WO2025083549A1

WO2025083549A1 - Methods and combinations of inhibitors of il-23 pathway and modulators of s1p signaling pathway for the treatment of autoimmune disorders

Info

Publication number: WO2025083549A1
Application number: PCT/IB2024/060098
Authority: WO
Inventors: Gajanan CHIDREWAR; Sanjay MANDHANE; Vikram Krishna Ramanathan
Original assignee: Sun Pharmaceutical Industries Ltd; Sun Pharma Advanced Research Co Ltd
Current assignee: Sun Pharmaceutical Industries Ltd; Sun Pharma Advanced Research Co Ltd
Priority date: 2023-10-16
Filing date: 2024-10-15
Publication date: 2025-04-24
Anticipated expiration: 2026-04-16

Abstract

The disclosure relates to methods of treating autoimmune disorders or reducing or suppressing the symptoms of a chronic inflammatory disorder of the digestive tract using an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1- phosphate signaling pathway. The disclosure also relates to pharmaceutical compositions comprising an inhibitor of the interleukin-23 pathway and a modulator of the sphingosine-1- phosphate signaling pathway. The disclosure further relates to combinations of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of autoimmune disorders. The disclosure further relates to pharmaceutical kits comprising an inhibitor of the interleukin-23 signaling pathway, a modulator of the sphingosine-1-phosphate signaling pathway, and instructions for use. The disclosure further relates to the use of a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for the manufacture of a medicament for treating an autoimmune disorder.

Description

METHODS AND COMBINATIONS OF INHIBITORS OF IL-23 PATHWAY AND MODULATORS OF S1P SIGNALING PATHWAY FOR THE TREATMENT OF AUTOIMMUNE DISORDERS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of Indian Patent Application No.202321070225, filed on October 16, 2023, which is incorporated by reference herein in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The instant application contains a Sequence Listing that has been submitted electronically and is hereby incorporated by reference in its entirety. The Sequence Listing was created on October 14, 2024, is named "23-1618-WO_Sequence-Listing.xml" and is 8547 bytes in size. FIELD OF THE DISCLOSURE [0003] The disclosure relates to methods of treating autoimmune disorders or reducing or suppressing the symptoms of a chronic inflammatory disorder of the digestive tract using an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1- phosphate signaling pathway. The disclosure also relates to pharmaceutical compositions comprising an inhibitor of the interleukin-23 pathway and a modulator of the sphingosine-1- phosphate signaling pathway. The disclosure further relates to combinations of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of autoimmune disorders. The disclosure further relates to pharmaceutical kits comprising an inhibitor of the interleukin-23 signaling pathway, a modulator of the sphingosine-1-phosphate signaling pathway, and instructions for use. The disclosure further relates to the use of a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for the manufacture of a medicament for treating an autoimmune disorder. BACKGROUND [0004] Interleukin-23 (IL-23) is a central pro-inflammatory cytokine with a wide range of influence over immune response. It is implicated in several autoimmune diseases. This has made IL-23 a key target of therapy for autoimmune disorders, such as, for example, psoriasis, rheumatoid arthritis, and chronic and inflammatory bowel diseases. Current autoimmune 1 treatments target IL-23 either by preventing IL-23 interaction with its receptor (IL-23R) via antibodies or by intervening in the IL-23 signaling pathway. [0005] Inflammatory bowel diseases (IBD), exemplified by Crohn's disease and ulcerative colitis), are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature, and is associated with various complications including stenoses, abscesses, fistulas, extra-intestinal manifestations, and colitis-associated neoplasia and cancer. Thus, effective therapeutic approaches are of high clinical relevance in patients with IBD. [0006] IL-12 (comprising p35 and p40 subunits) and IL-23 (comprising p19 and p40 subunits) are heterodimeric, pro-inflammatory cytokines that are induced in the inflamed mucosa of patients with Crohn's disease. Consistent with the Type 1 T helper cell (Th1)- inducing potential of IL-12, Crohn's disease was found to be associated with mucosal Th1 responses. Moreover, Type 17 T helper cell (Th17) responses were noted in patients with Crohn's disease as well as ulcerative colitis, possibly owing to the presence of IL-23 as a well-known activator of Th17 T cells. These data provided a rational basis for targeting the Th1 and Th17 cytokines in IBD. Functional studies with genetically engineered animals and IL-23 (comprising p19 and p40 subunits) blockers suggest that blockade of these cytokine subunits might effectively suppress intestinal inflammation in mouse models of colitis. In particular, IL-23 inhibition is effective and prevents activation of T cells and innate lymphoid cells and in vivo tissue destruction (Neurath, Nat. Rev. Gastroenterol. Hepatol.14(5): 269-78 (2017)). [0007] Subsequently, various antibodies against the IL-12/IL-23 p40 and IL-23 p19 subunits were developed. For example, ustekinumab has been approved for Crohn's disease, plaque psoriasis, psoriatic arthritis, and ulcerative colitis; guselkumab for plaque psoriasis, erythrodermic psoriasis, pustular psoriasis, palmoplantar pustulosis, and psoriatic arthritis; and tildrakizumab for plaque psoriasis. Guselkumab is currently in clinical development for Crohn's disease (Phase 3), and ulcerative colitis (Phase 2/3); mirikizumab for Crohn's disease, plaque psoriasis, and ulcerative colitis (Phase 3); risankizumab for Crohn's disease and ulcerative colitis (phase 3); and brazikumab for Crohn's disease (phase 3) and ulcerative colitis (phase 2). Thus, IL-23 plays a prominent role in chronic inflammatory diseases. [0008] Sphingosine 1-phosphate (S1P) is a potent extracellular lysolipid phosphoric acid mediator that is released after IgE-stimulation of mast cells. S1P is stored and released from platelets upon their activation, but can also be synthesized in a wide variety of cell types in response to extracellular stimuli like growth factors and cytokines. S1P modulates many cell 2 functions such as lymphocyte trafficking and signaling as well as keratinocyte proliferation. Cytokines of the IL-12 family play a dominant role in many inflammatory diseases as they have a significant impact on T-helper cell function. S1P has been shown to decrease the production of the pro-inflammatory cytokines IL-12 and IL-23 in LPS-stimulated dendritic cells (DCs) via the common subunit p40 as well as in the crosstalk with activated keratinocytes. S1P is also known to enhance the production of IL-27 in DCs (Schaper et al., Mol. Immunol.59(1): 10-18 ((2014)). [0009] Fingolimod (FTY720, a non-selective S1P receptor agonist) and VPC01091 (selective agonist) significantly reduced vascular permeability, and expression of pro- inflammatory cytokines, for example IL-12/IL-23 p40 (Stone et al., Am. J. Physiol. Lung Cell. Mol. Physiol.308(12): L1245-52 (2015)). It is also reported that S1P inhibits the secretion of tumor necrosis factor α and interleukin-12 (IL-12), whereas it enhances secretion of IL-10. As a consequence, mature DCs exposed to S1P show a reduced and increased capacity to generate allogeneic Th1 and Th2 responses, respectively (Idzco et al., FASEB J. 16(6): 625-27 (2002)). [0010] The advent of monoclonal antibodies such IL-23 pathway inhibitors has revolutionized IBD management. Nevertheless, these agents with their potential for immunogenicity are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs (Peyrin-Biroulet et al., Autoimmun. Rev. 16(5): 495-503 (2017)). Thus, there is a need in the art to provide an alternative therapy using an inhibitor of the IL-23 pathway. [0011] As discussed hereinbefore, inhibitors of the IL-23 pathway exhibit activity against IBD such as Crohn's disease and ulcerative colitis even when used alone. However, improved treatments are still required, and the present disclosure resides in the recognition that using such inhibitors in combination with other therapeutic agents such as a modulator of the S1P signaling pathway provides an increased beneficial effect. Such a combination therapy circumvents the problems associated with the use of an inhibitor of the IL-23 pathway alone. For example, addition of a modulator of the S1P signaling pathway will reduce the dose needed for the inhibitor of the IL-23 pathway while attaining the same or enhanced therapeutic effect. [0012] Furthermore, in the treatment of IBD, specific patients do not respond to therapies based on either an inhibitor of the IL-23 pathway or a modulator of the SIP signaling pathway alone. 3 [0013] Additionally, the currently available therapies are unable to completely suppress the disease, and are characterized by residual disease effects (e.g., gland loss, hyperplasia, etc.). Further reduction of disease effects in such areas can be difficult to achieve, but are still desirable therapeutically. The methods, combinations, compositions, uses, and kits of the disclosure successfully demonstrate further reduction or elimination of the residual disease. [0014] The present inventors have conducted intensive studies in order to solve the above- mentioned problems, and disclose herein that a combination of an IL-23 pathway inhibitor and a S1P signaling pathway modulator shows an excellent combination effect. SUMMARY [0015] As a result of intensive studies, the present inventors have found that a combination of an inhibitor of the interleukin-23 pathway and one or more therapeutic agents such as a modulator of the sphingosine-1-phosphate signaling pathway shows an excellent combination effect, and hence provides an alternative therapy that can mitigate disease burden, improve remission rates, and modify progression in immune disorders such as IBD. [0016] The methods, combinations, compositions, uses, and kits of the disclosure are particularly effective at reducing or eliminating residual disease effects (e.g., gland loss, hyperplasia), endoscopic remission, mucosal healing, and reduction in rates of colectomy, which remain poorly treated with administration of a single active ingredient. In particular, the methods, combinations, compositions, uses, and kits of the disclosure are particularly effective at treating disease within the distal colon. [0017] In one aspect, the disclosure provides a method of treating an autoimmune disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an inhibitor of the interleukin-23 signaling pathway and a therapeutically effective amount of a modulator of the sphingosine-1-phosphate signaling pathway. [0018] In another aspect, the disclosure provides a pharmaceutical composition comprising an inhibitor of the interleukin-23 pathway and a modulator of the sphingosine-1-phosphate signaling pathway. [0019] In another aspect, the disclosure provides a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of an autoimmune disorder. [0020] In another aspect, the disclosure provides a method of reducing or suppressing the symptoms of a chronic inflammatory disorder of the digestive tract in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an 4 inhibitor of the interleukin-23 signaling pathway and a therapeutically effective amount of a modulator of the sphingosine-1-phosphate signaling pathway. [0021] In another aspect, the disclosure provides a pharmaceutical kit comprising (i) an inhibitor of the interleukin-23 signaling pathway; (ii) a modulator of the sphingosine-1- phosphate signaling pathway; and (iii) instructions for the administration to a patient of therapeutically effective amounts of the inhibitor of interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway in accordance with the severity of an autoimmune disorder in the patient. [0022] In another aspect, the disclosure provides use of a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for the manufacture of a medicament for treating an autoimmune disorder. [0023] The aforementioned aspects and embodiments, and other aspects, objects, features, and advantages of the methods, combinations, compositions, uses, and kits of the disclosure and/or the claimed invention will be apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS [0024] FIG.1 is a bar graph showing Colon Weight Inhibition (compared to vehicle control) for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0025] FIG.2 is a bar graph showing the Ratio:Colon Weight per Length (g/cm) for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0026] FIG.3 is a bar graph showing Disease Activity Index (Day 42) for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 K-W test (Dunn’s post-hoc)/Mann-Whitney U test vs. Vehicle (DI Water); †p< 0.05 K-W test (Dunn’s post-hoc) vs. Vehicle + Isotype (49.4 mg/kg). [0027] FIG.4 is a bar graph showing Summed Score for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 K-W test (Dunn’s post-hoc)/Mann-Whitney U test vs. Vehicle (DI Water); †p< 0.05 K-W test (Dunn’s post-hoc) vs. Vehicle + Isotype (49.4 mg/kg). 5 [0028] FIG.5 is a bar graph showing Edema for the compound of Formula I and an anti-IL- 23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0029] FIG.6 is a bar graph showing Neutrophil Score for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 K-W test (Dunn’s post-hoc)/Mann-Whitney U test vs. Vehicle (DI Water); †p< 0.05 K-W test (Dunn’s post-hoc) vs. Vehicle + Isotype (49.4 mg/kg). [0030] FIG.7 is a bar graph showing Mucosal Thickness for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0031] FIG.8A is a bar graph showing IL-1B Protein Normalized Mid Colon Cytokine Levels for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0032] FIG.8B is a bar graph showing IL-6 Protein Normalized Mid Colon Cytokine Levels for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0033] FIG.8C is a bar graph showing TNF-a Protein Normalized Mid Colon Cytokine Levels for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0034] FIG.8D is a bar graph showing IFN-g Protein Normalized Mid Colon Cytokine Levels for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0035] FIG.8E is a bar graph showing IL-17a Protein Normalized Mid Colon Cytokine Levels for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. N=15/group; *p< 0.05 ANOVA (Tukey’s post-hoc)/Student’s t-test vs. 6 Vehicle (DI Water); †p< 0.05 ANOVA (Tukey's/Dunnett’s) vs. Vehicle + Isotype (49.4 mg/kg). [0036] FIG.9 is a bar graph showing MCD4-SUN-1 Mouse Colons CD3-Positive Immunolabeled Cells for the compound of Formula I and an anti-IL-23 antibody administered separately and in combination. DETAILED DESCRIPTION [0037] The disclosure relates to methods of treating autoimmune disorders or reducing or suppressing the symptoms of a chronic inflammatory disorder of the digestive tract using an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1- phosphate signaling pathway. The disclosure also relates to pharmaceutical compositions comprising an inhibitor of the interleukin-23 pathway and a modulator of the sphingosine-1- phosphate signaling pathway. The disclosure further relates to combinations of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of autoimmune disorders. The disclosure further relates to pharmaceutical kits comprising an inhibitor of the interleukin-23 signaling pathway, a modulator of the sphingosine-1-phosphate signaling pathway, and instructions for use. The disclosure further relates to the use of a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for the manufacture of a medicament for treating an autoimmune disorder. [0038] As used herein, the following definitions apply unless clearly indicated otherwise. It should be understood that unless expressly stated to the contrary, the singular forms "a" "an" and "the" include the plural reference unless the context clearly dictates otherwise. [0039] The methods, combinations, compositions, uses, and kits of the disclosure are based on the surprising finding that a combination of an inhibitor of the IL-23 pathway and a modulator of the sphingosine-1-phosphate (S1P) signaling pathway results in an unexpected combination effect for the prevention and/or treatment of an autoimmune disorder or disease. Further, the combination therapy according to the disclosure also demonstrates a synergistic therapeutic effect. [0040] Accordingly, in the first aspect of the disclosure is a pharmaceutical composition characterized in that an inhibitor of the IL-23 pathway and a modulator of the sphingosine-1- phosphate signaling pathway are administered in combination. [0041] The terms "combination therapy" or "combined treatment" or "in combination," as used herein, denote any form of concurrent or parallel treatment with the at least two distinct 7 therapeutic agents. The two therapeutic agents can be administered sequentially or simultaneously. When the therapeutic agents are administered simultaneously, they can be in the same or separate pharmaceutical formulations. [0042] The terms "inhibitor of the IL-23 pathway" or "inhibitor of the IL-23 signaling pathway," as used herein, refer to an IL-23 inhibitor and/or an IL-23 receptor inhibitor and/or an IL-17 inhibitor and/or an IL-17 receptor inhibitor. Optionally, the "inhibitor of the IL-23 signaling pathway" can be an IL-23 inhibitor and/or an IL-23 receptor inhibitor. Optionally, the "inhibitor of the IL-23 pathway" or "inhibitor of the IL-23 signaling pathway" can be an IL-23 inhibitor. [0043] IL-17 is produced by a group of T helper cells known as T helper 17 cells in response to their stimulation with IL-23. The IL-17 inhibitor can be an inhibitor of IL-17A or an inhibitor of IL-17F. The IL-17 receptor inhibitor can be an inhibitor of IL-17RA or an inhibitor of IL-17RC. [0044] The term "IL-23 inhibitor," as used herein, refers to an agent that inhibits or reduces IL-23 activity. The agent may, for example, bind IL-23 thereby inhibiting IL-23 activity. Alternatively, the agent may act to decrease levels of IL-23 mRNA or IL-23 protein. Examples of IL-23 inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small molecules, and nucleic acids (e.g., mRNA, DNA, siRNA, shRNA, antisense RNA, miRNA). An IL-23 inhibitor can act on either of the subunits of IL-23 (i.e., p19 or p40), or alternatively can act on both subunits, e.g., overlapping or combinatorial epitope. Thus, in some embodiments, an IL-23 inhibitor binds to p19 (e.g., anti-p19 antibody) and inhibits or reduces IL-23 activity. In other embodiments, an IL-23 inhibitor binds to p40 (e.g., anti-p40 antibody) and inhibits or reduces IL-23 activity. Where the terms "p19" and "p40" are used herein, they refer to the respective subunits that make up human IL- 23. [0045] The term "IL-23 receptor inhibitor," as used herein, refers to an agent that inhibits or reduces IL-23 activity through binding to the receptor for IL-23, in particular to the membrane-bound receptor for IL-23. The agent may, for example, bind IL-23R preventing the binding of IL-23 itself, thereby inhibiting IL-23 activity. The IL-23 receptor is formed from two subunits, IL-12Rβ1 (which binds to the p40 subunit of IL-23) and IL-23R (which binds to the p19 subunit of IL-23). Adnectin-2 binds to the IL-23R subunit of the IL-23 receptor, thereby competing with IL-23. Alternatively, the agent may act to decrease levels of IL-23 receptor mRNA or IL-23 receptor protein. Examples of IL-23 receptor inhibitors include, but are not limited to, antibodies or antigen-binding fragments thereof, small 8 molecules, and nucleic acids (e.g., mRNA, DNA, siRNA, shRNA, antisense RNA, miRNA). An IL-23 receptor inhibitor can act on either of the subunits of the IL-23 receptor (i.e., IL- 12Rβ1 or IL-23R), or alternatively can act on both subunits, e.g., overlapping or combinatorial epitope. Thus, in some embodiments, an IL-23 receptor inhibitor binds to IL- 12Rβ1 (e.g., anti-IL-12Rβ1 antibody) and thereby inhibits or reduces IL-23 activity. In other embodiments, an IL-23 receptor inhibitor binds to IL-23R (e.g., anti-IL-23R antibody) and thereby inhibits or reduces IL-23 activity. [0046] The terms "compound of Formula I" or "Formula I," as used herein, refer to a compound with following structure: , and

