Combination therapy for treating inflammatory bowel disease

Abstract

The invention provides methods related to combination therapies comprising an anti- alpha4beta7 antibody, e.g., vedolizumab, and. a pan-JAK inhibitor, e.g., tofacitinib, for treating inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

Description

[0001] COMBINATION THERAPY FOR TREATING INFLAMMATORY BOWEL DISEASE RELATED APPLICATION This application claims priority to US Provisional Application No.63 / 555,546, filed on February 20, 2024, the contents of which are hereby incorporated by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on February 13, 2025, is named T103022_1360WO_SL.xml and is 8,007 bytes in size. FIELD OF THE INVENTION The present invention relates to a combination therapy comprising an anti- 4 7 antibody(e.g., vedolizumab), and a pan-JAK inhibitor, e.g., tofacitinib. BACKGROUND OF THE INVENTION Inflammatory bowel disease is a chronic, relapsing, inflammatory disorder of the gastrointestinal (GI) tract. Examples of IBD include ulcerative colitis and Crohn’s disease. Ulcerative colitis is characterized by superficial, continuous mucosal inflammation and ulcers limited to the colon. The prevalence of UC is approximately 200 / 100,000 of the United States (US) population (Loftus, E. V., Jr.2004. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology, 126, 1504-17.). The pathophysiology of UC is complex with multiple environmental and genetic factors interacting to cause expression of disease. Untreated, the clinical course of UC is unpredictable and marked by alternating periods of exacerbation and remission. Approximately 15% of patients experience an aggressive disease course, and 20% of these patients may require hospitalization for severe disease activity. The 5- and 10-year cumulative risk of colectomy is 10% to 15%, primarily limited to patients with moderate to severe disease activity; a subset of hospitalized patients with acute severe UC have short-term colectomy rates of 25% to 30% (Feuerstein, J. D., et al.2020. AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology, 158, 1450-1461.; and Zafer, M., Zhang, H., Dwadasi, S., Goens, D., Paknikar, R., Dalal, S., Cohen, R. D., Pekow, J., Rubin, D. T., Sakuraba, A. & Micic, D.2022. A Clinical Predictive Model for One-year Colectomy in Adults Hospitalized for Severe Ulcerative Colitis. Crohns Colitis 360, 4, otab082.). Treatment of UC is chosen according to disease activity and the extent of colonic involvement. There are a number of different drug classes for long-term management ofmoderate to severe UC, including TNF- antagonists (infliximab, adalimumab, golimumab),anti-integrin agents (VDZ), Janus kinase inhibitors (TOF), interleukin 12 / 23 antagonist (ustekinumab), and immunomodulators (thiopurines, MTX) (Burri, E., et al, 2020. Treatment Algorithm for Mild and Moderate-to-Severe Ulcerative Colitis: An Update. Digestion, 101 Suppl 1, 2-15.). Corticosteroids are recommended for short-term use due to the potential for serious adverse effects. Immunomodulators, although effective for the maintenance (but not induction) of remission, are also associated with serious adverse effects. They do, however, demonstrate a synergistic effect with biologics (Hashash, J. G., Fadel, C. G. A., Rimmani, H. H. & Sharara, A. I.2021. Biologic monotherapy versus combination therapy with immunomodulators in the induction and maintenance of remission of Crohn's disease and ulcerative colitis. Ann Gastroenterol, 34, 612-624.). Advanced treatments for UC typically result in clinical remissionrates at 1 year of 30% to 50%, suggesting there may be a therapeutic ceiling for the use of singleagents (Danese, S., et al, L.2022. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut, 71, 2380-2387.). Additionally, short- and long-term (1-year) clinical remission rates in Crohn’s disease (CD) currently range between 30% and 50%, suggesting that a therapeutic ceiling has been reached with single biologic agents including vedolizumab (Berinstein, E. M., et al.2023. Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature. Dig Dis Sci, 68(6), 2604-23). There is, therefore, an overall unmet medical need within the IBD community for patients with moderately to severely active disease who may not respond to monotherapy or the combination of a biologic with an immunosuppressant. Dual targeted therapy (DTT) has been gaining increasing interest because of the varied cytokine pattern driving inflammatory bowel disease (IBD) (Berinstein et al.2023; Neurath, M. F.2014. Cytokines in inflammatory bowel disease. Nat Rev Immunol, 14(5), 329-42) targeting more than one pathogenic pathway simultaneously may provide an additive or even synergistic benefit compared with monotherapy (Solitano, V., et al.2023. Advanced combination treatment with biologic agents and novel small molecule drugs for inflammatory bowel disease. Gastroenterol Hepatol, 19(5), 251). Thus, combination therapies for IBD may provide additional treatments for IBD patients in need. SUMMARY OF THE INVENTION In various aspects, the present disclosure provides a method of treating an inflammatorybowel disease (IBD) by administering a combination of an anti- 7 antibody, or an antigen-binding fragment thereof, and a pan-JAK inhibitor, such as tofacitinib. The combination therapydescribed herein may include administration of both an anti- 7 antibody and a pan-JAKinhibitor during an induction phase of treatment for IBD in a patient, followed by monotherapycomprising administration of the anti- 7 antibody for maintenance (in the absence of the pan-JAK inhibitor). In one aspect, provided herein is a method of treating a human patient in need thereof, e.g., having inflammatory bowel disease (IBD), said method comprising administering ahumanized anti- 4 7 antibody and a pan-Janus kinase (JAK) inhibitor, e.g., tofacitinib, to thehuman patient, wherein the anti- 4 7 antibody is an IgG1 antibody; comprises