumab heavy chain variable region (HCVR) QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSS

SEQ ID NO: 2 Migelizumab light chain variable region (LCVR) DIQMTQSPSSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK SEQ ID NO: 3 Migelizumab heavy chain (HC) QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

SEQ ID NO: 4 Migelizumab light chain (LC) DIQMTQSPSSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

TW202448503A_113106404_SEQL.xml

Claims (111)

A method for treating moderate to severe ulcerative colitis in a patient in need thereof, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated relative to a reference value for the specific gene transcript. A method for treating bowel urgency in a patient with moderate to severe ulcerative colitis in need thereof, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated relative to a reference value for the specific gene transcript. A method for prognosticating the response of a patient with moderate to severe ulcerative colitis, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and determining whether the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated relative to a reference value of the specific gene transcript to determine the disease activity of the patient. A method for predicting the suitability of treating moderate to severe ulcerative colitis with an anti-IL23p19 antibody in a patient in need thereof, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated relative to a reference value for the specific gene transcript. The method of claim 1, comprising measuring the expression of 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 administering at least a first dose of the anti-IL-23p19 antibody; and if the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value for a specific gene transcript, then continuing to administer the anti-IL23p19 antibody to the patient. A method as claimed in any one of claims 1 to 5, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B in a patient sample; and administering the anti-IL23p19 antibody to the patient if the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B in the patient sample is differentially regulated relative to a reference value of a specific gene transcript. A method as claimed in any one of claims 1 to 5, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A in a patient sample; and administering the anti-IL23p19 antibody to the patient if the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A in the patient sample is differentially regulated compared to a reference value of a specific gene transcript. A method as claimed in any one of claims 1 to 5, comprising: measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 in the patient sample is differentially regulated compared to a reference value of a specific gene transcript. A method as claimed in any one of claims 1 to 5, comprising: measuring the expression of gene transcripts ABI1, HNF4A and IL1B in a patient sample; and administering an anti-IL23p19 antibody to the patient if the expression of gene transcripts ABI1, HNF4A and IL1B in the patient sample is differentially regulated compared to a reference value of a specific gene transcript. A method as claimed in any one of claims 1 to 5, comprising: Measuring the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in a patient sample; and If the expression of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is increased and/or if the expression of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 in the patient sample is decreased, administering an anti-IL23p19 antibody to the patient. A method as claimed in any one of claims 1 to 10, comprising: Measuring the expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B in a patient sample; and If the expression level of one or more gene transcripts selected from ABI1, IL1B, PTPRC, IL23A and DEFB4B in the patient sample is increased and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 in the patient sample is decreased, administering an anti-IL23p19 antibody to the patient. A method as claimed in any one of claims 1 to 10, comprising: Measuring the expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A in a patient sample; and If the expression level of one or more gene transcripts selected from ABI1, IL1B, PTPRC and IL23A in the patient sample is increased and if the expression level of one or more gene transcripts selected from HFN4A, SLC26A2 and OTOP2 in the patient sample is decreased, administering an anti-IL23p19 antibody to the patient, relative to a reference value of a specific gene transcript. A method as claimed in any one of claims 1 to 10, comprising: measuring the expression level of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 in a patient sample; 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 in the patient sample is increased and if the expression level of one or more gene transcripts selected from HFN4A and SLC26A2 in the patient sample is decreased compared to a reference value of a specific gene transcript. A method as claimed in any one of claims 1 to 10, comprising: Measuring the expression of gene transcripts ABI1, HNF4A, IL1B in a patient sample; and If the expression of one or more gene transcripts selected from ABI1 and IL1B in the patient sample is increased and if the expression of the gene transcript HFN4AH in the patient sample is decreased compared to a reference value of a specific gene transcript, administering an anti-IL23p19 antibody to the patient. The method of claim 1, wherein the method comprises measuring the expression level of at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten of the gene transcripts. The method of any one of claims 1 to 15, 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 relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement in intestinal urgency, relief of bowel frequency, improvement in bowel frequency, and improvement in fatigue. The method of claim 16, wherein the at least one or more therapeutic effects are achieved within about 2 weeks, 4 weeks, 8 weeks or 12 weeks of treatment