3-yl]benzyl}-4- (2-methoxyethoxymethyl)piperidine-4-carboxylic acid. The methods, combinations, compositions, uses, and kits of the disclosure intend to cover salts and stereoisomers of the compound of Formula I. [0047] In some embodiments, the term "inhibitor of the IL-23 signaling pathway" encompasses an agent that binds to or inhibits the function of any one or more of p19 (e.g., anti-p19 antibody), p40 (e.g., anti-p40 antibody), or IL-23R (anti-IL-23R antibody), or in general anti-IL-23-specific antibody, which are herein collectively termed "anti-IL-23 antibody." The term "anti-IL-23 antibody" further refers to at least one portion of an IL-23 receptor or binding protein, which can be incorporated into an antibody. The reference herein to an "antibody" includes any protein or peptide-containing molecule that comprises at least a portion of an immunoglobulin molecule, such as but not limited to, at least one complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof. As noted above, the anti-IL-23 antibodies of interest for the methods, combinations, compositions, uses, and kits of the disclosure are able to bind specifically to at least a portion of the IL-23 protein or IL-23 receptor. Such anti-IL-23 antibodies optionally specifically bind to a designated ligand, where such antibodies modulate, decrease, increase, antagonize, agonize, mitigate, alleviate, 9 block, inhibit, abrogate, and/or interfere with at least one IL-23 activity or binding, or with at least one IL-23 receptor activity or binding, in vitro, in situ, and/or in vivo. As a non-limiting example, a suitable anti-IL-23 antibody, specified portion, or variant can bind to at least one IL-23 molecule (domain), or specified portions, variants, or domains thereof or can bind to at least one IL-23 receptor (domain), or specified portions, variants, or domains thereof. A suitable anti-IL-23 antibody, specified portion, or variant can also optionally affect at least one of IL-23 activity or function, such as but not limited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL- 23 production and/or synthesis, or IL-23 receptor production and/or synthesis. [0048] In various embodiments, the IL-23 inhibitor comprises a pharmaceutical composition of an anti-p19 antibody, an anti-p40 antibody or an antigen binding fragment thereof. In some embodiments, the anti-IL-p19 antibody and/or anti-p40 antibody comprises a human antibody or a humanized antibody. [0049] In various embodiments, the IL-23 receptor inhibitor comprises a pharmaceutical composition of an anti-IL-12Rβ1 antibody, an anti-IL23R antibody, or an antigen binding fragment thereof. In some embodiments, the anti-IL-12Rβ1 antibody and/or anti-IL-23R antibody comprises a human antibody or a humanized antibody. [0050] In various embodiments, the antibodies and fragments thereof that bind to IL-23p19 are an antibody or fragment thereof disclosed in U.S. Patent Nos.8,404,813 and 8,293,883, the disclosures of which are incorporated by reference herein in their entireties, including the sequences disclosed therein. In particular embodiments, the IL-23 inhibitor is the anti-IL- 23p19 antibody hum13B8-b (tildrakizumab) disclosed in U.S. Patent Nos.8,404,813 and 8,293,883 comprising a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-23 inhibitor of U.S. Patent Nos.8,404,813 and 8,293,883 comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises CDR1, CDR2, and CDR3 sequences of the amino acid sequences of SEQ ID NOs: 3-5, and wherein the light chain variable domain comprises CDR1, CDR2, and CDR3 sequences of the amino acid sequences of SEQ ID NOs: 6-8. [0051] In some embodiments, the IL-23 inhibitor comprises the tildrakizumab antibody (also referred to as MK-3222, SCH-900222, SUNPG 1622, SUNPG 1622 I, SUNPG 1623 I, SUNPG 1623 II, SUNPG 1623 III, SUNPG 1623 IV, or SUNPG1623) (marketed by Sun Pharmaceutical Industries, Inc. as ILUMYA) or an antigen binding fragment thereof as disclosed in U.S. Patent Nos.8,404,813 and 8,293,883. Tildrakizumab is a humanized 10 IgG1/k antibody that specifically binds to the p19 subunit of interleukin-23 (IL-23). It is produced in a recombinant Chinese hamster ovary (CHO) cell line and has an approximate molecular mass of 147 kilodaltons. It is indicated for the treatment of moderate-to-severe plaque psoriasis. It is at pre-registration stage for psoriatic arthritis, and in clinical development for ankylosing spondylitis, intervertebral disc degeneration, non-radiographic axial spondyloarthritis (Phase 2/3), and prostate cancer (Phase 1/2). [0052] Hum13B8-b Light Chain (SEQ ID NO: 1) DIQMTQSPSSLSASVGDRVTITCRTSENIYSYLAWYQQKPGKAPKLLIYNAKTLAEGVPSRF SGSGSGTDFTLTISSLQPEDFATYYCQHHYGIPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC [0053] Hum13B8-b Heavy Chain (SEQ ID NO: 2) QVQLVQSGAEVKKPGASVKVSCKASGYIFITYWMTWVRQAPGQGLEWMGQIFPASGSADYNE KFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGGGFAYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK [0054] Hum13B8-b Heavy Chain CDR1 (SEQ ID NO: 3) GYIFITYWMT [0055] Hum13B8-b Heavy Chain CDR2 (SEQ ID NO: 4) QIFPASGSADYNEKFE [0056] Hum13B8-b Heavy Chain CDR3 (SEQ ID NO: 5) GGGGFAY [0057] Hum13B8-b Light Chain CDR1 (SEQ ID NO: 6) RTSENIYSYLA [0058] Hum13B8-b Light Chain CDR2 (SEQ ID NO: 7) NAKTLAE [0059] Hum13B8-b Light Chain CDR3 (SEQ ID NO: 8) QHHYGIPFT [0060] In some embodiments, the IL-23 inhibitor comprises the guselkumab antibody (also referred to as CNTO-1959) (marketed by Janssen Biotech, Inc., as TREMFYA) or an antigen 11 binding fragment thereof as disclosed in U.S. Patent No.7,993,645 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0061] Guselkumab, an IL-23p19 inhibitor, is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. Guselkumab is produced in a mammalian cell line using recombinant DNA technology. It is approved for the treatment of adults with moderate-to-severe plaque psoriasis. Guselkumab is under development for Crohn's disease (Phase 3), ulcerative colitis (Phase 2/3), giant cell arteritis, hidradenitis suppurativa, lupus nephritis (Phase 2), and familial adenomatous polyposis (Phase 1). [0062] In some embodiments, the IL-23 inhibitor comprises the risankizumab antibody (also referred to as ABBV066 and BI-655066) (marketed by AbbVie as SKYRIZI) or an antigen binding fragment thereof as disclosed in U.S. Patent No.8,778,346 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0063] Risankizumab, an IL-23p19 inhibitor, is a humanized immunoglobulin G1 (IgG1) monoclonal antibody. It is produced in a mammalian cell line using recombinant DNA technology. SKYRIZI is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Orphan Drug Status has been granted for Crohn's disease. It is approved for plaque psoriasis, and registered erythrodermic psoriasis, psoriatic arthritis, and pustular psoriasis. Risankizumab is under development for Crohn's disease, palmoplantar pustulosis, ulcerative colitis (Phase 3), atopic dermatitis, and hidradenitis suppurativa (Phase 2). [0064] In some embodiments, the IL-23 inhibitor comprises the brazikumab antibody (also referred to as AMG-139; MEDI-2070) (discovered by Amgen) or an antigen binding fragment thereof as disclosed in U.S. Patent No.8,722,033 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0065] Brazikumab is a monoclonal antibody that specifically binds to the p19 subunit of interleukin-23 (IL-23). Brazikumab selectively blocks the IL-23 immune signal, preventing intestinal inflammation. It is currently in development for Crohn's disease (Phase 3) and ulcerative colitis (Phase 2). In Phase II trials, it demonstrated a clinical effect at week eight in tumour necrosis factor-resistant Crohn's disease patients. [0066] In some embodiments, the IL-23 inhibitor comprises the mirikizumab antibody (also referred to as LY-3074828) (discovered by Eli Lilly and Company) or an antigen binding fragment thereof as disclosed in U.S. Patent No.9,023,358 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. 12 [0067] Mirikizumab is a monoclonal antibody that specifically binds to the p19 subunit of interleukin-23 (IL-23). Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 subunit of interleukin-23. Mirikizumab is being studied for the treatment of immune diseases, including psoriasis, ulcerative colitis, and Crohn's disease (phase 3). [0068] In some embodiments, the IL-23 inhibitor comprises the ustekinumab antibody (also referred to as CNTO-1275) (marketed by Janssen, a member of Johnson & Johnson) or an antigen binding fragment thereof as disclosed in U.S. Patent No.6,902,734 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0069] Ustekinumab is a human IgG1κ monoclonal antibody against the p19 subunit of the IL-23 cytokines. Using DNA recombinant technology, ustekinumab is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 daltons. It is approved for the treatment of moderate or severe psoriasis, psoriatic arthritis, moderately to severely active Crohn's disease, or moderately to severely active ulcerative colitis. [0070] In certain embodiments, the antibodies and fragment thereof that bind to IL-23p40 and IL-12p40 are intended. [0071] In certain embodiments, IL-23 inhibitor comprises the briakinumab antibody (also referred to as A-796874.0, ABT-874, BSF415977, J695, LU 415977, and WAY-165772) (discovered by Cambridge Antibody Technology and Abbott GmbH & Co. KG) or an antigen binding fragment thereof as disclosed in U.S. Patent No.8,178,092 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0072] Briakinumab is a human anti-IL-12/23 monoclonal antibody being developed for the treatment of a number of T-cell driven autoimmune diseases. It targets and neutralizes p40 subunit of IL-12 and IL-23, two proteins associated with inflammation, such as pro- inflammatory interleukins or tumour necrosis factor-alpha. Briakinumab represents a novel approach to treating psoriasis, multiple sclerosis, Crohn's disease, and other autoimmune and inflammatory disorders. [0073] In certain embodiments, the antibody binds with IL-17, which is produced by a group of T helper cell known as T helper 17 cells in response to their stimulation with IL-23. Recently, the FDA approved multiple highly effective psoriasis therapies such as secukinumab, ixekizumab, and brodalumab that disrupt IL-17. [0074] In certain embodiments, IL-17 inhibitor comprises the ixekizumab antibody (also referred to as LY-2439821) (marketed by Eli Lilly and Company as TALTZ) or an antigen 13 binding fragment thereof as disclosed in U.S. Patent No.7,838,638 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0075] Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) with neutralizing activity specifically against IL-17A. Ixekizumab is produced by recombinant DNA technology in a recombinant mammalian cell line and purified using standard technology for bioprocessing. It is comprised of two identical light chain polypeptides of 219 amino acids each and two identical heavy chain polypeptides of 445 amino acids each, and has a molecular weight of 146,158 Daltons for the protein backbone of the molecule. TALTZ is indicated for the treatment of moderate-to- severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. The antibody is currently in development for bullous pemphigoid, pityriasis rubra pilaris, and pyoderma gangrenosum (Phase 2). [0076] In certain embodiments, IL-17 inhibitor comprises the brodalumab antibody (also referred to as AMG-827, KHK-4827, LP0160) (marketed by Amgen as SILIQ) or an antigen binding fragment thereof disclosed in U.S. Patent No.7,767,206 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0077] Brodalumab is a human monoclonal IgG2κ antibody directed against human interleukin-17 receptor A (IL-17RA). It is expressed in a Chinese Hamster Ovary (CHO) cell line. Brodalumab is comprised of 1312 amino acids and has an estimated molecular mass of 144,000 Daltons. It is indicated for the treatment of moderate to severe plaque psoriasis. It is at pre-registration stage axial spondylarthritis, and in development for palmoplantar pustulosis and systemic scleroderma (Phase 3). [0078] In certain embodiments, IL-17 inhibitor comprises the bimekizumab antibody (also referred to as CDP-4940; UCB-4940) (discovered by UCB) or an antigen binding fragment thereof disclosed in U.S. Patent No.8,580,265 B2, which is incorporated herein by reference in its entirety, including the sequences thereof. [0079] Bimekizumab is a potent and selective monoclonal antibody inhibiting the activity of both IL-17A and IL-17F, which are key pro-inflammatory cytokines overexpressed in skin lesions of patients with psoriasis. Bimekizumab has been used in trials studying the treatment of psoriatic arthritis, ankylosing spondylitis, chronic plaque psoriasis, and mild to moderate psoriasis. It is at pre-registration stage plaque psoriasis, while under development for ankylosing spondylitis, axial spondylarthritis, hidradenitis suppurativa, psoriatic arthritis (Phase 3), and for ulcerative colitis (Phase 2). 14 [0080] In certain embodiments, the disclosure provides a pharmaceutical composition characterized in that an anti-p19 antibody and a modulator of the sphingosine-1-phosphate signaling pathway are administered in combination. The two therapeutic agents can be administered sequentially or simultaneously. When the therapeutic agents are administered simultaneously, they can be in the same or separate pharmaceutical formulations. [0081] In certain embodiments, the disclosure provides a pharmaceutical composition characterized in that anti-IL-12/23 antibody (for example an anti-p40 antibody) and a modulator of the sphingosine-1-phosphate signaling pathway are administered in combination. The two therapeutic agents can be administered sequentially or simultaneously. When the therapeutic agents are administered simultaneously, they can be in the same or separate pharmaceutical formulations. [0082] In certain embodiments, the disclosure provides a pharmaceutical composition characterized in that anti-IL-17A antibody and a modulator of the sphingosine-1-phosphate signaling pathway are administered in combination. The two therapeutic agents can be administered sequentially or simultaneously. When the therapeutic agents are administered simultaneously, they can be in the same or separate pharmaceutical formulations. [0083] In various embodiments, the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate receptor (S1P) agonist (herein a "sphingosine-1-phosphate agonist" or "S1P agonist"), wherein the term "S1P" refers to a bioactive sphingolipid metabolite that is intimately involved in mediating various immunological processes by its actions on S1P receptors. S1P receptor, originally termed as endothelial differentiation gene (EDG) receptor, is a family of five related G-protein coupled receptors, namely S1P1/EDG1, S1P2/EDG5, S1P₃/EDG₃, S1P₄/EDG₆, and S1P₅/EDG₈. These receptors have widespread cellular and tissue distribution and are well conserved in human and rodent species. The beneficial effects of S1P agonists are understood to be mediated via S1P₁; the other S1P receptor subtypes may contribute to off-target effects such as bradycardia, which is reported to be mediated via S1P₃ in rodents. [0084] In some embodiments, the term "modulator of the sphingosine-1-phosphate signaling pathway" refers to a sphingosine-1-phosphate agonist, which typically exerts its effect through binding to one or more subunits of the S1P receptor. In certain embodiments, the sphingosine-1-phosphate agonist is a selective S1P₁ agonist. In some embodiments, sphingosine-1-phosphate agonist is an S1P1/5 agonist having selectivity over S1P3 which is responsible for some side effects such as bradycardia. 15 [0085] In certain embodiments, selective S1P1 agonist is a compound of formula (disclosed in U.S. Patent No.9,266,867 B2; cited herein as reference in its entirety)