a heavy chainvariable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6. In one embodiment, the human patient has inflammatory bowel disease (IBD). In one embodiment, the IBD is ulcerative colitis (UC). In one embodiment, the UC is moderately to severely active UC. In one embodiment, the human patient has ulcerative colitis (UC), e.g., moderately to severely active UC. In one embodiment, the IBD is Crohn’s disease. In one embodiment, the Crohn’s disease is moderately to severely active Crohn’s disease. In one embodiment, the human patient has Crohn’s disease, e.g., moderately to severely active Crohn’s disease. In one embodiment, the human patient is biologic-naïve. In one embodiment, the human patient had an inadequate response or intolerance to at least one TNF-alpha inhibitor. In one embodiment, the human patient had an inadequate response or intolerance to two TNF-alpha inhibitors. In one embodiment, the human patient had an inadequate response or a lack of remissionafter initial treatment with an anti- 4 7 antibody (optionally with vedolizumab); an inadequateresponse with, loss of response to, or was dependent on corticosteroid therapy; an inadequate response with, loss of response to, or was dependent on an immunomodulator; and / or an inadequate response with, loss of response to, or was intolerant to treatment with biologic therapy. In one embodiment, the human patient had an inadequate response, treatment failure, lack of remission, loss of response, or was intolerant to treatment with two agents selected from ananti- 4 7 antibody, optionally with vedolizumab; corticosteroid therapy; an immunomodulator;or a biologic therapy. In one embodiment, the treating of the human patient results in a reduction, optionally an elimination, of corticosteroid use or immunomodulator use. In one embodiment, the human patient has not been previously exposed to at least one of, optionally has not been previously exposed to any of, approved or investigational anti-integrins (e.g., vedolizumab or natalizumab), or JAK inhibitors (e.g., TOF, upadacitinib), or interleukin 12 / 23 inhibitors (e.g., ustekinumab), or S1P receptor agonists (e.g., ozanimod). In one embodiment, an anti- 4 7 antibody and a pan-JAK inhibitor are administered tothe human patient during an induction phase. In certain embodiments, the induction phase is eight weeks. In some embodiments, the pan-JAK inhibitor is selected from the group consisting of tofacitinib, baricitinib, cerdulatinib, delgocitinib, gusaticinib, izencitinib, momelotinib, and peficitinib. In certain embodiments. the pan-JAK inhibitor is tofacitinib. In certain embodiments, 10 mg of tofacitinib is orally administered twice daily. In one embodiment, 300 mg of the anti- 4 7 antibody is intravenously administered tothe human patient at Weeks 0, 2, and 6. Also disclosed herein is an induction phase followed by a maintenance phase comprisingadministration of the anti- 4 7 antibody as a monotherapy.In one embodiment, a maintenance phase begins when the human patient achieves clinical remission and / or a clinical response. In one embodiment, the human patient achieves an improvement in health-related quality of life measure as compared to a baseline level. In one embodiment, the health-related quality of life measure is measured by an assessment tool selected from Inflammatory Bowel Disease Questionnaire (IBDQ), Health- Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items); a Functional Assessment of Chronic Illness Therapy—Fatigue Scale (FACIT-F), or a Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). In one embodiment, the human patient has an improvement in bowel urgency. In one embodiment, the human patient achieves a reduction in C-reactive protein (CRP) level or a reduction in fecal calprotectin concentrations. In one embodiment, the maintenance phase begins at Week 14. In one embodiment, the human patient is intravenously administered a first dose of 300mg of the anti- 4 7 antibody at Week 0, followed by a second dose of 300 mg of the anti- 4 7antibody at Week 2. In one embodiment, the method further comprises intravenouslyadministering a third dose of 300 mg of the anti- 4 7 antibody at Week 6.In one embodiment, 10 mg of tofacitinib is orally administered twice daily for eight weeks. In one embodiment, 300 mg of the anti- 4 7 antibody is intravenously administered tothe human patient every eight weeks starting at week 14. In one embodiment, the human patient achieves a clinical remission. In one embodiment, the human patient achieves a clinical remission by week 8. In one embodiment, clinical remission is achieved at week 52. In one embodiment, the clinical remission is corticosteroid-free clinical remission. In certain embodiments, the clinical remission is defined by a complete Mayo score of 2 points and no individual subscore >1 point. In one embodiment, the human patient is subcutaneously administered a dose of 108 mgof the anti- 4 7 antibody at week 6, followed by a 108 mg dose every two weeks thereafter.In one embodiment, the human patient is subcutaneously administered a dose of 108 mgof the anti- 4 7 antibody at week 14, followed by a 108 mg dose every two weeks thereafter.In a certain embodiment, the 108 mg dose is self-administered. In another embodiment, the human patient is administered a first dose of 300 mg of theanti- 4 7 antibody at Week 0, followed by a second dose of 300 mg of the anti- 4 7 antibodyat Week 2. In certain embodiments, the method further comprises administering a third dose of300 mg of the anti- 4 7 antibody at Week 6.In one embodiment, the method further comprises administering 300 mg of the anti- 4 7antibody to the human patient every eight weeks starting at 14 weeks. In other embodiments, 300 mg of the anti- 4 7 antibody is administered to the humanpatient every four weeks instead of every eight weeks if the patient is not showing clinical improvement. In one embodiment, the human