with the anti-IL23p19 antibody. The method of any one of claims 16 to 17, wherein the patient exhibits a sustained therapeutic effect of at least one or more of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of bowel frequency, improvement in bowel frequency, improvement in fatigue, for at least about 12 weeks to about 104 weeks. The method of claim 18, wherein the therapeutic effect lasts for about 24 weeks, 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 of treatment with the anti-IL23p19 antibody. The method of any one of claims 1 to 19, wherein the expression level of the gene transcripts is prognostic for at least one of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement of endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement of intestinal urgency, relief of bowel frequency, improvement of bowel frequency, and improvement of fatigue. The method of any one of claims 1 to 19, wherein the expression level of the gene transcripts is predictive of at least one of the following for treatment with the anti-IL23p19 antibody: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement in endoscopic histological inflammation, corticosteroid-free remission, relief of bowel urgency, improvement in bowel urgency, relief of bowel frequency, improvement in bowel frequency, and improvement in fatigue. The method of any one of claims 1 to 21, wherein the anti-IL23p19 antibody is mirikizumab. The method of any one of claims 1 to 21, wherein the anti-IL23p19 antibody is guselkumab, tildrakizumab, risankizumab, or brazikumab. The method of any one of claims 1 to 23, wherein the patient is biologic naïve. The method of any one of claims 1 to 23, wherein the patient has failed treatment with a biologic agent. The method of any one of claims 1 to 23, wherein the patient is a known treatment failure. The method of any one of claims 1 to 23, wherein the patient has failed treatment with a biologic and is accustomed to treatment failure. The method of any one of claims 1 to 23, wherein the patient has failed to respond to, responded inadequately to, lost response to, or is intolerant to at least one prior treatment for ulcerative colitis. The method of any one of claims 25 to 28, wherein the patient has failed one or more of the following: anti-TNF therapy failure, anti-α4β7 therapy failure, JAK inhibitor treatment failure, S1P receptor modulator treatment failure, or TYK2 inhibitor treatment failure. The method of claim 22, comprising: a. administering three induction doses of migidizumab to the patient by intravenous infusion at 4-week intervals, wherein each induction dose is 300 mg of migidizumab; and b. administering a maintenance dose of migidizumab to the patient by subcutaneous injection at 4-week or 12-week intervals, wherein the first maintenance dose is administered 2 to 8 weeks after the last induction dose, and wherein each maintenance dose is 200 mg of migidizumab. The method of claim 30, wherein the first maintenance dose is administered 4 weeks after the last induction dose. The method of claim 30, wherein the maintenance dose is administered at 4 week intervals. The method of any one of claims 1 to 15, wherein the expression levels of the three or more gene transcripts are measured by a gene expression profiling method. The method of claim 33, wherein the method is a PCR-based method. The method of claim 33, wherein the method is an RNA sequencing method. The method of claim 33, wherein the method is based on in-situ hybridization technology. The method of claim 33, wherein the method is immunohistochemistry. The method of claim 33, wherein the method is a proteomic technique. The method of claim 33, 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. A method as in any one of claims 1 to 15, wherein the measurement of the expression levels of the three or more gene transcripts is performed using an analyzer unit, and wherein the comparison of the measured expression levels of the three or more gene transcripts with a reference value of a specific gene transcript is performed using a computing device. The method of any one of claims 1 to 15, wherein the patient sample is from a colon biopsy or a rectal biopsy. The method of claim 41, wherein the colon tissue biopsy is from a tissue selected from the group consisting of: terminal ileum, ascending colon, descending colon, and sigmoid colon. The method of claim 42, wherein the colon tissue biopsy is from a non-inflamed colon area. The method of claim 44, wherein the colon tissue biopsy is from an inflamed colon region. An anti-IL23p19 antibody for 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient having three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 whose expression levels are differentially regulated compared to a reference value of the specific gene transcripts. An anti-IL23p19 antibody for treating enterotensive urgency in patients 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating intestinal urgency in patients with moderate to severe ulcerative colitis, wherein the patient has the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 differentially regulated compared to a reference value of the specific gene transcripts. An anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, the patient having no response, inadequate response, loss of response, or intolerance 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, the patient having no response, insufficient response, loss of response or intolerance to at least one previous 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 compared to a reference value of the specific gene transcript. An anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof who has no response, inadequate response or loss of 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof who has no response, inadequate response or loss of 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof who has no response, inadequate response or loss of response to anti-α4β7 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof who has no response, inadequate response or loss of response to anti-α4β7 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 compared to a reference value for the specific gene transcripts. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating frequent stools in patients 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 compared to a reference value of the specific gene transcript. An anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein if the patient has the expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 that are differentially regulated compared to a reference value for the specific gene transcript, then 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 of the patient's ulcerative colitis disease activity. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein if the patient has the expression of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 differentially regulated compared to a reference value of a specific gene transcript, the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 is a prognosis of the disease activity of ulcerative colitis in the patient. An anti-IL23p19 antibody for treating moderate to severe ulcerative colitis in a patient in need thereof, 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 compared to a reference value for a specific gene transcript, then the expression levels of at least three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 compared to a reference value for a specific gene transcript can predict the suitability of treatment with the anti-IL23p19 antibody. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, 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 compared to a reference value of a specific gene transcript, then the expression levels of at least three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 compared to a reference value of a specific gene transcript can predict the suitability of treatment with the anti-IL23p19 antibody. An anti-IL23p19 antibody for 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 compared to a reference value of a specific gene transcript, wherein the anti-IL23p19 antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2. An anti-IL23p19 antibody for use in the manufacture of a medicament for treating moderate to severe ulcerative colitis in a patient in need thereof, wherein the patient has three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 whose expression levels are differentially regulated compared to a reference value of a specific gene transcript, wherein the anti-IL23p19 antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2. An anti-IL23p19 antibody for 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 compared to a reference value for the specific gene transcript, Wherein if the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of the specific gene transcript, the patient continues to be treated with the anti-IL23p19 antibody at about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody. An anti-IL23p19 antibody for use in the manufacture of a medicament for 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 compared to a reference value of a specific gene transcript, Wherein if the expression of the three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A, DEFB4B, MMP3 and CXCL1 in the patient sample is differentially regulated compared to a reference value of the specific gene transcript, the patient continues to be treated with the anti-IL23p19 antibody at about 12 weeks to about 40 weeks after the first dose of the anti-IL-23p19 antibody. The use of any one of claims 60 to 78, wherein the patient has expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2, IL23A and DEFB4B that are differentially regulated compared to a reference value of the specific gene transcripts. The use of any one of claims 60 to 78, wherein the patient has expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC, SLC26A2, OTOP2 and IL23A that are differentially regulated compared to a reference value of the specific gene transcript. The use of any one of claims 60 to 78, wherein the patient has expression levels of three or more gene transcripts selected from ABI1, HNF4A, IL1B, PTPRC and SLC26A2 that are differentially regulated compared to a reference value of the specific gene transcripts. The use of any one of claims 60 to 78, wherein the patient has expression levels of gene transcripts ABI1, HNF4A and IL1B that are differentially regulated compared to reference values of specific gene transcripts. 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, compared to a reference value of a specific gene transcript. 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, compared to reference values of specific gene transcripts. 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 a decreased expression level of one or more gene transcripts selected from HNF4A, SLC26A2 and OTOP2, compared to a reference value of a specific gene transcript, wherein the anti-IL23p19 antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 1 and a variable light chain having an amino acid sequence of SEQ ID NO: 2. The use of any one of claims 60 to 85, wherein the patient has increased expression of one or more gene transcripts selected from Abl, IL1B, PTPRC, IL23A and DEFB4B, and decreased expression of one or more gene transcripts selected from HNF4A, SLC26A2 and OTOP2, compared to a reference value of a specific gene transcript. The use of any one of claims 60 to 85, wherein the patient has increased expression of one or more gene transcripts selected from AbI1, IL1B, PTPRC and IL23A, and decreased expression of one or more gene transcripts selected from HNF4A, SLC26A2 and OTOP2, compared to a reference value of specific gene transcripts. The use of any one of claims 60 to 85, wherein the patient has increased 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, compared to reference values of specific gene transcripts. The use of any one of claims 60 to 85, wherein the patient has an increased expression level of one or more gene transcripts selected from ABI1 and IL1B, and a decreased expression level of the gene transcript HNF4, compared to a reference value of a specific gene transcript. 