by one or more identical or different group(s) selected from the group consisting of halogen, alkyl, cycloalkyl, —Oalkyl, and phenyl; R1 represents —X—(Y)_n— where —X— is selected from the group consisting of -alkyl-, -alkenyl-, -alkynyl-, -aryl-, and -alkylaryl-, each Y, identical or different is selected from the group consisting of H, OH, halogen, —Oalkyl, —Oalkylaryl, —OalkylOalkyl, —Oaryl, heteroaryl, —Oaryl(Oalkyl), — Ocycloalkyl, -cycloalkyl, and heterocyclyl; n is 1 to 3; and where R1 is not —C(═O)OH; and R2 is H or alkyl; or one of its stereoisomers or salts thereof. [0086] In some embodiments, the sphingosine-1-phosphate agonist is selected from the group consisting of: 1-{4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- methylpiperidine-4-carboxylic acid, 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- methylpiperidine-4-carboxylic acid, 1-{4-[5-(3-chloro-4-cyclopentylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- methylpiperidine-4-carboxylic acid, 1-{4-[5-(2-Chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-methylpiperidine- 4-carboxylic acid, 1-{4-[5-(3-chloro-4-cyclopentylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- methoxymethylpiperidine-4-carboxylic acid, 16 1-{4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- methoxymethylpiperidine-4-carboxylic acid, 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- ethylpiperidine-4-carboxylic acid, 4-allyl-1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}piperidine- 4-carboxylic acid, 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- propylpiperidine-4-carboxylic acid, 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-(2- methoxyethoxymethyl)piperidine-4-carboxylic acid, 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- hydroxymethylpiperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutylphenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4- methoxymethylpiperidine-4-carboxylic acid, 4-Allyl-1-{4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}piperidine-4- carboxylic acid, 1-{4-[5-(2-Chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-propylpiperidine- 4-carboxylic acid, 1-{4-[5-(2-Chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(2- methoxyethoxymethyl)piperidine-4-carboxylic acid, 4-Benzyloxymethyl-1-{4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]- benzyl}piperidine-4-carboxylic acid, 4-Benzyloxymethyl-1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]- benzyl}piperidine-4-carboxylic acid, 1-{4-[5-(2-Chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4- hydroxymethylpiperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4- phenylpiperidine-4-carboxylic acid, 4-Benzyl-1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}- piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(4-fluoro- benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(2-fluoro- benzyl)-piperidine-4-carboxylic acid 17 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(4-methoxy- benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(2-methoxy- benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(2-chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4- methoxymethylpiperidine-4-carboxylic acid, 1-{4-[5-(2-Chlorobiphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-ethylpiperidine-4- carboxylic acid, 1-{4-[5-(4-Isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methyl-piperidine-4- carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(4-methoxy- butyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-(2- methoxyethoxymethyl)piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(2-phenoxy- ethyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(2,6- difluoro-benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-isobutyl- piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-isopropyl- piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(3-trifluoro methyl-benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-furan-2- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-pyridin-2- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-[2-(2- methoxy-phenoxy)-ethyl]-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-pyridin-3- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-pyridin-4- ylmethyl-piperidine-4-carboxylic acid, 18 1-{4-[5-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methyl- piperidine-4-carboxylic acid, 1-{4-[5-(4-tert-Butyl-3-chloro-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methyl- piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-propyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methyl- piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(2- methoxy-ethoxymethyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-ethyl- piperidine-4-carboxylic acid, 4-Allyl-1-{4-[5-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}- piperidine-4-carboxylic acid, 1-{4-[5-(2-Chloro-biphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-pyridin-2- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(2-Chloro-biphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(4-methoxy- benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(2-Chloro-biphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(4-fluoro- benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(4- methoxy-benzyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-ethyl- piperidine-4-carboxylic acid, 4-Benzyl-1-{4-[5-(2-chloro-biphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}- piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-cyclohexyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-pyridin-2- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4- methoxymethyl-piperidine-4-carboxylic acid, 1-{4-[5-(2-Chloro-biphenyl-4-yl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-pyridin-3- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(2-ethoxy- ethoxymethyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-isopropoxy methyl-piperidine-4-carboxylic acid, 19 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4- cyclopentyloxymethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-thiophen-2- ylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4- cyclopropylmethyl-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-(2- morpholin-4-yl-ethyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(3-piperidin- 1-yl-propyl)-piperidine-4-carboxylic acid, 1-{4-[5-(3-Chloro-4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(3-pyrrolidin- 1-yl-propyl)-piperidine-4-carboxylic acid, and their pharmaceutically acceptable salts thereof. [0087] In one embodiment, the selective S1P1 agonist is the compound of Formula I. [0088] In some embodiments, the S1P agonist comprises fingolimod (also referred to as FTY-720, TDI-132) (marketed by Novartis as Gilenya) and its analogs disclosed in U.S. Patent No.5,604,229 A. [0089] Fingolimod is a non-selective S1P1/3/4/5 agonist. It is chemically known as 2-amino-2- [2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride. [0090] In some embodiments, the S1P agonist comprises ozanimod (also referred to as RPC- 1063, RPC-1063-HCl) (marketed by Bristol-Myers Squibb as ZEPOSIA) and its analogs disclosed in U.S. Patent Nos.8,481,573 B2 and 8,796,318 B2. [0091] Ozanimod is a selective S1P₁ and S1P₅ dual modulator. It is chemically known as 5- (3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-1,2,4-oxadiazol-5-yl)- 2[(propan-2-yl)oxy]benzonitrile, monohydrochloride. [0092] In some embodiments, the S1P agonist comprises siponimod (also referred to as BAF- 312, NVPBAF312AEA, NVP-BAF312-NX) (marketed by Novartis as MAYZENT) and its analogs disclosed in U.S. Patent No.7,939,519 B2. [0093] A 2:1 co-crystal of siponimod and fumaric acid is chemically known as 1-[[4-[(1E)-1- [[[4-Cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]- 3azetidinecarboxylic acid (2E)-2-butenedioate (2:1), which is currently in development for stroke. 20 [0094] In some embodiments, the S1P agonist comprises ceralifimod (also referred to as ONO-4641) (discovered by Ono Pharma) and its analogs disclosed in International Publication No. WO 2006/064757 A1 and U.S. Patent No.7,906,549 B2. [0095] Ceralifimod is a, a selective S1P_1/5 agonist chemically known as 1-({6-[(2-Methoxy- 4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid. [0096] In some embodiments, the S1P agonist comprises laquinimod (also referred to as ABR-215062, TV-5600) (discovered by Active Biotech) and its analogs disclosed in International Publication No. WO 99/55678 A1 and U.S. Patent No.6,077,851 A. [0097] Laquinimod is a selective S1P₁ agonist. Laquinimod has been granted orphan drug status in the United States by the Food and Drug Administration (FDA). It is chemically known as 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide. [0098] In some embodiments, the S1P agonist comprises etrasimod (also referred to as APD- 334) (discovered by Arena Pharmaceuticals) and its analogs disclosed in International Publication No. WO 2010/011316 A1. [0099] Etrasimod is a selective S1P1/4/5 agonist which is chemically known as (R)-2-(7-((4- cyclo-pentyl-3- (trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydro-cyclopenta[b]indol-3- yl)acetic acid). [0100] In some embodiments, the S1P agonist comprises mocravimod (also referred to as KRP-203) (discovered by Kyorin Pharmaceutical) and its analogs disclosed in International Publication No. WO 2003/029205 A1 and U.S. Patent No.6,960,692 B2. [0101] Mocravimod is a selective S1P1 agonist and is chemically known as 2-amino-2-[2-[2- chloro-4-(3-phenylmethoxyphenyl)sulfanylphenyl]ethyl]propane-1,3-diol. [0102] In some embodiments, the S1P agonist comprises cenerimod (also referred to as ACT-334441) (discovered by Actelion Pharmaceuticals) and its analogs disclosed in International Publication No. WO 2011/007324. [0103] Cenerimod is a selective S1P₁ agonist and is chemically known as (2S)-3-[4-[5-(2- cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl]-2-ethyl-6- methylphenoxy]propane-1,2-diol. [0104] In some embodiments, the S1P agonist comprises ponesimod (also referred to as ACT-128800, R-3477, or RG 3477) (discovered by Actelion Pharmaceuticals) and its analogs disclosed in International Publication No. WO 2005/054215 A1. 21 [0105] Ponesimod is a selective S1P1 modulator and is chemically known as (5Z)-5-[[3- chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylidene]-3-(2-methylphenyl)-2- propylimino-1,3-thiazolidin-4-one. [0106] In some embodiments, the S1P agonist comprises amiselimod (also referred to as MT- 1303) (discovered by Mitsubishi Tanabe Pharma Corporation) and its analogs disclosed in International Publication No. WO 2007/069712 A1 and U.S. Patent No.8,809,304 B2. [0107] Amiselimod is a highly selective S1P1 modulator and is chemically known as 2- amino-2-[2-[4-heptoxy-3-(trifluoromethyl)phenyl]ethyl]propane-1,3-diol. [0108] In some embodiments, the S1P agonist comprises BMS-986104 (discovered by Bristol-Myers Squibb) and its analogs disclosed in International Publication No. WO 2014/130752 A2. [0109] BMS-986104 is a selective S1P₁ modulator and is chemically known as((1R,3S)-1- Amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopentyl)methanol. [0110] In some embodiments, the S1P agonist comprises CS-0777 (discovered by Daiichi Sankyo Company) and its analogs disclosed in International Publication No. WO 2005/005383 A1. [0111] CS-0777 is a selective S1P1 modulator and is chemically known as (R)-1-(5-(3- amino-4-hydroxy-3-methylbutyl)-1-methyl-1H-pyrrol-2-yl)-4-(p-tolyl)butan-1-one. [0112] In some embodiments, the S1P agonist comprises GSK2018682 (discovered by GlaxoSmithKline) and its analogs disclosed in International Publication No. WO 2008/074821 A1. [0113] GSK2018682 is a selective S1P₁ modulator and is chemically known as 4-[4-[5-(5- chloro-6-propan-2-yloxypyridin-3-yl)-1,2,4-oxadiazol-3-yl]indol-1-yl]butanoic acid. [0114] In some embodiments, the S1P agonist comprises PF-462991 (also known as PF 991) (discovered by Pfizer) and its analogs disclosed in International Publication No. WO 2009/060278 A1. [0115] PF-462991 is a selective S1P1 modulator and is chemically known as (1S,3s)-3-(((R)- 1-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)amino)cyclobutane-1- carboxylic acid. [0116] In some embodiments, the S1P agonist comprises ASP4058 (discovered by Astellas Pharma Global Development, Inc.) and its analogs disclosed in International Publication No. WO 2007/116866 A1. 22 [0117] ASP4058 is a selective S1P1/5 modulator and is chemically known as 5-{5-[3- (trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H- benzimidazole (ASP4058). [0118] In some embodiments, the S1P agonist comprises CBP-307 (discovered by Suzhou Connect Biopharmaceuticals) and its analogs disclosed in International Publication No. WO 2015/039587 A1. [0119] CBP-307 is a selective S1P1 modulator and is chemically known as (1S,3S)-3-((2- fluoro-4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl)benzyl)amino)cyclobutane-1-carboxylic acid. [0120] In one embodiment, the inhibitor of the IL-23 signaling pathway is tildrakizumab, guselkumab, risankizumab, brazikumab, mirikizumab, ustekinumab, briakinumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. [0121] In another embodiment, the S1P agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. The methods, combinations, compositions, uses, and kits of the disclosure envisage the combination products (IL-23 inhibitor and S1P agonist), which include, but are not limited to: Combination Product IL-23 Inhibitor S1P Agonist Tildrakizumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P1 agonist, preferably the compound of Formula I. 23 The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Guselkumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P₁ agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Risankizumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment the S1P agonist is a selective S1P1 agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Brazikumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P1 agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Mirikizumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P₁ agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Ustekinumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P1 agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Briakinumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P₁ agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Ixekizumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P₁ agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Brodalumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P1 agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. Bimekizumab The compound of Formula I, fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In one embodiment, the S1P agonist is a selective S1P₁ agonist, preferably the compound of Formula I. The combination optionally further comprises an additional agent that is an immunomodulator such as oral azathioprine, 6- mercaptopurine, or methotrexate. [0122] In various embodiments, the modulator of the sphingosine-1-phosphate signaling pathway significantly reduces (a) the expression of IL-12/IL-23 p40 or IL-23p19, an action that promotes an increase in the effectiveness of the inhibitor of the IL-23 pathway; and/or reduces (b) the dose of the IL-23 inhibitor. [0123] In various embodiments, the IL-23 inhibitor is an anti-IL-23p19 antibody or an antigen binding fragment thereof. Exemplary anti-IL-23p19 antibodies and fragments are described in U.S. Patent No.8,404,813 B2, which is incorporated by reference herein in its entirety, including the sequences thereof. [0124] The compositions and combination products as discussed hereinbefore are useful for the treatment of autoimmune disorders. Thus, in another aspect, the disclosure provides a combination of an inhibitor of the IL-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of an autoimmune disorder. [0125] The term "autoimmune disorder," as used herein, refers to a disorder whereby the body's immune system attacks and destroys healthy body tissue. There are a number of autoimmune disorders including, but not limited to, plaque psoriasis, erythrodermic psoriasis, pustular psoriasis, rheumatoid arthritis, psoriatic arthritis, giant cell arteritis, ankylosing 26 spondylitis, axial spondylarthritis, hidradenitis suppurativa, palmoplantar pustulosis, systemic scleroderma, bullous pemphigoid, pityriasis rubra pilaris, pyoderma gangrenosum, atopic dermatitis, lupus nephritis, familial adenomatous polyposis, ermatomyositis, polymyositis, systemic lupus erythematosus, chronic inflammatory disorder, and/or inflammatory bowel disease (IBD), such as, but not limited to, ulcerative colitis or Crohn's disease. [0126] In certain embodiments, the human patient has moderately to severely active ulcerative colitis. It causes inflammation and ulcers (sores) in digestive tract. Colitis can involve irritation, swelling, and other signs of inflammation of the colon. [0127] In other embodiments, the human patient has moderately to severely active Crohn's disease. Crohn's disease is a chronic, or long-term, condition that causes inflammation of the digestive tract. Crohn's disease may be confined to the colon, but may also be present in other tissues such as the small intestine. Crohn's disease can involve inflammation of the colon and small intestine. There may even be inflammation of the mouth, anus, skin, eyes, joints, and/or liver. [0128] In various embodiments, the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen binding fragment thereof. [0129] In certain embodiments, the inhibitor of IL-23 signaling pathway is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination thereof. [0130] In various embodiments, the anti-IL-23p19 antibody is tildrakizumab. [0131] Optionally, the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0132] In some embodiments, the sphingosine-1-phosphate agonist is a selective S1P₁ agonist. [0133] Optionally, the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. 27 [0134] In some embodiments, the sphingosine-1-phosphate agonist is the compound of Formula I: .