patient is administered a first dose of 300 mg of the anti- 47 antibody at week 0, followed by a second dose of 300 mg of the anti- 4 7 antibody atweek 2, followed by third dose of 108 mg of the anti- 4 7 antibody at week 6, followed by a108 mg dose every two weeks thereafter. In certain embodiments, the 108 mg dose is administered subcutaneously and / or the 108 mg dose is self-administered. In one embodiment, the pan-JAK inhibitor is tofacitinib. In certain embodiments, tofacitinib is orally administered twice daily for eight weeks. In some embodiments, 10 mg of tofacitinib is administered. In certain embodiments, the 300 mg of the anti- 4 7 antibody is administeredintravenously. In one embodiment, the anti- 4 7 antibody comprises a heavy chain variable domaincomprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5. In one embodiment, the anti- 4 7 antibody is vedolizumab. In one aspect, provided herein is a method of treating a human patient having an inflammatory bowel disease (IBD), said method comprising administering a humanized anti- 47 antibody and tofacitinib to the human patient, wherein the humanized anti- 4 7 antibody isan IgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6, wherein the human patient is intravenouslyadministered a first dose of 300 mg of the anti- 4 7 antibody at week 0, followed by a seconddose of 300 mg of the anti- 4 7 antibody at week 2; and wherein 10 mg of tofacitinib is orallyadministered twice daily for eight weeks. In one embodiment, the method further comprises intravenously administering a thirddose of 300 mg of the anti- 4 7 antibody at week 6.In one embodiment, 300 mg of the anti- 4 7 antibody is intravenously administered tothe human patient every eight weeks starting at week 14. In one embodiment, the human patient achieves a clinical remission by week 8. In one embodiment, clinical remission is achieved at week 52. In one embodiment, the clinical remission is achieved at week 8 and at week 52. In one embodiment, the clinical remission is corticosteroid-free clinical remission. In one embodiment, the clinical remission is defined by a complete Mayo score of 2 points and no individual subscore >1 point. In one embodiment, the human patient achieves an improvement in health-related quality of life as compared to a baseline level. In one embodiment, the health-related quality of life is measured by an assessment tool selected from Inflammatory Bowel Disease Questionnaire (IBDQ), Health-Related Quality-of- Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function Function (5 items); a Functional Assessment of Chronic Illness Therapy—Fatigue Scale (FACIT-F), or a Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). In one embodiment, the human patient has an improvement in bowel urgency. In one embodiment, the human patient is subcutaneously administered a dose of 108 mgof the anti- 4 7 antibody at week 6, followed by a 108 mg dose every two weeks thereafter.In one embodiment, the human patient is subcutaneously administered a dose of 108 mgof the anti- 4 7 antibody at week 14, followed by a 108 mg dose every two weeks thereafter.In one embodiment, the 108 mg dose is self-administered. In one embodiment, the anti- 4 7 antibody comprises a heavy chain variable domaincomprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5. In one embodiment, the anti- 4 7 antibody is vedolizumab.Also contemplated in the invention are the dosing regimens and patient characteristics described in the Examples provided below. BRIEF DESCRIPTION OF DRAWINGS FIG.1 shows a schematic of the study design. Abbreviations: BID: twice daily; IV: intravenous; LOR: loss of response; PNR: primary nonresponse; Q8W: every 8 weeks; TOF: tofacitinib;TNF- : tumor necrosis factor–alpha; UC: ulcerative colitis; VDZ: vedolizumab.DETAILED DESCRIPTION OF THE INVENTION I. Definitions In order that the present invention may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also part of this invention. The cell surface molecule, “ 4 7 integrin,” or “ 4 7” (used interchangeably throughout)is a heterodimer of an 4 chain (CD49D, ITGA4, OMIM 192975, human GeneID 3676) and a 7 chain (ITGB7, OMIM 147559; human GeneID 3695). Human 4-integrin and 7-integrin genes (GenBank (National Center for Biotechnology Information, Bethesda, Md.) RefSeq Accession numbers NM_000885 and NM_000889, respectively) are expressed by B and Tlymphocytes, particularly memory CD4+ lymphocytes. Typical of many integrins, 4 7 canexist in either a resting or activated state. Ligands for 4 7 include vascular cell adhesionmolecule (VCAM), fibronectin and mucosal addressin (MAdCAM (e.g., MAdCAM-1)). As used herein, an antibody, or antigen-binding fragment thereof, that has “bindingspecificity for the 4 7 complex” binds to 4 7, but not to 4 1 or EB7. Vedolizumab is anexample of an antibody that has binding specificity for the 4 7 complex.As used herein, an “anti- 4 7 antibody” or “anti- 4 7 integrin antibody” refers to anantibody which specifically binds to human 4 7 integrin. In one embodiment, an anti- 4 7antibody blocks or inhibits the binding of 4 7 integrin to one or more of its ligands. In oneembodiment, an anti- 4 7 antibody binds to 4 7, but not to 4 1 or EB7. In oneembodiment, an anti- 4 7 antibody is vedolizumab.The term “antibody” broadly refers to an immunoglobulin molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region (CH). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. As used herein, the term “antibody fragment” or “antigen-binding fragment” of an antibody refers to Fab, Fab’, F(ab)2, and Fv fragments, single chain antibodies, functional heavy chain antibodies (nanobodies), as well as any portion of an antibody having specificity toward at least one desired epitope, that competes with the intact antibody for specific binding (e.g., an isolated portion of a complementarity determining region having sufficient framework sequences so as to bind specifically to an epitope). Antigen binding fragments can be produced by recombinant techniques, or by enzymatic or chemical cleavage of an antibody. As used herein, the term “humanized antibody” refers to an antibody that is derived from a non-human antibody (e.g., murine) that retains or substantially retains the antigen binding properties of the parent antibody but is less immunogenic in humans and contains minimal sequence derived from non-human immunoglobulins. Generally, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops (complementary determining regions) correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.2:593-596 (1992). The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example. As used herein, the term “recombinant antibody” refers to an antibody produced as the result of the transcription and translation of a gene carried on a recombinant expression vector. In one embodiment, the vector has been introduced into a host cell. Alternatively, a vector can be used in a cell free system. As used herein, a “pan-JAK inhibitor” or “pan-Janus kinase (JAK) inhibitor” refers to a therapeutic agent, e.g., a therapeutic compound, that inhibits the activity of at least two (e.g., at least three) of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, and / or TYK2). An example of a pan-JAK inhibitor is tofacitinib (XELJANZ), which inhibits JAK1, JAK2, JAK3, and to a lesser extent TYK2 phosphorylation. The term "baseline" refers to a starting point used for a comparison. In a preferred embodiment, baseline is Day 1 of treatment. The term "treatment" or "treating" means any treatment of a disease or disorder (e.g., IBD) in a human subject, including: preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop; inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and / or relieving the disease or disorder that is, causing the regression of clinical symptoms. In one embodiment, treatment of IBD is achieved where a subject having IBD sees an improvement in symptoms as measured by an accepted IBD index (e.g., a clinical measure for ulcerative colitis) dosing regimen with ananti- 4 7 antibody and a pan-JAK inhibitor.The term “combination therapy” refers to the use of two or more therapies, e.g., two or more agents, for the treatment of a disease or disorder. Use of the term "in combination" or “combination therapy” does not restrict the order in which therapeutic agents are administered to a subject having a disease. The term “combination therapy” is not intended to refer to apharmaceutical composition comprising two active agents, e.g., an anti- 4 7 antibody and apan-JAK inhibitor. The terms "patient" and "subject" are used interchangeably herein. Preferably, a patient is a human patient. As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" includes values slightly outside the cited values, namely, plus or minus 5%. II. Combination Therapies Disclosed herein is a treatment method comprising a combination therapy that decreasesinflammation associated with IBD, e.g., ulcerative colitis, by blocking the trafficking of 4 7 Tcells to the lamina propria of the colon via an anti- 4 7 antibody, such as vedolizumab, andmodulating the signaling of the JAK-dependent cytokines underlying the inflammatory burden and signs and symptoms of IBD using a pan-JAK inhibitor, such as tofacitinib. Vedolizumab (ENTYVIO; Takeda) and tofacitinib (XELJANZ; Pfizer) are both effective for treating patients with moderately to severely active ulcerative colitis (UC), particularly in patients who have had an inadequate response, lost response, or were intolerant to other treatments. Vedolizumab and tofacitinib have different mechanisms of action: vedolizumab is anantibody that binds to the human lymphocyte integrin 4 7, thus impairing the migration of guthoming lymphocytes to the gastrointestinal (GI) mucosa, whereas tofacitinib is a non-selective and reversible Janus kinase (JAK) inhibitor that modulates the signaling of the JAK-dependent cytokines associated with inflammation associated with IBD. VDZ’s efficacy is decreased inpatients who have failed a TNF- antagonist but combining it with tofacitinib may provide thebenefit of improving remission rates without compromising safety (Sands, B. E. et al.2017. Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naive to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis, 23, 97-106.). Provided herein are methods for treating a human patient having inflammatory bowel disease(IBD) using a combination therapy comprising an anti- 4 7 antibody, e.g., vedolizumab, and apan-JAK inhibitor, e.g., tofacitinib. The combination therapy disclosed herein includes administering a pan-JAK inhibitor, such as tofacitinib, to the human patient in need thereof, e.g., patient having ulcerative colitis. In some aspects, the therapeutic method has two phases, i.e., an induction phase and a maintenance phase. In one embodiment, a combination therapy as described herein is administered to a human patient having IBD in an induction phase. In the induction phase, ananti- 4 7 antibody and a pan-JAK inhibitor are administered in a way that quickly provides aneffective amount of the antibody and pan-JAK inhibitor suitable for a certain purpose(s), such as inducing a clinical response and ameliorating inflammatory bowel disease symptoms. A patient can be administered an induction phase treatment when first being treated by ananti- 4 7 antibody and / or a pan-JAK inhibitor, when being treated after a long absence from therapy, e.g., more than three months, more than four months, more than six months, more than nine months, more than one year, more than eighteen months or more than two years since anti- 47 antibody therapy or during maintenance phase of anti- 4 7 antibody therapy if there hasbeen a return of inflammatory bowel disease symptoms, e.g., a relapse from remission of disease. In the maintenance phase, the anti- 4 7 antibody is administered according to a dosingregimen