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 described in claims 60 to 81 or 83 to 88. 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 described in claims 60 to 81 or 83 to 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 recited in claims 60 to 80 or 83 to 87. 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 recited in claims 60 to 80 or 83 to 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 recited in claims 60 to 79 or 83 to 86. The use of any one of claims 60 to 77 or 83 to 85, wherein the patient has the expression levels of at least nine of the gene transcripts as recited in claims 60 to 77 or 83 to 85 being differentially regulated. The use of any one of claims 60 to 77 or 83 to 85, wherein the patient has the expression levels of ten of the gene transcripts described in claims 60 to 77 or 83 to 85 being differentially regulated. 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, symptom relief, improvement of endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement of intestinal urgency, relief of bowel frequency, improvement of bowel frequency, and improvement of fatigue. The use of claim 97, wherein the therapeutic effect is achieved within about 2 weeks, 4 weeks, 8 weeks or 12 weeks of treatment with the anti-IL23p19 antibody. The use of any one of claims 97 to 98, wherein the patient exhibits a sustained therapeutic effect of at least one or more of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement of endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement of intestinal urgency, relief of bowel frequency, improvement of bowel frequency, improvement of fatigue, lasting for at least about 12 weeks to about 104 weeks. The use of claim 99, wherein the therapeutic effect lasts for about 24 weeks, 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 of the anti-IL23p19 antibody treatment. The use of any one of claims 60 to 96, wherein the expression level of the gene transcripts is a prognosis of at least one of the following: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement of endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement of intestinal urgency, relief of bowel frequency, improvement of bowel frequency, and improvement of fatigue. The use of any one of claims 60 to 96, wherein the expression level of the gene transcripts can predict at least one of the following for treatment with the anti-IL23p19 antibody: clinical response, clinical remission, endoscopic remission, endoscopic cure, symptom relief, improvement of endoscopic histological inflammation, corticosteroid-free remission, relief of intestinal urgency, improvement of intestinal urgency, relief of bowel frequency, improvement of bowel frequency, and improvement of fatigue. The use of any one of claims 60 to 102, wherein the anti-IL23p19 antibody is migizizumab. The use of any one of claims 60 to 74, 77 to 84 or 86 to 102, wherein the anti-IL23p19 antibody is guselkumab, tirazumab, risakizumab or brezumab. The use of any one of claims 60 to 96, wherein the patient is biologic treatment-naive. The use of any one of claims 60 to 96, wherein the patient has failed treatment with a biologic agent. The use of any one of claims 60 to 96, wherein the patient is a known treatment failure. The use of any one of claims 60 to 96, wherein the patient has failed treatment with a biologic and is accustomed to treatment failure. The use of any one of claims 105 to 106, wherein the patient is resistant to TNF therapy. The use of any one of claims 105 to 106, wherein the patient has failed anti-TNF therapy, anti-α4β7 therapy, JAK inhibitor therapy, S1P receptor modulator therapy, or TYK2 inhibitor therapy. The use of any of claim 103, comprising: a. administering three induction doses of migidizumab to the patient by intravenous infusion at 4-week intervals, wherein each induction dose is 300 mg of migidizumab; and b. administering a maintenance dose of migidizumab to the patient by subcutaneous injection at 4-week or 12-week intervals, wherein the first maintenance dose is administered 2 to 8 weeks after the last induction dose, and wherein each maintenance dose is 200 mg of migidizumab. The use of claim 111, wherein the first maintenance dose is administered 4 weeks after the last induction dose. The use of any one of claims 111 to 112, wherein the maintenance dose is administered at 4-week intervals. The use of any one of claims 111 to 113, wherein the maintenance dose is 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 104 weeks. The use of any one of claims 60 to 96, wherein the expression level of the one or more gene transcripts is measured by a gene expression profiling method. The use of claim 115, wherein the method is a PCR-based method. The use of claim 115, wherein the method is an RNA sequencing method. The use as in claim 115, wherein the method is based on in-situ hybridization technology. The use as in claim 115, wherein the method is immunohistochemistry. The use of claim 115, wherein the method is proteomic technology. The use of claim 115, wherein the expression level of the one or more gene transcripts is normalized relative to the expression level of one or more reference genes or their expression products. The use of any one of claims 60 to 96, wherein the expression level of the one or more gene transcripts is measured using an analyzer unit, and wherein the measured expression level of the one or more gene transcripts is compared with a reference value of a specific gene transcript using a computing device. The use of any one of claims 60 to 96, wherein the patient sample is from a colon tissue biopsy or a rectal tissue biopsy. The use of claim 123, wherein the colon tissue biopsy is from a tissue selected from the group consisting of: terminal ileum, ascending colon, descending colon and sigmoid colon. The use of claim 124, wherein the colon tissue biopsy is from a non-inflamed colon area. The use of claim 124, wherein the colon tissue biopsy is from an inflamed colon area.