and the sphingosine-1- phosphate agonist is the compound of Formula I: .

a chronic inflammatory disorder. [0137] In some embodiments, the chronic inflammatory disorder is a disorder of the digestive tract. [0138] In some embodiments, the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease. [0139] In some embodiments, the inflammatory bowel disease is ulcerative colitis. [0140] In other embodiments, the inflammatory bowel disease is Crohn's disease. [0141] In certain embodiments, the combination of an inhibitor of the IL-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of an autoimmune disorder further comprises administering an additional agent. In some embodiments, the additional agent is an immunomodulator, for example, oral azathioprine, 6-mercaptopurine, or methotrexate. [0142] Optionally, the inhibitor of IL-23 signaling pathway (which may be, for example, an IL-23 inhibitor) and the modulator of the sphingosine-1-phosphate signaling pathway (which may be, for example, an S1P agonist) are administered simultaneously, either in the same composition or in separate compositions. In some embodiments, the inhibitor of IL-23 signaling pathway (e.g., IL-23 inhibitor) and the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) are administered sequentially, i.e., the IL-23 inhibitor is administered either prior to or after the administration of the modulator of the sphingosine-1- 28 phosphate signaling pathway. In some embodiments, the administration of the inhibitor of IL-23 signaling pathway (e.g., IL-23 inhibitor) and the modulator of the sphingosine-1- phosphate signaling pathway are concurrent, i.e., the administration period of the inhibitor of IL-23 signaling pathway (e.g., IL-23 inhibitor) and that of the modulator of the sphingosine- 1-phosphate signaling pathway overlap with each other. In some embodiments, the inhibitor of IL-23 signaling pathway (e.g., IL-23 inhibitor) and the modulator of the sphingosine-1- phosphate signaling pathway (e.g., S1P agonist) are administered within one day of one another. In some embodiments, the inhibitor of IL-23 signaling pathway (e.g., IL-23 inhibitor) and modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) are contained as active ingredients in same or different therapeutic composition, and are administered at the same time or at different times. In various embodiments, the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) and the inhibitor of IL-23 signaling pathway (e.g., an IL-23 inhibitor such as an anti-IL-23 antibody) are administered in a ratio of from 1:100 to 100:1 (w/w). In some embodiments, the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) and the inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) are administered in a ratio of from 1:5 to 1:40, for example 1:8 to 1:30, for example 1:2 to 2:1 (w/w), for example in a ratio of 1:2 to 1:1.8 (w/w). In some embodiments, the ratio of modulator of the sphingosine-1- phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.9 to 1:1.7 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.8 to 1:1.6 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.7 to 1:1.5 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1- phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.6 to 1:1.4 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.5 to 1:1.3 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.4 to 1:1.2 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1- phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.3 to 1:1.1 (w/w). In some embodiments, the ratio of the 29 modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.2 to 1:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1.1 to 1.1:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1- phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1:1 to 1.2:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.1:1 to 1.3:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.2:1 to 1.4:1 (w/w). In some embodiments, the ratio of S1P agonist to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.3:1 to 1.5:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.4:1 to 1.6:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1- phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.5:1 to 1.7:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.6:1 to 1.8:1 (w/w). In some embodiments, the ratio of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) to inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) is from 1.7:1 to 1.9:1 (w/w). [0143] The ratio may be calculated from the dosage of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) in a patient in mg/kg and the dosage of inhibitor of IL-23 signaling pathway (e.g., anti-IL23 antibody) in the same patient in mg/kg. The administration of the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) and an inhibitor of IL-23 signaling pathway (e.g., anti-IL-23 antibody) in a ratio of from 1:2 to 2:1 (w/w) can provide enhanced treatment of inflammatory bowel diseases such as colitis and Crohn's disease. [0144] For example, the modulator of the sphingosine-1-phosphate signaling pathway (e.g., S1P agonist) may conveniently be taken orally, once or twice a day as required. Suitable doses may be from 0.1 mg to 2 mg daily, for example 0.3 mg / day to 1.5 mg / day. Mention may be made of a daily dose of 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, or 1.0 mg / day. The modulator of the sphingosine-1-phosphate signaling pathway may be, for example the compound of 30 Formula I . anti-IL-23 antibody) may be

administered intravenously at a dose of from 5 to 15 mg/kg/day, for example from 6 to 12 mg/kg/day, for example 8, 9, or 10 mg/kg/day. The inhibitor of the IL-23 signaling pathway may be an anti-IL-23 antibody, for example tildrakizumab. [0146] Optionally, the modulator of the sphingosine-1-phosphate signaling pathway, for example the compound of Formula I, can be administered at a daily dose of 0.3 mg to 1 mg and the inhibitor of IL- 23 signaling pathway, for example an anti-IL-23 antibody, such as tildrakizumab, can be administered at a daily dose of 8 to 10 (for example, 9) mg/kg. [0147] The disclosure further provides a method of treating an autoimmune disorder comprising administering to a patient in need thereof a combination therapy comprising an inhibitor of the IL-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway, as described herein. [0148] In another aspect, the disclosure provides a combination of an inhibitor of the IL-23 signaling pathway and the compound of Formula I:

some embodiments, the inflammatory bowel disease is Crohn's disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. [0149] One aspect of the disclosure is a method of treating an inflammatory bowel disease in a patient. The method comprises administering a therapeutically effective amount of an IL- 23 inhibitor and sequentially or simultaneously administering a therapeutically effective amount of a sphingosine-1-phosphate agonist. The method is effective to treat the inflammatory bowel disease. 31 [0150] In some embodiments, the patient has previously been treated with an IL-23 inhibitor alone but the inflammatory bowel disease did not undergo remission after the previous treatment and/or response loss and/or disease relapse has occurred over time. In some embodiments, the subject was previously treated with sphingosine-1-phosphate agonist alone but the inflammatory bowel disease did not undergo remission after the previous treatment and/or response loss and/or disease relapse has occurred over time. Therefore, a patient may respond much better to the combination according to the disclosure, for example a combination of an IL-23 inhibitor (e.g., an anti-IL-23p19 antibody) and a sphingosine-1- phosphate agonist. Therefore, the disclosure provides an alternative therapy that can mitigate disease burden, improve remission rates, and modify progression inflammatory bowel disease. [0151] In some embodiments, the inflammatory bowel disease is ulcerative colitis. [0152] In other embodiments, the inflammatory bowel disease is Crohn's disease. [0153] In various embodiments, the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof. [0154] In certain embodiments, the inhibitor of IL-23 signaling pathway is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination thereof. [0155] In various embodiments, the anti-IL-23p19 antibody is tildrakizumab. [0156] In various embodiments, the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0157] In some embodiments, the sphingosine-1-phosphate agonist is a selective S1P1 agonist. [0158] In various embodiments, the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. 32 [0159] In some embodiments, the sphingosine-1-phosphate agonist is the compound of Formula I: .