such that treatment continues the response achieved by induction therapy with a stablelevel of anti- 4 7 antibody. A maintenance regimen can prevent return of symptoms or relapseof inflammatory bowel disease. In a certain embodiment, a treatment method for treating IBD in a patient comprises aninduction phase comprising a combination therapy (e.g., an anti- 4 7 antibody and a pan-JAKinhibitor) and a maintenance phase comprising a monotherapy (e.g., anti- 4 7 antibody in theabsence of a pan-JAK inhibitor). In certain embodiments, a maintenance phase comprising monotherapy (e.g., anti- 4 7antibody in the absence of a pan-JAK inhibitor), can include administration of an agent that is not a pan-JAK inhibitor. In certain embodiments, maintenance comprising monotherapy can include intermittent administration of one or more non-pan-JAK agents (a non-pan-JAK agent inhibits the activity of only one of the Janus kinase family of enzymes, e.g., upadacitinib which inhibits JAK1), for example, to treat or otherwise manage symptoms of IBD. The disclosed combination therapy is effective for treating IBD, including Crohn’s disease or ulcerative colitis. In certain embodiments, the human patient has ulcerative colitis, e.g., moderately to severely active ulcerative colitis. In other embodiments, the human patient receiving the therapeutic methods disclosed herein has Crohn’s disease, e.g., moderately to severely active Crohn’s disease. In a combination therapy, an anti- 4 7 antibody can be administered before,concurrently with, or after administration of a pan-JAK inhibitor to a subject having inflammatory bowel disease (IBD), e.g., ulcerative colitis. Similarly, the pan-JAK inhibitor canbe administered before, concurrently with, or after administration of the anti- 4 7 antibody to asubject having inflammatory bowel disease (IBD), e.g., ulcerative colitis. In one embodiment, the anti- 4 7 antibody (e.g., vedolizumab) is administered beforethe pan-JAK inhibitor, (e.g., tofacitinib), for treatment. In other embodiments, the anti- 4 7antibody (e.g., vedolizumab) is administered after the pan-JAK inhibitor, (e.g., tofacitinib). Inyet other embodiments, the anti- 4 7 antibody (e.g., vedolizumab) is administeredconcomitantly with the pan-JAK inhibitor, (e.g., tofacitinib). Further, an anti- 4 7 antibody (e.g., vedolizumab) and a pan-JAK inhibitor may beadministered in a combination therapy whereby one agent is administered according to its own specific dosing regimen that overlaps in time, e.g., eight weeks, with the other agent. The anti- 4 7 antibody (e.g., vedolizumab) may be administered according to a dosingregimen comprising administering a first dose of 300 mg of the anti- 4 7 antibody at week 0,followed by a second dose of 300 mg of the anti- 4 7 antibody at week 2. In someembodiments, the method further comprises administering a third dose of 300 mg of the anti- 47 antibody at week 6. The dosing regimen of the anti- 4 7 antibody (e.g., vedolizumab)may further comprise intravenously administering 300 mg of the anti- 4 7 antibody to thehuman patient every eight weeks starting at 14 weeks. If needed, 300 mg of the anti- 4 7antibody may be administered to the human patient every four weeks instead of every eight weeks during maintenance phase if the patient is not showing clinical improvement or experiences a return of inflammatory bowel disease symptoms, e.g., a relapse from remission of disease. A pan-JAK inhibitor is also administered according to the disclosure herein. In other embodiments, the anti- 4 7 antibody (e.g., vedolizumab) is administeredaccording to a dosing regimen comprising administering a first dose of 300 mg of the anti- 4 7antibody at week 0, followed by a second dose of 300 mg of the anti- 4 7 antibody at week 2,followed by third dose of 108 mg of the anti- 4 7 antibody at week 6, followed by a 108 mgdose every two weeks thereafter. If needed, 108 mg of the anti- 4 7 antibody may beadministered to the human patient every week instead of every two weeks during maintenance phase if the patient is not showing clinical improvement or experiences a return of inflammatory bowel disease symptoms, e.g., a relapse from remission of disease. A pan-JAK inhibitor is also administered according to the disclosure herein. In some embodiments, the anti- 4 7 antibody (e.g., vedolizumab) is administeredaccording to a dosing regimen comprising intravenously administered a first dose of 300 mg ofthe anti- 4 7 antibody at week 0, followed by a second dose of 300 mg of the anti- 4 7antibody at week 2, further comprising intravenously administering a third dose of 300 mg of theanti- 4 7 antibody at week 6 and subcutaneously administering a dose of 108 mg of the anti-4 7 antibody at week 14, followed by a 108 mg dose every two weeks thereafter. If needed,108 mg of the anti- 4 7 antibody may be administered to the human patient every week insteadof every two weeks during maintenance phase if the patient is not showing clinical improvement or experiences a return of inflammatory bowel disease symptoms, e.g., a relapse from remission of disease. The anti- 4 7 antibody may be administered to the human patient intravenously orsubcutaneously. For example, the 300 mg dose of the anti- 4 7 antibody may be administeredto the human patient intravenously, while the 108 mg dose of the anti- 4 7 antibody may beadministered subcutaneously. In certain embodiments, the anti- 4 7 antibody may be self-administered subcutaneously by the human patient. In one embodiment, the anti- 4 7 antibody is administered to the human patient havingIBD, e.g., ulcerative colitis, according to a dosing regimen comprising intravenouslyadministering a first dose of 300 mg of the anti- 4 7 antibody to the human patient at week 0,followed by a second dose of 300 mg of the anti- 4 7 antibody intravenously administered atweek 2, followed by third dose of 300 mg of the anti- 4 7 antibody intravenously administeredat