hyperplasia in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an S1P agonist and a therapeutically effective amount of an IL-23 inhibitor. [0161] Another aspect of the disclosure is a method of reducing edema in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an S1P agonist and a therapeutically effective amount of an IL-23 inhibitor. [0162] In yet another aspect there is provided a method of reducing gland loss in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an S1P agonist and a therapeutically effective amount of an IL-23 inhibitor. [0163] According to another aspect there is provided a method of suppressing weight gain of the colon in a patient suffering from an inflammatory bowel disease, the method comprising administering an effective amount of an S1P agonist and an IL-23 inhibitor. [0164] In some embodiments, the inflammatory bowel disease is ulcerative colitis. [0165] In other embodiments, the inflammatory bowel disease is Crohn's disease. [0166] In some embodiments, the reduction in gland loss is for the proximal end of the colon. [0167] In some embodiments, the weight gain is weight gain per length of the colon. [0168] In various embodiments, the IL-23 inhibitor comprises an anti-IL-23p19 antibody or an antigen-binding fragment thereof. [0169] In various embodiments, the anti-IL-23p19 antibody is tildrakizumab. [0170] In certain embodiments, the inhibitor of the IL-23 signaling pathway is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination thereof. 33 [0171] In various embodiments, the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0172] In some embodiments, the sphingosine-1-phosphate agonist is a selective S1P1 agonist. [0173] In various embodiments, the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0174] In some embodiments, the sphingosine-1-phosphate agonist is the compound of Formula I: .

of reducing hyperplasia in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an inhibitor of the IL-23 signaling pathway that is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination thereof. The method further comprises administering a second therapeutic agent that is the compound of Formula I: 34 , d, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In some embodiments, the first therapeutic agent is tildrakizumab and the second therapeutic agent is the compound of Formula I: .

of reducing edema in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an inhibitor of the IL-23 signaling pathway that is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination thereof. The method further comprises administering a second therapeutic agent that is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In some embodiments, the first therapeutic agent is tildrakizumab and the second therapeutic agent is the compound of Formula I: 35 . d of reducing gland loss in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an inhibitor of the IL-23 signaling pathway that is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination thereof. The method further comprises administering a second therapeutic agent that is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. In some embodiments, the first therapeutic agent is tildrakizumab and the second therapeutic agent is the compound of Formula I: .

of suppressing weight gain of the colon in a patient suffering from an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of an inhibitor of the IL-23 signaling pathway that is ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, tildrakizumab, bimekizumab, or a combination 36 thereof. The method further comprises administering a second therapeutic agent that is the compound of Formula I: ,

herein, refers to the amount of a therapeutic agent that is effective to alleviate autoimmune disease or disorder or any adverse effects. For example, a therapeutically effective amount of the inhibitor of the IL-23 signaling pathway (e.g., anti-IL-23 antibody) can be from 1 to 10 mg/kg/day, for example from 2.5 to 7.5 mg/kg. For example, a therapeutically effective amount of the modulator of the sphingosine-1-phosphate signaling pathway (for example, the S1P agonist) can be from 2 mg/kg to 20 mg/kg/day. [0180] The terms "patient" or "subject," as used herein, refer to any human or nonhuman animal (e.g., primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, and the like). As used herein, the term "treatment" refers to curing the disease and/or disorder as rapidly as possible and preventing progression to severe disease. [0181] The combination of the disclosure may provide a systemic impact as well as a local impact on the bowel or colon. The combination may provide a greater systemic impact than by treatment with either anti-IL-23 antibody alone or S1P agonist alone. The combination can provide for superior anti-inflammatory activity in treating IBD in a human. An anti-IL- 23 antibody can be highly efficacious in blocking the development of IBD (e.g., colitis and 37 Crohn's disease) when combined with a selective S1P1 agonist, preferably the compound of Formula I. [0182] Various anti-IL-23 and/or IL-17 antibodies may be used in the methods, combinations, compositions, uses, and kits of the disclosure, including, for example, any of the anti-IL-23 and/or anti-IL-17 antibodies described in U.S. Patent Nos.8,404,813; 6,902,734; 8,178,092; 8,722,033; 9,023,358; 7,993,645; 8,778,346; 7,838,638; 7,767,206; and 8,580,265, all of which are incorporated herein by reference in their entireties, including the sequences thereof. In some embodiments, the IL-23 inhibitor is an anti-IL-23p19 antibody or an antigen binding fragment thereof. Exemplary anti-IL-23p19 antibodies and fragments are described in U.S. Patent Nos.8,404,813 B2; 7,993,645 B2; 8,778,346 B2; 8,722,033 B2; 9,023,358 B2; and 6,902,734 B2. In some embodiments, the IL-23 inhibitor is a dual anti-IL-23p40 and anti-IL-12p40 antibody or an antigen binding fragment thereof. Exemplary dual IL-12p40 and IL-23p40 antibodies are described in U.S. Patent No. 8,178,092 B2. In some embodiments, the IL-17A inhibitor is an anti-IL17A antibody or an antigen binding fragment thereof. Exemplary dual IL-12p40 and IL-23p40 antibodies are described in U.S. Patent Nos.7,838,638 B2; 7,767,206 B2; and 8,580,265 B2. [0183] Various S1P agonists may be used in the methods, combinations, compositions, uses, and kits of the disclosure, including, for example, any of the S1P agonists described in U.S. Patent Nos.9,266,867; 5,604,229; 8,481,573; 8,796,318; 7,939,519; 8,809,304; 7,906,549; 6,077,851 and 6,960,692, and International Publication Nos. WO 2009/151529; WO 94/08943; WO 2005/054215; WO 2005/000833; WO 2007/069712; WO 2014/130752; WO 2005/005383; WO 2008/074821; WO 2009/060278; WO 2007/116866; WO 2006/064757; WO 99/55678; WO 2010/011316; WO 2003029205; WO 2011/007324; WO 2013/094761; and WO 2015/039587; all of which are incorporated herein by reference in their entireties. [0184] In some embodiments, the S1P agonists are S1P_1/3/4/5 modulators. Exemplary S1P1/3/4/5 agonists are described in U.S. Patent No.5,604,229 A. [0185] In some embodiments, S1P agonists are S1P_1/4/5 modulators. Exemplary S1P_1/4/5 agonists are described in International Publication No. WO 2010/011316 A1. [0186] In some embodiments, S1P agonists are S1P_1/5 modulators. Exemplary S1P_1/5 agonists are described in U.S. Patent Nos.8,796,318B2; 7,939,519 B2; and 7,906,549 B2; and International Publication Nos. WO 2006/064757 A1 and WO 2007/116866 A1. [0187] In some embodiments, S1P agonists are selective S1P1 modulators. Exemplary S1P1 agonists are described in U.S. Patent Nos.9,266,867 B2; 6,077,851 A; 6,960,692 B2 and 8,809,304 B2; and International Publication Nos. WO 99/55678 A1; WO 2003/029205 A1; 38 WO 2011/007324 A1; WO 2005/054215 A1; WO 2007/069712 A1; WO 2014/130752 A2; WO 2005/005383 A1; WO 2008/074821 A1; WO 2009/060278 A1; and WO 2015/039587 A1. [0188] In certain embodiments, the pharmaceutical composition is formulated for oral or parenteral administration. In some embodiments, the pharmaceutical composition is administered as an oral dosage form. Preferably, the oral dosage form is in the form of tablet, capsule, dispersible tablets, sachets, sprinkles, liquids, solution, suspension, emulsion, or the like. If the oral dosage form is a tablet, the tablet can be of any suitable shape such as round, spherical, or oval. The tablet may have a monolithic or a multi-layered structure. In some embodiments, the pharmaceutical compositions of the disclosure can be obtained by conventional approaches using conventional pharmaceutically acceptable excipients well known in the art. Examples of pharmaceutically acceptable excipients suitable for tablet preparation include, but are not limited to, diluents (e.g., calcium phosphate-dibasic, calcium carbonate, lactose, glucose, microcrystalline cellulose, cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, or polyols such as mannitol, sorbitol, xylitol, maltitol, and sucrose), binders (e.g., starch, pregelatinized starch, carboxymethyl cellulose, sodium cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crospovidone, or combinations thereof), disintegrants (e.g., crosslinked cellulose, crosslinked- polyvinylpyrrolidone (crospovidone), sodium starch glycolate, polyvinylpyrrolidone (polyvidone, povidone), sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), hydroxypropyl cellulose, hydroxypropyl methylcellulose, xanthan gum, alginic acid, or soy polysaccharides), wetting agents (e.g., polysorbate, sodium lauryl sulphate, or glyceryl stearate), or lubricants (e.g., sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, or zinc stearate). The tablets so prepared may be uncoated or coated for altering their disintegration, and subsequent enteral absorption of the active ingredient, or for improving their stability and/or appearance. In both cases, conventional coating agents and approaches well known in the art can be employed. [0189] In certain embodiments, the parenteral administration (comprising the anti-IL-23 antibody, for example) can be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and about 1- 10% human serum albumin. Liposomes and non-aqueous vehicles, such as fixed oils, can also be used. 39 The vehicle or lyophilized powder can contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation is sterilized by known or suitable techniques. In some embodiments, a parenteral formulation may comprise a common excipient that includes, but is not limited to, sterile water or saline, polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, and the like. Aqueous or oily suspensions for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known methods. Parenteral route of administration includes, but is not limited to, subcutaneous route, intramuscular route, intravenous route, intrathecal route, or intraperitoneal. [0190] The formulations of the disclosure can be prepared by a process known or otherwise described in the prior art, for example, the process disclosed in Remington's Pharmaceutical Sciences. [0191] According to yet another aspect there is provided a pharmaceutical kit comprising (i) an IL-23 inhibitor, (ii) a S1P agonist, and (iii) instructions for administering therapeutically effective amounts of the IL-23 inhibitor and S1P agonist, in accordance with the severity of the disease, patient age, patient weight, etc. [0192] In one embodiment, the kit is useful in treating inflammatory bowel disease such as Crohn's disease and/or ulcerative colitis. In another embodiment, the kit contains a first pharmaceutical composition comprising an anti-IL23 antibody and a second pharmaceutical composition comprising a S1P agonist for oral administration, for example such as in tablet forms. In another embodiment, a first composition comprises an anti-IL23 antibody and a second pharmaceutical composition comprises an S1P agonist for parenteral administration. In yet another embodiment, a first composition comprises an anti-IL23 antibody in a formulation suitable for parenteral administration and a second pharmaceutical composition comprising a S1P agonist in a formulation suitable for oral administration and vice versa. Embodiments: [0193] Embodiment 1: A method of treating an autoimmune disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an inhibitor of the interleukin-23 signaling pathway and a therapeutically effective amount of a modulator of the sphingosine-1-phosphate signaling pathway. [0194] Embodiment 2: The method of embodiment 1, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of 40 interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin- 17 receptor. [0195] Embodiment 3: The method of embodiment 2, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. [0196] Embodiment 4: The method of embodiment 3, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. [0197] Embodiment 5: The method of embodiment 4, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. [0198] Embodiment 6: The method of any one of embodiments 1 to 5, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0199] Embodiment 7: The method of embodiment 6, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0200] Embodiment 8: The method of embodiment 7, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1- phosphate pathway is the compound of Formula I: 41 . iments 1 to 8, wherein the inhibitor of the interleukin-23 signaling pathway is administered simultaneously with the modulator of the sphingosine-1-phosphate signaling pathway. [0203] Embodiment 11: The method of any one of embodiments 1 to 8, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are for administered sequentially. [0204] Embodiment 12: The method of any one of embodiments 1 to 11, wherein the method further comprises administering an immunomodulator to the patient. [0205] Embodiment 13: The method of embodiment 12, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. [0206] Embodiment 14: The method of any one of embodiments 1 to 13, wherein the autoimmune disorder is a chronic inflammatory disorder. [0207] Embodiment 15: The method of embodiment 14, wherein the chronic inflammatory disorder is a disorder of the digestive tract. [0208] Embodiment 16: The method of embodiment 15, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. [0209] Embodiment 17: A pharmaceutical composition comprising an inhibitor of the interleukin-23 pathway and a modulator of the sphingosine-1-phosphate signaling pathway. [0210] Embodiment 18: The pharmaceutical composition of embodiment 17, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. [0211] Embodiment 19: The pharmaceutical composition of embodiment 18, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. [0212] Embodiment 20: The pharmaceutical composition of embodiment 19, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, 42 brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. [0213] Embodiment 21: The method of embodiment 20, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. [0214] Embodiment 22: The pharmaceutical composition of any one of embodiments 17 to 21, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0215] Embodiment 23: The pharmaceutical composition of embodiment 22, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0216] Embodiment 24: The pharmaceutical composition of embodiment 23, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

of embodiment 17, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate pathway is the compound of Formula I: .

43 [0218] Embodiment 26: The pharmaceutical composition of any one of embodiments 17 to 25, wherein the pharmaceutical composition further comprises an immunomodulator. [0219] Embodiment 27: The pharmaceutical composition of embodiment 26, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. [0220] Embodiment 28: The pharmaceutical composition of any of embodiments 17 to 27 for use in the treatment of an autoimmune disorder. [0221] Embodiment 29: The pharmaceutical composition for use in the treatment of an autoimmune disorder of embodiment 28, wherein the autoimmune disorder is a chronic inflammatory disorder. [0222] Embodiment 30: The pharmaceutical composition for use in the treatment of an autoimmune disorder of embodiment 29, wherein the chronic inflammatory disorder is a disorder of the digestive tract. [0223] Embodiment 31: The pharmaceutical composition for use in the treatment of an autoimmune disorder of embodiment 30, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. [0224] Embodiment 32: A combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of an autoimmune disorder. [0225] Embodiment 33: The combination for use in the treatment of an autoimmune disorder of embodiment 32, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. [0226] Embodiment 34: The combination for use in the treatment of an autoimmune disorder of embodiment 33, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. [0227] Embodiment 35: The combination for use in the treatment of an autoimmune disorder of embodiment 34, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. [0228] Embodiment 36: The combination for use in the treatment of an autoimmune disorder of any one of embodiments 32 to 35, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. 44 [0229] Embodiment 37: The combination for use in the treatment of an autoimmune disorder of embodiment 36, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: BMS-986104, CS-0777,

GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0230] Embodiment 38: The combination for use in the treatment of an autoimmune disorder of embodiment 37, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

of an autoimmune disorder of embodiment 32, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate signaling pathway is the compound of Formula I: .

of an autoimmune disorder of any one of embodiments 32 to 39, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are administered simultaneously. 45 [0233] Embodiment 41: The combination for use in the treatment of an autoimmune disorder of any one of embodiments 32 to 39, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are administered sequentially. [0234] Embodiment 42: The combination for use in the treatment of an autoimmune disorder of any one of embodiments 32 to 41, wherein the combination further comprises an immunomodulator. [0235] Embodiment 43: The combination for use in the treatment of an autoimmune disorder of embodiment 42, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. [0236] Embodiment 44: The combination for use in the treatment of an autoimmune disorder of any one of embodiments 32 to 43, wherein the autoimmune disorder is a chronic inflammatory disorder. [0237] Embodiment 45: The combination for use in the treatment of an autoimmune disorder of embodiment 44, wherein the chronic inflammatory disorder is a disorder of the digestive tract. [0238] Embodiment 46: The combination for use in the treatment of an autoimmune disorder of embodiment 45, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. [0239] Embodiment 47: A method of reducing or suppressing the symptoms of a chronic inflammatory disorder of the digestive tract in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an inhibitor of the interleukin-23 signaling pathway and a therapeutically effective amount of a modulator of the sphingosine-1-phosphate signaling pathway. [0240] Embodiment 48: The method of embodiment 47, wherein the method results in the reduction or suppression of one or more of the following symptoms: hyperplasia, edema, gland loss, and/or weight gain of the colon. [0241] Embodiment 49: The method of embodiment 47, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin- 17 receptor. [0242] Embodiment 50: The method of embodiment 49, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. 46 [0243] Embodiment 51: The method of embodiment 50, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. [0244] Embodiment 52: The method of embodiment 51, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. [0245] Embodiment 53: The method of any one of embodiments 47 to 52, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0246] Embodiment 54: The method of embodiment 53, wherein the sphingosine-1- phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0247] Embodiment 55: The method of embodiment 54, wherein the sphingosine-1- phosphate agonist is the compound of Formula I: .

the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1- phosphate pathway is the compound of Formula I: 47 . iments 47 to 56, wherein the inhibitor of the interleukin-23 signaling pathway is administered simultaneously with the modulator of the sphingosine-1-phosphate signaling pathway. [0250] Embodiment 58: The method of any one of embodiments 47 to 56, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1- phosphate signaling pathway are for administered sequentially. [0251] Embodiment 59: The method of any one of embodiments 47 to 58, wherein the method further comprises administering an immunomodulator to the patient. [0252] Embodiment 60: The method of embodiment 59, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. [0253] Embodiment 61: The method according to any one of embodiments 47 to 60, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. [0254] Embodiment 62: A pharmaceutical kit comprising (i) an inhibitor of the interleukin- 23 signaling pathway; (ii) a modulator of the sphingosine-1-phosphate signaling pathway; and (iii) instructions for the administration to a patient of therapeutically effective amounts of the inhibitor of interleukin-23 signaling pathway and the modulator of the sphingosine-1- phosphate signaling pathway in accordance with the severity of an autoimmune disorder in the patient. [0255] Embodiment 63: The pharmaceutical kit of embodiment 62, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin- 17 receptor. [0256] Embodiment 64: The pharmaceutical kit of embodiment 63, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. [0257] Embodiment 65: The pharmaceutical kit of embodiment 64, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, 48 brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. [0258] Embodiment 66: The pharmaceutical kit of embodiment 65, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. [0259] Embodiment 67: The pharmaceutical kit of any one of embodiments 62 to 66, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1- phosphate agonist. [0260] Embodiment 68: The pharmaceutical kit of embodiment 67, wherein the sphingosine- 1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0261] Embodiment 69: The pharmaceutical kit of embodiment 68, wherein the sphingosine- 1-phosphate agonist is the compound of Formula I: .

62, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine- 1-phosphate pathway is the compound of Formula I: .

49 [0263] Embodiment 71: The pharmaceutical kit of any one of embodiments 62 to 70, wherein the pharmaceutical kit further comprises an immunomodulator. [0264] Embodiment 72: The pharmaceutical kit of embodiment 71, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. [0265] Embodiment 73: The pharmaceutical kit of any one of embodiments 62 to 72, wherein the autoimmune disorder is a chronic inflammatory disorder. [0266] Embodiment 74: The pharmaceutical kit of embodiment 73, wherein the chronic inflammatory disorder is a disorder of the digestive tract. [0267] Embodiment 75: The pharmaceutical kit of embodiment 74, wherein the chronic inflammatory disorder of digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. [0268] Embodiment 76: Use of a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for the manufacture of a medicament for treating an autoimmune disorder. [0269] Embodiment 77: The use of embodiment 76, wherein the inhibitor of the interleukin- 23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. [0270] Embodiment 78: The use of embodiment 77, wherein the inhibitor of the interleukin- 23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof [0271] Embodiment 79: The use of embodiment 78, wherein the inhibitor of the interleukin- 23 signaling pathway is tildrakizumab. [0272] Embodiment 80: The use of any one of embodiments 76 to 79, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. [0273] Embodiment 81: The use of embodiment 80, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, 50 GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. [0274] Embodiment 82: The use of embodiment 81, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

the inhibitor of the interleukin- 23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate signaling pathway is the compound of Formula I: .

76 to 83, wherein the inhibitor of the interleukin-23 signaling pathway is to be administered simultaneously with the modulator of the sphingosine-1-phosphate signaling pathway. [0277] Embodiment 85: The use of any one of embodiments 76 to 83, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are for administration sequentially. [0278] Embodiment 86: The use of any one of embodiments 76 to 85, wherein the medicament further comprises an immunomodulator. [0279] Embodiment 87: The use of embodiment 86, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. [0280] Embodiment 88: The use of any one of embodiments 76 to 87, wherein the autoimmune disorder is a chronic inflammatory disorder. [0281] Embodiment 89: The use of embodiment 88, wherein the chronic inflammatory disorder is a disorder of the digestive tract. 51 [0282] Embodiment 90: The use of embodiment 89, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. [0283] The methods, combinations, compositions, uses, and kits of the disclosure are illustrated below by reference to the following examples. However, one skilled in the art will appreciate that specific methods and results discussed are merely illustrative of the claimed invention, as innumerable variations, modifications, applications, and extensions of these embodiments and principles can be made without departing from the spirit and scope of the claimed invention. EXAMPLES Example 1: Efficacy of S1P agonist and anti-IL-23p19 antibody combination in T-cell transfer (TCT) induced mouse colitis model [0284] Induction of Colitis and Evaluations: In this experiment, female C57BL/6 donor mice and female RAGn12 recipient mice were used. On Day -2, mice were weighed and evenly distributed into treatment groups based on body weight. On study Day 0, C57BL/6 mice were sacrificed and spleen tissue was obtained for the isolation of CD4+CD45RBhigh cells according to the RAG IBD cell separation protocol. CD4+ T cells were enriched with CD4 Cell Enrichment Kit, Stem Cell. After the cells were sorted, each animal received an IP injection of a minimum of 4 x 10⁵ cells (200 µl/mouse injections). On study Day 49, animals were anesthetized with isoflurane and bled to exsanguination, then euthanized by cervical dislocation for tissue collection. From each animal, the entire colon was harvested, inspected visually, and measured for length and weight. Middle colons (approximately 1 cm per colon) were collected and snap-frozen in liquid nitrogen and stored (-80°C) for cytokine analysis. Remaining proximal and distal colons were collected into 10% neutral buffered formalin for histopathology and CD3+ cells immunohistochemistry. [0285] Treatments: On study Day -1, treatment with Formula I was initiated orally (PO) twice daily and continued until Day 48. Anti mouse anti-IL-23 (p19) antibody was administered intraperitoneally (IP) once weekly on Day 0, Day 7, Day 14, Day 21, Day 28, Day 35, and Day 42. The treatments are described in Table 1. Table 1: Treatment Group Summary 52 ^{Group N Disease Treatment Dose} (_mg/kg) ^{Route Regimen Dosing Days} 1 15 N Normal N/A PO BID D(-1) -48 2 15 Y Vehicle N/A PO BID D(-1) -48 Vehicle N/A, PO BID, D(-1) -48, 3 15 Y + Isotype 49.4 mg/kg IP 1x weekly D0, 7, 14, 21, 28, 35 & 42 compound 4 15 Y of 5 mg/kg PO BID D(-1) -48 Formula I 5 15 Y mIL-23 Ab 2.5 mg/kg IP 1x weekly D0, 7, 14, 21, 28, 35 & 42 6 15 Y mIL-23 Ab 7.5 mg/kg IP 1x weekly D0, 7, 14, 21, 28, 35 & 42 7 15 Y mIL-23 Ab 48.4 mg/kg IP 1x weekly D0, 7, 14, 21, 28, 35 & 42 compound of 5 mg/kg, PO BID, D(-1) -48, 8 15 Y Formula I + 2.5 mg/kg IP 1x weekly D0, 7, 14, 21, 28, 35 & 42 mIL-23 Ab compound of 5 mg/kg, PO BID, D(-1) -48, 9 15 Y Formula I + 7.5 mg/kg IP 1x weekly D0, 7, 14, 21, 28, 35 & 42 mIL-23 Ab 1_{0 15 Y Anti-IL-12} ^{0.5 mg/} m_{ouse IP 1x weekly D(-1) - 48} [0286] Results from the study are provided in FIGs.1 to 9 and Tables 2 to 8. [0287] Colon Weight [0288] At study termination on Day 49, treatment with 5 mg/kg BID of Formula I treatment showed 79% reduction in colon weight compared to vehicle. [0289] Anti-IL-23 Ab at 2.5, 7.5, and 48.4 mg/kg doses (Q7D, intraperitoneal) showed 34%, 69%, and 73% reduction in colon weight, respectively. These results indicate that the mid dose of anti-IL-23 Ab (7.5 mg/kg) is the maximally efficacious dose. [0290] Combination treatments of 5 mg/kg BID of the compound of Formula I and 2.5 mg/kg or 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody resulted in 100% and 98% 53 reductions in colon weight respectively. [0291] Colon Weight-per-Length Ratio [0292] At study termination on Day 49, treatment with 5 mg/kg BID of Formula I showed 81% reduction in colon weight-per-length, compared to vehicle. [0293] Anti-IL-23 Ab at 2.5, 7.5, and 48.4 mg/kg doses (Q7D, intraperitoneal) showed 36%, 70%, and 73% reduction in colon weight-per-length, respectively. These results indicate that the mid dose of anti-IL-23 Ab (7.5 mg/kg) is the maximally efficacious dose. [0294] Combination treatments of 5 mg/kg BID of Formula I and 2.5 mg/kg or 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody resulted in 99% reduction in colon weight in both the combination groups. [0295] Disease Activity Index [0296] Disease Activity Index (DAI) represents the summed score for body weight loss, stool consistency, and blood in stools. The DAI assessment on Day 42 showed that Formula I at 5 mg/kg BID significantly reduced the sum DAI score (0.53) compared to vehicle control score (2.53). [0297] Anti-IL-23 Ab at 2.5 mg/kg, 7.5 mg/kg, and 48.4 mg/kg doses significantly reduced body weight loss scores (0.64, 0.07, and 0.08, respectively) compared to isotype control score (1.60). Mean stool consistency scores (0.86, 0.80, and 0.77, respectively) and summed DAI scores (2.07, 1.33, and 1.23, respectively) were also reduced as compared to isotype control scores (1.07 for stool consistency and 3.40 for summed DAI, respectively), but these reductions did not reach statistical significance. [0298] Combination of 5 mg/kg BID of Formula I with 2.5 mg/kg intraperitoneal dose of anti-IL-23 antibody resulted in a significantly smaller body weight loss score (0.07) compared to isotype control score (1.60). Mean stool consistency (0.60) and summed score (1.13) were also reduced compared to isotype control, but these reductions did not reach statistical significance. [0299] Combination of 5 mg/kg BID dose of the compound of Formula I with 7.5 mg/kg intraperitoneal dose of anti-IL-23 showed significant reduction in all the individual DAI parameter scores as seen in reduction of summed DAI score (0.67), compared to isotype control (3.40). [0300] Colon Histopathology 54 [0301] Colon histopathology assessments scored tissue collected at study conclusion for inflammation, gland loss, erosion, hyperplasia, edema, neutrophil score, and mucosal thickness. [0302] The compound of Formula I at 5 mg/kg BID resulted in significant reduction of scores for all the histopathology parameters except erosion compared to vehicle control. Anti-IL-23 antibody at 2.5 and 7.5 mg/kg significantly inhibited inflammation. In addition, 7.5 mg/kg dose also showed inhibition of PMN cells, mucosal thickness, and edema. The high dose of 48.4 mg/kg significantly inhibited all the histopathology parameters except erosion and lymphoid aggregate counts compared to isotype controls. [0303] Results of combination treatments showed that 5 mg/kg BID of the compound of Formula I combined with 2.5 and 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody caused potent reductions in all colon histopathology scores except erosion (individual parameter scores are presented in FIGs.5, 6, 7, and 8A-8E). Table 2: Summed Score of Inflammation, Gland Loss, Erosion and Hyperplasia Graph Data "Summed Score" SE F_{ull Colon Proximal Distal Full Colon Proximal Distal} Normal Control (DI Water) 0.4 0.8 0.0 0.06 0.11 0.02 Vehicle (DI Water) 5.0 4.8 5.3 0.58 0.49 0.72 Vehicle + Isotype (49.4 mg/kg) 6.0 6.2 5.9 0.75 0.72 0.91 compound of formula I (5 mg/kg) 1.5 2.7 0.3 0.20 0.32 0.13 Vehicle + Anti-IL-23 (2.5 mg/kg) 4.4 4.6 4.2 0.84 0.73 0.99 Vehicle + Anti-IL-23 (7.5 mg/kg) 2.8 3.6 2.1 0.65 0.66 0.78 Vehicle + Anti-IL-23 (48.4 mg/kg) 1.8 2.2 1.5 0.66 0.61 0.75 compound of formula I (5 mg/kg) + A_{nti-IL-23 (2.5 mg/kg)} ^{0.6 1.0 0.1 0.07 0.14 0.04} compound of formula I (5 mg/kg) + A_{nti-IL-23 (7.5 mg/kg)} ^{0.4 0.6 0.2 0.13 0.20 0.08} Vehicle + Anti-IL-12 (0.5 mg/mouse) 1.2 1.7 0.7 0.17 0.21 0.20 Table 3: Edema Data Graph Data "Edema (µm)" SE Full Colon Proximal Distal Full Colon Proximal Distal Normal Control (DI Water) 0 0 0 0.00 0.00 0.00 Vehicle (DI Water) 39.44 37.77 41.11 3.59 3.80 4.56 Vehicle + Isotype (49.4 mg/kg) 42.26 45.23 39.28 3.65 2.09 5.95 compound of Formula I (5 mg/kg) 16.12 28.88 3.34 3.30 4.73 3.33 Vehicle + Anti-IL-23 (2.5 mg/kg) 37.5 40.47 34.52 5.84 5.45 7.51 Vehicle + Anti-IL-23 (7.5 mg/kg) 25 31.11 18.88 4.74 4.84 6.27 Vehicle + Anti-IL-23 (48.4 mg/kg) 15.38 21.79 8.97 4.10 5.13 4.47 55 compound of Formula I (5 mg/kg) + A_{nti-IL-23 (2.5 mg/kg)} ^{6.66 12.22 1.11 1.85 3.80 1.11} compound of Formula I (5 mg/kg) + A_{nti-IL-23 (7.5 mg/kg)} ^{5.55 11.11 0 1.56 3.11 0.00} Vehicle + Anti-IL-12 (0.5 mg/mouse) 11.66 18.88 4.44 2.79 3.59 3.44 Table 4: Neutrophil Score Data Graph Data "Neutrophil Score" SE Full Colon Proximal Distal Full Colon Proximal Distal Normal Control (DI Water) 0.032 0.06 0 0.00 0.01 0.00 Vehicle (DI Water) 0.43 0.36 0.50 0.06 0.04 0.10 Vehicle + Isotype (49.4 mg/kg) 0.44 0.45 0.42 0.06 0.08 0.07 compound of Formula I (5 m_g/kg) ^{0.12 0.21 0.02 0.02 0.03 0.01} Vehicle + Anti-IL-23 (2.5 mg/kg) 0.39 0.27 0.50 0.09 0.05 0.15 Vehicle + Anti-IL-23 (7.5 mg/kg) 0.19 0.23 0.14 0.04 0.05 0.05 Vehicle + Anti-IL-23 (48.4 mg/kg) 0.13 0.16 0.10 0.05 0.05 0.06 compound of Formula I (5 m_{g/kg) + Anti-IL-23 (2.5 mg/kg)} ^{0.04 0.08 0.01 0.01 0.01 0.00} compound of Formula I (5 m_{g/kg) + Anti-IL-23 (7.5 mg/kg)} ^{0.03 0.04 0.01 0.01 0.01 0.01} Vehicle + Anti-IL-12 (0.5 m_g/mouse) ^{0.17 0.28 0.07 0.04 0.06 0.04} Table 5: Mucosal Thickness Data Graph Data "Mucosal Thickness (µm)" SE Full Colon Proximal Distal Full Colon Proximal Distal Normal Control (DI Water) 171.11 175.55 166.66 2.46 4.10 1.99 Vehicle (DI Water) 356.11 294.44 417.77 26.22 20.50 35.45 Vehicle + Isotype (49.4 mg/kg) 415.17 373.21 457.14 36.69 32.57 47.24 compound of Formula I (5 m_g/kg) ^{217.22 231.66 202.77 10.39 12.18 11.17} Vehicle + Anti-IL-23 (2.5 mg/kg) 342.85 319.04 366.66 35.18 29.84 44.89 Vehicle + Anti-IL-23 (7.5 mg/kg) 274.16 290 258.33 24.61 28.29 28.58 Vehicle + Anti-IL-23 (48.4 mg/kg) 230.44 228.20 232.69 22.45 20.38 27.89 compound of Formula I (5 m_{g/kg) + Anti-IL-23 (2.5 mg/kg)} ^{182.77 186.11 179.44 4.47 7.39 3.62} compound of Formula I (5 m_{g/kg) + Anti-IL-23 (7.5 mg/kg)} ^{185 178.88 191.11 6.20 9.55 3.59} Vehicle + Anti-IL-12 (0.5 m_g/mouse) ^{212.5 218.33 206.66 7.24 9.32 8.77} [0304] Colon Cytokines Levels [0305] Cytokine concentrations of individual animals were normalized with their total protein concentrations and compared. 56 [0306] IL-6: the compound of Formula I at 5 mg/kg BID significantly inhibited IL-6 concentration in the colon compared to vehicle control. [0307] Anti-IL-23 antibody treatments resulted in a reduction in IL-6 levels in the colon at all the dose levels (2.5 mg/kg, 7.5 mg/kg, and 48.4 mg/kg) compared to isotype controls. The reductions were statistically significant, except at 48.4 mg/kg dose of anti-IL-23 antibody, indicating that the mid dose of anti-IL-23 antibody (7.5 mg/kg) caused maximal effect. [0308] Results of combination treatments showed that 5 mg/kg BID of the compound of Formula I combined with 2.5 and 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody caused potent reductions in IL-6 in both the dose levels. [0309] IL-1β, TNFα, IFN-γ, and IL-17a: the compound of Formula I at 5 mg/kg BID dose reduced the levels of IL-1β, TNFα, IFN-γ, and IL-17a in the colon compared to vehicle control, however the effects were statistically non-significant. [0310] Anti-IL-23 antibody treatment at 2.5 mg/kg dose significantly inhibited IL-1β, TNFα, IFN-γ, and IL-17a. An anti-IL-23 antibody 7.5 mg/kg dose significantly inhibited levels of IL-1β, IFN-γ, and IL-17a, but not TNFα. At 48.4 mg/kg dose, anti-IL-23 antibody treatment significantly inhibited IL-1β, TNFα, IFN-γ, and IL-17a, compared to isotype controls. [0311] Results of combination treatments showed that 5 mg/kg BID dose of the compound of Formula I combined with 2.5 and 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody caused a marked reduction in the levels of IL-1β, TNFα, IFN-γ and IL-17a, compared to isotype controls. Table 6: Protein Normalized Mid Colon Cytokine Levels Graph Data "Protein Normalized Mid Colon Cytokine Levels SE (pg cytokine/ug protein)" IL-1β IL-6 TNFα IFNg IL-17a IL-1β IL-6 TNFα IFNg IL-17a Normal Control (DI _Water) ^{0.001 0.001 0.001 0.002 0.002 0.000 0.000 0.000 0.000 0.000} _{Vehicle (DI Water)} ^{0.569 0.039 0.009 1.107 0.035 0.253 0.010 0.001 0.836 0.025} Vehicle + Isotype (49.4 _mg/kg) ^{0.859 0.048 0.012 2.454 0.134 0.273 0.011 0.001 1.074 0.057} compound of Formula I _{(5 mg/kg)} ^{0.143 0.004 0.005 0.070 0.002 0.067 0.001 0.001 0.029 0.000} Vehicle + Anti-IL-23 (2.5 _mg/kg) ^{0.178 0.019 0.007 0.243 0.009 0.046 0.006 0.001 0.083 0.005} Vehicle + Anti-IL-23 (7.5 _mg/kg) ^{0.171 0.012 0.011 0.172 0.001 0.071 0.004 0.001 0.053 0.000} Vehicle + Anti-IL-23 _{(48.4 mg/kg)} ^{0.047 0.020 0.006 0.079 0.001 0.040 0.016 0.001 0.036 0.000} 57 compound of Formula I (5 mg/kg) + Anti-IL-23 0.005 0.005 0.003 0.007 0.002 0.001 0.000 0.000 0.002 0.000 (2.5 mg/kg) compound of Formula I (5 mg/kg) + Anti-IL-23 0.040 0.005 0.005 0.008 0.001 0.012 0.001 0.001 0.003 0.000 (7.5 mg/kg) Vehicle + Anti-IL-12 (0.5 _mg/mouse) ^{0.017 0.003 0.003 0.007 0.001 0.016 0.000 0.000 0.002 0.000} [0312] Immunohistochemical Evaluation of Colon CD3+ Cells Infiltration of lymphocytes was observed predominantly in the mucosa and submucosa. The compound of Formula I at 5 mg/kg BID treatment caused reduction of CD3+ cells with the mean values of 7.01%, 2.53%, and 5.66% of the total cells, compared to vehicle control values of 14.22%, 13.17%, and 13.70%, in the proximal colon, distal colon, and total colon, respectively. [0313] Isotype control group showed 15.15%, 14.60%, and 14.96% CD3+ cells in the proximal colon, distal colon, and total colon samples, respectively. Anti-IL-23 anti9body treatment resulted in reduction in CD3+ cells. Thus, mean values of CD3+ in anti-IL-23 antibody treatment were 12.69%, 9.79%, and 11.63% at 2.5 mg/kg dose; 12.27%, 5.51%, and 10.09% at 7.5 mg/kg dose; and 8.89%, 5.26%, and 7.67% at 48.4 mg/kg dose in the proximal colon, distal colon, and total colon samples, respectively. [0314] Combination treatment of 5 mg/kg BID dose of the compound of Formula I with 2.5 mg/kg intraperitoneal dose of anti-IL-23 antibody showed CD3+ cells were 1.49%, 0.88%, and 1.29% of total cells. Combination treatment of 5 mg/kg BID dose of the compound of Formula I with 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody showed CD3+ cells were 2.90%, 1.42%, and 2.39% of the total cells, in the proximal colon, distal colon, and total colon samples, respectively. Table 7: Mouse Colon CD3-Positive Immunolabeled Cells Graph Data "Mouse Colon CD3-Positive Immunolabeled Cells" SE CD3+ CD3+ Distal CD3+ Total CD3+ CD3+ Distal CD3+ Total Proximal Colon (%) Colon (%) Proximal Colon (%) Colon (%) Colon (%) Colon (%) Normal Control (DI Water) 0.37% 0.52% 0.42% 0.05% 0.10% 0.05% Vehicle (DI Water) 14.22% 13.17% 13.70% 2.06% 1.52% 1.53% Vehicle + Isotype (49.4 mg/kg) 15.15% 14.60% 14.96% 2.32% 2.55% 2.35% compound of Formula I (5 _mg/kg) ^{7.01% 2.53% 5.66% 1.27% 0.38% 0.93%} Vehicle + Anti-IL-23 (2.5 _mg/kg) ^{12.69% 9.79% 11.63% 2.36% 2.07% 2.07%} 58 Vehicle + Anti-IL-23 (7.5 _mg/kg) ^{12.27% 5.51% 10.09% 1.75% 1.34% 1.50%} Vehicle + Anti-IL-23 (48.4 _mg/kg) ^{8.89% 5.26% 7.67% 1.72% 1.49% 1.56%} compound of Formula I (5 _{mg/kg) + Anti-IL-23 (2.5 mg/kg)} ^{1.49% 0.88% 1.29% 0.22% 0.15% 0.18%} compound of Formula I (5 _{mg/kg) + Anti-IL-23 (7.5 mg/kg)} ^{2.90% 1.42% 2.39% 1.08% 0.39% 0.83%} Vehicle + Anti-IL-12 (0.5 _mg/mouse) ^{7.56% 5.02% 6.63% 0.52% 0.50% 0.39%} [0315] In conclusion, treatment with the compound of Formula I (5 mg/kg, BID) caused potent inhibition of inflammation in the T-cell transfer colitis model as indicated by reduction in colon weight and symptoms of colitis, normalization of histopathology scores, and inhibition of colon IL-6 and CD3+ immunolabeled cells. Anti-mouse IL-23 antibody was used at 2.5, 7.5, and 48.4 mg/kg dose levels. All the doses of anti-IL-23 antibody showed inhibition of colon weight, symptoms of colitis and histopathology scores, cytokines (IL-1β, IL-6, TNFα, IFN-γ, and IL-17a), and CD3+ immunolabeled cells. For the parameters that showed inhibitions, the effect was dose-dependent between 2.5 and 7.5 mg/kg doses, with a maximal inhibition reached at 7.5 mg/kg dose, except for inhibition of TNF-α. [0316] Combination treatment of 5 mg/kg BID dose of the compound of Formula I with 2.5 and 7.5 mg/kg intraperitoneal dose of anti-IL-23 antibody showed much higher inhibition of disease parameters compared to monotherapy with these agents, showing no-to-minimal residual inflammation which was seen after each monotherapy. These results indicate that different mechanisms for these therapies may complement each other to provide advantage over monotherapy in the treatment of colitis. Table 8: Summary of Results of Compound of Formula I, mIL-23 Ab, and Their Combination in T-Cell Colitis Model in Mice Parameters Vehicle + Vehicle compound mIL-23 Ab mIL-23 Ab compound compound Isotype (49.4 (DI of Formula (2.5 mg/kg, (7.5 mg/kg, of Formula of Formula mg/kg, i.p., Water) I i.p., q7d) i.p., q7d) I I q7d) (5 mg/kg, (5 mg/kg, (5 mg/kg, p.o., BID) p.o., BID) + p.o., BID) + mIL-23 Ab mIL-23 Ab (2.5 mg/kg, (7.5 mg/kg, i.p., q7d) i.p. q7d) Signs and Symptoms Body weight loss (g) -1.12 -0.37 1.49^* 0.48^† 2.02^† 0.79^† 1.17^† 59 Disease activity index- 3.40 2.53 0.53^* 2.07 1.33 1.13 0.67^† summed score (Day 42) Colon weights (g) 0.462 0.438 0.236^* 0.367^† 0.269^† 0.182^† 0.188^† Weight/length ratio 0.067 0.062 0.031^* 0.052^† 0.037^† 0.025^† 0.024^† (g/cm) Colon Histopathology Inflammation score 2.6 2.5 1.1^* 2.1^† 1.4^† 0.5^† 0.3^† Gland Loss score 1.3 1.0 0.1^* 0.9 0.5 0.0^† 0.0^† Erosion score 0.0 0.0 0.0 0.0 0.1 0.0 0.0 Hyperplasia score 2.1 1.5 0.3^* 1.4 0.9 0.1^† 0.1^† Summed score 6.0 5.0 1.5^* 4.4 2.8 0.6^† 0.4^† Edema width (µm) 42.26 39.44 16.12^* 37.5 25.00^† 6.66^† 5.55^† Neutrophil score 0.44 0.43 0.12^* 0.39 0.19 0.04^† 0.03^† Mucosal Thickness (µm) 415.17 356.11 217.22^* 342.85 274.16^† 182.77^† 185.00^† Lymphoid aggregate- 0.0 0.0 0.3^* 0.2 0.2 0.5^† 0.3^† count Lymphoid aggregate-size 120.83 141.66 105.12 137.50 117.42 93.05 89.88 (µm) Protein Normalized Mid Colon Cytokine Levels (pg cytokine/ug protein) IL-1β 0.859 0.569 0.143 0.178^† 0.171^† 0.005^† 0.040^† IL-6 0.048 0.039 0.004^* 0.019^† 0.012^† 0.005^† 0.005^† TNFα 0.012 0.009 0.005 0.007^† 0.011 0.003^† 0.005^† IFN-γ 2.454 1.107 0.070 0.243^† 0.172^† 0.007^† 0.008^† IL-17a 0.134 0.035 0.002 0.009^† 0.001^† 0.002^† 0.001^† Mouse Colons CD3-Positive Immunolabeled Cells CD3+ Total Colon (%) 14.96% 13.70% 5.66% 11.63% 10.09% 1.29% 2.39% *p ≤ 0.05 vs. Vehicle (DI Water); †p ≤ 0.05 vs. Vehicle + Isotype (49.4 mg/kg) 60

Claims

WHAT IS CLAIMED IS: Claim 1: A method of treating an autoimmune disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an inhibitor of the interleukin-23 signaling pathway and a therapeutically effective amount of a modulator of the sphingosine-1-phosphate signaling pathway. Claim 2: The method of claim 1, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. Claim 3: The method of claim 2, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. Claim 4: The method of claim 2, wherein the inhibitor of the interleukin-23 sigaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. Claim 5: The method of claim 4, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. Claim 6: The method of any one of claims 1 to 5, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. Claim 7: The method of claim 6, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

61 fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. Claim 8: The method of claim 7, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

Claim 9: The method of claim 1, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate pathway is the compound of Formula I: .

Claim 10: The method of any one of claims 1 to 8, wherein the inhibitor of the interleukin-23 signaling pathway is administered simultaneously with the modulator of the sphingosine-1-phosphate signaling pathway. Claim 11: The method of any one of claims 1 to 8, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are for administered sequentially. Claim 12: The method of any one of claims 1 to 11, wherein the method further comprises administering an immunomodulator to the patient. 62 Claim 13: The method of claim 12, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. Claim 14: The method of any one of claims 1 to 13, wherein the autoimmune disorder is a chronic inflammatory disorder. Claim 15: The method of claim 14, wherein the chronic inflammatory disorder is a disorder of the digestive tract. Claim 16: The method of claim 15, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. Claim 17: A pharmaceutical composition comprising an inhibitor of the interleukin-23 pathway and a modulator of the sphingosine-1-phosphate signaling pathway. Claim 18: The pharmaceutical composition of claim 17, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin- 17 receptor. Claim 19: The pharmaceutical composition of claim 18, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. Claim 20: The pharmaceutical composition of claim 18, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. Claim 21: The method of claim 20, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. Claim 22: The pharmaceutical composition of any one of claims 17 to 21, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. 63 Claim 23: The pharmaceutical composition of claim 22, wherein the sphingosine-1- phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. Claim 24: The pharmaceutical composition of claim 23, wherein the sphingosine-1- phosphate agonist is the compound of Formula I: .

Claim 25: The pharmaceutical composition of claim 17, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1- phosphate pathway is the compound of Formula I: .

Claim 26: The pharmaceutical composition of any one of claims 17 to 25, wherein the pharmaceutical composition further comprises an immunomodulator. 64 Claim 27: The pharmaceutical composition of claim 26, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. Claim 28: The pharmaceutical composition of any of claims 17 to 27 for use in the treatment of an autoimmune disorder. Claim 29: The pharmaceutical composition for use in the treatment of an autoimmune disorder of claim 28, wherein the autoimmune disorder is a chronic inflammatory disorder. Claim 30: The pharmaceutical composition for use in the treatment of an autoimmune disorder of claim 29, wherein the chronic inflammatory disorder is a disorder of the digestive tract. Claim 31: The pharmaceutical composition for use in the treatment of an autoimmune disorder of claim 30, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. Claim 32: A combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for use in the treatment of an autoimmune disorder. Claim 33: The combination for use in the treatment of an autoimmune disorder of claim 32, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin- 17 and/or an inhibitor of interleukin-17 receptor. Claim 34: The combination for use in the treatment of an autoimmune disorder of claim 33, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. Claim 35: The combination for use in the treatment of an autoimmune disorder of claim 34, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. 65 Claim 36: The combination for use in the treatment of an autoimmune disorder of any one of claims 32 to 35, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. Claim 37: The combination for use in the treatment of an autoimmune disorder of claim 36, wherein the sphingosine-1-phosphate agonist is the compound of Formula I:

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. Claim 38: The combination for use in the treatment of an autoimmune disorder of claim 37, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

Claim 39: The combination for use in the treatment of an autoimmune disorder of claim 32, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate signaling pathway is the compound of Formula I: .

66 Claim 40: The combination for use in the treatment of an autoimmune disorder of any one of claims 32 to 39, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are administered simultaneously. Claim 41: The combination for use in the treatment of an autoimmune disorder of any one of claims 32 to 39, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are administered sequentially. Claim 42: The combination for use in the treatment of an autoimmune disorder of any one of claims 32 to 41, wherein the combination further comprises an immunomodulator. Claim 43: The combination for use in the treatment of an autoimmune disorder of claim 42, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. Claim 44: The combination for use in the treatment of an autoimmune disorder of any one of claims 32 to 43, wherein the autoimmune disorder is a chronic inflammatory disorder. Claim 45: The combination for use in the treatment of an autoimmune disorder of claim 44, wherein the chronic inflammatory disorder is a disorder of the digestive tract. Claim 46: The combination for use in the treatment of an autoimmune disorder of claim 45, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. Claim 47: A method of reducing or suppressing the symptoms of a chronic inflammatory disorder of the digestive tract in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an inhibitor of the interleukin-23 signaling pathway and a therapeutically effective amount of a modulator of the sphingosine-1- phosphate signaling pathway. Claim 48: The method of claim 47, wherein the method results in the reduction or suppression of one or more of the following symptoms: hyperplasia, edema, gland loss, and/or weight gain of the colon. 67 Claim 49: The method of claim 47, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. Claim 50: The method of claim 49, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. Claim 51: The method of claim 49, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, 68isankizum, 68isankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. Claim 52: The method of claim 51, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. Claim 53: The method of any one of claims 47 to 52, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. Claim 54: The method of claim 53, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. Claim 55: The method of claim 54, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: 68

. Claim 56: The method of claim 47, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate pathway is the compound of Formula I: .

Claim 57: The method of any one of claims 47 to 56, wherein the inhibitor of the interleukin-23 signaling pathway is administered simultaneously with the modulator of the sphingosine-1-phosphate signaling pathway. Claim 58: The method of any one of claims 47 to 56, wherein the inhibitor of the interleukin-23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are for administered sequentially. Claim 59: The method of any one of claims 47 to 58, wherein the method further comprises administering an immunomodulator to the patient. Claim 60: The method of claim 59, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. Claim 61: The method according to any one of claims 47 to 60, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. 69 Claim 62: A pharmaceutical kit comprising (i) an inhibitor of the interleukin-23 signaling pathway; (ii) a modulator of the sphingosine-1-phosphate signaling pathway; and (iii) instructions for the administration to a patient of therapeutically effective amounts of the inhibitor of interleukin-23 signaling pathway and the modulator of the sphingosine-1- phosphate signaling pathway in accordance with the severity of an autoimmune disorder in the patient. Claim 63: The pharmaceutical kit of claim 62, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. Claim 64: The pharmaceutical kit of claim 63, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23. Claim 65: The pharmaceutical kit of claim 63, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. Claim 66: The pharmaceutical kit of claim 65, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. Claim 67: The pharmaceutical kit of any one of claims 62 to 66, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. Claim 68: The pharmaceutical kit of claim 67, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

70 fingolimod, ozanimod, ponesimod, siponimod, amiselimod, BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. Claim 69: The pharmaceutical kit of claim 68, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

Claim 70: The pharmaceutical kit of claim 62, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate pathway is the compound of Formula I: .

Claim 71: The pharmaceutical kit of any one of claims 62 to 70, wherein the pharmaceutical kit further comprises an immunomodulator. Claim 72: The pharmaceutical kit of claim 71, wherein the immunomodulator is oral azathioprine, 6-mercaptopurine, or methotrexate. Claim 73: The pharmaceutical kit of any one of claims 62 to 72, wherein the autoimmune disorder is a chronic inflammatory disorder. Claim 74: The pharmaceutical kit of claim 73, wherein the chronic inflammatory disorder is a disorder of the digestive tract. 71 Claim 75: The pharmaceutical kit of claim 74, wherein the chronic inflammatory disorder of digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. Claim 76: Use of a combination of an inhibitor of the interleukin-23 signaling pathway and a modulator of the sphingosine-1-phosphate signaling pathway for the manufacture of a medicament for treating an autoimmune disorder. Claim 77: The use of claim 76, wherein the inhibitor of the interleukin-23 signaling pathway is an inhibitor of interleukin-23 and/or an inhibitor of interleukin-23 receptor and/or an inhibitor of interleukin-17 and/or an inhibitor of interleukin-17 receptor. Claim 78: The use of claim 77, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab, ustekinumab, briakinumab, brazikumab, mirikizumab, guselkumab, risankizumab, ixekizumab, brodalumab, bimekizumab, or a combination thereof. Claim: The use of claim 78, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab. Claim 80: The use of any one of claims 76 to 79, wherein the modulator of the sphingosine-1-phosphate signaling pathway is a sphingosine-1-phosphate agonist. Claim 81: The use of claim 80, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: ,

BMS-986104, CS-0777, GSK2018682, PF-462991, ASP4058, ceralifimod, laquinimod, etrasimod, mocravimod, cenerimod, CP-1050, CBP-307, or a combination thereof. 72 Claim 82: The use of claim 81, wherein the sphingosine-1-phosphate agonist is the compound of Formula I: .

Claim 83: The use of claim 76, wherein the inhibitor of the interleukin-23 signaling pathway is tildrakizumab and the modulator of the sphingosine-1-phosphate signaling pathway is the compound of Formula I: .

Claim 84: The use of any one of claims 76 to 83, wherein the inhibitor of the interleukin- 23 signaling pathway is to be administered simultaneously with the modulator of the sphingosine-1-phosphate signaling pathway. Claim 85: The use of any one of claims 76 to 83, wherein the inhibitor of the interleukin- 23 signaling pathway and the modulator of the sphingosine-1-phosphate signaling pathway are for administration sequentially. Claim 86: The use of any one of claims 76 to 85, wherein the medicament further comprises an immunomodulator. Claim 87: The use of claim 86, wherein the immunomodulator is oral azathioprine, 6- mercaptopurine, or methotrexate. 73 Claim 88: The use of any one of claims 76 to 87, wherein the autoimmune disorder is a chronic inflammatory disorder. Claim 89: The use of claim 88, wherein the chronic inflammatory disorder is a disorder of the digestive tract. Claim 90: The use of claim 89, wherein the chronic inflammatory disorder of the digestive tract is inflammatory bowel disease, Crohn's disease, or ulcerative colitis. 74