week 6, followed by intravenously administering 300 mg of the anti- 4 7 antibody to thehuman patient every eight weeks starting at 14 weeks. A pan-JAK inhibitor is also administered according to the disclosure herein. In another embodiment, the anti- 4 7 antibody is administered to the human patienthaving IBD, e.g., ulcerative colitis, according to a dosing regimen comprising intravenouslyadministering a first dose of 300 mg of the anti- 4 7 antibody to the human patient at week 0,followed by a second dose of 300 mg of the anti- 4 7 antibody intravenously administered atweek 2, followed by third dose of 108 mg of the anti- 4 7 antibody subcutaneouslyadministered at week 6, followed by a 108 mg dose subcutaneously administered every two weeks thereafter. A pan-JAK inhibitor is also administered according to the disclosure herein. In one embodiment, the pan-JAK inhibitor is tofacitinib and is administered orally twice daily for eight weeks beginning at Week 0. In certain embodiments, 10 mg of tofacitinib is administered to the human patient. In an embodiment, tofacitinib is administered twice daily for eight weeks. In some embodiments, tofacitinib is administered for at least eight weeks. In other embodiments, tofacitinib is administered one to eight weeks.In some embodiments, the anti- 4 7 antibody is administered to a human patient havingIBD as a first dose of 300 mg at week 0, followed by a second dose of 300 mg of the anti- 4 7antibody at week 2, followed by third dose of 300 mg of the anti- 4 7 antibody at week 6. Themethod may further comprise administering 300 mg of the humanized anti- 4 7 antibody to thehuman patient every eight weeks beginning 8 weeks after the third dose. In an alternativeembodiment, the method described herein may comprise administering 300 mg of the anti- 4 7antibody to the human patient every four weeks if the human patient is not showing clinical improvement, e.g., clinical remission of Crohn’s disease or ulcerative colitis. In otherembodiments, the method comprises administering, e.g., intravenously, 300 mg of the anti- 4 7antibody to the human patient every four weeks beginning eight weeks after the third dose. In some embodiments in combination with dosing regimens described herein for the anti- 47 antibody, a pan-JAK inhibitor is administered orally (e.g., as oral capsules or tablets). In anembodiment, the pan-JAK inhibitor is administered twice daily for eight weeks. In some embodiments, the pan-JAK inhibitor is administered for at least eight weeks. In other embodiments, the pan-JAK inhibitor is administered for one to eight weeks. In an embodiment, 10 mg of the pan-JAK inhibitor is administered. In some embodiments, the human patient is administered a first dose of 300 mg of theanti- 4 7 antibody at week 0, followed by a second dose of 300 mg of the anti- 4 7 antibody,at week 2, and a third dose of 300 mg of the anti- 4 7 antibody at week 6 in combination withtofacitinib. In some embodiments, 10 mg tofacitinib is administered orally daily, e.g., twice daily, for an initial eight weeks. The combination therapy may be adjusted according to certain clinical achievements orfailures seen in the human patient receiving the pan-JAK inhibitor and the anti- 4 7 antibody.In some embodiments, the human patient is one previously treated with oral corticosteroids (e.g., at a dose of 40 mg / d prednisone or 9 mg / d budesonide or equivalent for at least 2 weeks prior to treatment) and is tapered off of the oral corticosteroids. In some embodiments, a human patient receiving oral corticosteroids begins a corticosteroid taper beginning at baseline. For example, in certain embodiments, for prednisone at doses >10 mg / d (or equivalent), the dose may be reduced at a rate of 5 mg / week until the dose reaches 5 mg / d, and then the dose may be reduced at a rate of 2.5 mg / week until discontinuation. For prednisone at doses 10 mg / d (or equivalent) achieved by tapering, the dose may be reduced at a rate of 2.5 mg / week until discontinuation. As an additional example, budesonide may be reduced at a rate of 3 mg every 2 weeks until discontinuation. If the human patient has a clinical worsening of disease (i.e., recurrence of symptoms) during the corticosteroid taper, the dose may be increased (e.g., increased once) up to the dose received at enrollment. A human patient who is administered a therapy described herein comprising the anti- 47 antibody and the pan-JAK inhibitor may achieve certain clinical endpoints indicative ofefficacy. For example, in some embodiments, a human patient who is administered a combination therapy as disclosed herein may achieve a clinical remission. For example, in some embodiments, the clinical remission for an ulcerative colitis patient is defined as a complete Mayo score (e.g., stool frequency, rectal bleeding, physician’s global assessment (PGA), and endoscopic subscore) of 2 points and no individual subscore >1 point (e.g., at Week 8). The complete Mayo Clinic Score includes 4 variables: Stool frequency, rectal bleeding, a Physician's Global Assessment (PGA) and Mayo endoscopic subscore (MES). Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease and summed to give a total disease activity score (range, 0-12), with higher scores representing more severe disease activity. In certain embodiments, the clinical remission is defined as a complete Mayo score (e.g., stool frequency, rectal bleeding, physician’s global assessment (PGA), and endoscopic subscore) of 2 points and no individual subscore >1 point at Week 8. In some embodiments, the participants achieve durable clinical remission (e.g., as defined as complete Mayo score clinical remission at Weeks 8 and 52). In some embodiments, the clinical remission is defined as a partial Mayo score (stool frequency, rectal bleeding, PGA) score of 2 and no individual subscore >1) (e.g., at Weeks 8, 14, and 26). The partial Mayo Score includes 3 variables of the Mayo Clinic Score: stool frequency, rectal bleeding and PGA. Each variable is scored on a 4-point scale (0-3 points) where 0=none and 3=severe disease. These scores are summed to give a total score range of 0 to 9 where higher scores indicate maximum disease activity. In some embodiments, the clinical remission is defined as a modified Mayo score (stool frequency, rectal bleeding, and endoscopic subscore) of 2 with endoscopic subscore 1, rectal bleeding = 0, and stool frequency 1) (e.g., at Weeks 8 and 52). The modified Mayo Score includes 3 variables: stool frequency, rectal bleeding and MES. Each variable is scored on a 4- point scale (0-3 points) where 0=none and 3=severe disease. These scores are summed to give a total score range of 0 to 9 where higher scores indicate maximum disease activity. In some embodiments, the human patient achieves a corticosteroid-free clinical remission. In some embodiments, a human patient using oral corticosteroids at baseline achieves a complete Mayo score clinical remission (e.g., at Week 8) and can discontinue corticosteroids (e.g., at Week 8). In some embodiments, a human patient using oral corticosteroids at baseline achieves a complete Mayo score clinical remission at Week 52 and has discontinued corticosteroids within 90 days prior to Week 52. In some embodiments, the clinical remission is achieved by Week 8 to Week 52. In certain embodiments, the clinical remission is achieved by Week 8. In certain embodiments, the clinical remission is achieved by Week 14. In certain embodiments, the clinical remission is achieved by Week 26. In certain embodiments, the clinical remission is achieved by Week 52. In other embodiments, a human patient who is administered a combination therapy as disclosed herein may achieve a clinical response. In some embodiments, the clinical response defined as a reduction in complete Mayo score of 3 points and 30% from baseline (or a reduction in partial Mayo score of 2 points and 25% from baseline, if the complete Mayo score was not performed at the visit) with an accompanying decrease in rectal bleeding subscore of 1 point or absolute rectal bleeding subscore of 1 point (e.g., at Weeks 2, 6, 8, 14, 26, and 52). In some embodiments, the human patient achieves mucosal healing (defined as Mayo Endoscopic subscore (MES) of 1 point) (e.g., by Week 52). MES is a subscale of the Mayo score, an instrument designed to measure disease activity of UC. The subscale is graded from 0 to 3 based on the findings on endoscopy where 0= Normal appearance of mucosa, 1=mild disease (erythema, decreased vascular pattern), 2=moderate disease (marked erythema, lack of vascular pattern, friability, erosions), 3=severe disease (spontaneous bleeding, ulceration). Higher scores indicate more severe disease. In some embodiments, the clinical response is achieved by Week 2 to Week 52. In certain embodiments, the clinical response is achieved by Week 2. In certain embodiments, the clinical response is achieved by Week 6. In certain embodiments, the clinical response is achieved by Week 8. In certain embodiments, the clinical response is achieved by Week 14. In certain embodiments, the clinical response is achieved by Week 26. In certain embodiments, the clinical response is achieved by Week 38. In certain embodiments, the clinical response is achieved by Week 52. A human patient who is administered a combination therapy as disclosed herein may achieve other measures of therapeutic response or remission, such as histological remission or changes in the level of markers in a biological sample from the patient. For example, in some embodiments, the human patient achieves histological remission (defined as Geboes score <2B.0) (e.g., at Week 52). The Geboes score is a histological grading system for assessing histological disease activity in UC. The Geboes score evaluates 7 histological features. It consists of 6 grades (0-6). Each of the grades is divided into subgrades, based on the severity of tissue abnormalities or the extent of inflammatory cell infiltration. The Geboes score ranges from 0.0 to 5.4, and higher grades are indicative of more severe disease activity. In some embodiments, the combination therapy results in a change (e.g., decrease) in a biomarker, such as C-reactive protein (CRP) or fecal calprotectin, from baseline. CRP is a useful marker of inflammation in participants with inflammatory bowel disease (IBD). In participants with UC, elevated CRP has been associated with severe clinical activity. Fecal calprotectin is a biomarker for intestinal inflammatory activity. In some embodiments, the combination therapy results in a change in CRP levels from baseline (e.g., to Weeks 2, 6, 8, 14, 26, 38, and 52) as detected in a sample from the human patient. In some embodiments, the combination therapy results in a change in fecal calprotectin levels from baseline (e.g., to Weeks 2, 6, 8, 14, 26, 38, and 52) as detected in a sample from the human patient. In some embodiments, the combination therapy results in a change in health-related quality of life. In some embodiments, health-related quality of life is measured by a change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline to, e.g., Weeks 8, 26, and 52, in the human patient. The IBDQ is an instrument used to assess quality of life in adult participants with inflammatory bowel disease (IBD). It includes 32 questions on 4 domains of Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). Participants are asked to recall symptoms and quality of life from the last 2 weeks and rate each item on a 7-point Likert scale (1=worst to 7=best). A total IBDQ score is calculated by summing the scores from each domain; the total IBDQ score ranges from 32 to 224, with lower scores reflecting worse HRQOL. A positive change from Baseline indicates improvement. In some embodiments, the combination therapy results in a change in Functional Assessment of Chronic Illness Therapy—Fatigue Scale (FACIT-F) score from baseline to Weeks 8, 26, and 52 in the human patient. The FACIT-F is a validated, 13-item questionnaire to assess fatigue in participants with a variety of chronic illnesses, including participants with IBD. Items are rated on a 5-point Likert scale and the total score ranges from 0 to 52 with lower scores representing greater fatigue. In some embodiments, the combination therapy results in disease clearance. In certain embodiments disease clearance is determined based on the proportion of participants with corticosteroid-free symptomatic remission (rectal bleeding subscore = 0) plus endoscopic remission (MES 1) plus histologic remission (Geboes score <2B.0) (e.g., at Week 52). In some embodiments, the combination therapy results in a decrease in bowel urgency, stool frequency, rectal bleeding, and / or abdominal pain. In certain embodiments, such improvements are measured by a change in Urgency Numeric Rating Scale (Urgency NRS), stool frequency, rectal bleeding, and abdominal pain scores from baseline to, e.g., Weeks 1, 2, 4, 6, 8, 14, 26, or 52. In some embodiments, the combination therapy results in a decrease in colectomy rates, hospitalizations, and required surgeries (e.g., as measured based on the rate of colectomy, hospitalizations, and surgeries from baseline to Week 52). In some embodiments, the method described herein may comprise administering 300 mgof the anti- 4 7 antibody to the human patient every four weeks if the human patient is notshowing clinical improvement, e.g., clinical remission of Crohn’s disease or ulcerative colitis. In some embodiments, the patient has ulcerative colitis disease and the clinical improvement is a complete Mayo score (e.g., stool frequency, rectal bleeding, physician’s global assessment (PGA), and endoscopic subscore) of 2 points and no individual subscore >1 point at Week 8. In certain embodiments, administration of the anti- 4 7 antibody (e.g., vedolizumab) iscontinued after the pan-JAK inhibitor is no longer administered. In one aspect, the invention provides a method of treating IBD in a subject comprisingadministering to a human subject an anti- 4 7 antibody (e.g., vedolizumab) and a pan-JAKinhibitor (e.g., tofacitinib) each in an amount effective to treat IBD. The human subject may be an adult (e.g., 18 years or older), an adolescent, or a child (juvenile or pediatric). The human subject may be a person 65 years or older. In certain embodiments, the human subject may be a person 70 years or older. In certain embodiments, the human subject is a child who is less than 18 years old. In certain embodiments, the combination therapy described herein results in a human subject having IBD achieving a clinical response as defined herein for Crohn’s disease or ulcerative colitis. In some embodiments a clinical response in ulcerative colitis is determined by a decrease from baseline in the Mayo score by greater than or equal to 30% and greater than or equal to 3 points and a decrease from baseline in the rectal bleeding subscore greater than or equal to 1 points or a rectal bleeding subscore of 0 or 1 by week 8 of treatment with the combination therapy. In some embodiments, the combination therapy results in a clinical response or a clinical remission of Crohn’s disease (CD). One measurement of clinical response for CD is the CDAI. “CDAI” used herein refers to Crohn’s Disease Activity Index and can be used to determine clinical improvement of a patient having Crohn’s disease. CDAI-defined clinical remission is defined as CDAI <150. CDAI-defined clinical response is defined as a > 100-point decrease from baseline in CDAI. Corticosteroid-free clinical remission is defined as CDAI <150 and not receiving corticosteroids at the assessment time point. CDAI-defined scores may be determined in comparison to a patient’s baseline score, which is obtained prior to treatment with a combination therapy described herein. A CDAI score includes 3 participant-reported items and 5 objective items. Scores are computed as a weighted sum of the items and range from 0 to 600 with higher scores indicating more disease activity. A score below 150 indicates remission; scores ranging from 150 to 219 indicate mildly active disease; scores ranging from 220 to 450 indicate moderately active disease; and scores above 450 indicate severe disease. In some embodiments, the patient achieves a CDAI reduction relative to baseline following administration of the combination therapy herein. Prior to treatment with a therapeutic method as disclosed herein, the human patient may be selected as having certain characteristic or a combination thereof. For example, a human patient having Crohn’s disease may also have active inflammation on ileocolonoscopy. Thus, a human patient may be selected as having Crohn’s disease and active inflammation onileocolonoscopy prior to administration of a combination therapy comprising an anti- 4 7antibody and a pan-JAK inhibitor. In addition to or alternatively, a human patient did not have treatment for IBD with a biologic prior to treatment with a combination therapy disclosed herein, i.e., the patient is biologic-naïve. In a separate embodiment, the human patient had an inadequate response or intolerance to one or more TNF-alpha inhibitors prior to treatment with a combination therapy disclosed herein. In certain embodiments, the subject who is administered the method of the invention may have had a lack of an adequate response with, loss of response to, or was intolerant to treatment, e.g., initial treatment, with an immunomodulator, a TNF-alpha antagonist, or combinations thereof. In some embodiments, the subject who is administered the combination therapy of the invention may have had a lack of an adequate response or a lack of remission after initialtreatment with an anti- 4 7 antibody (e.g., vedolizumab).In certain embodiments, the subject who is administered the combination therapy of the invention may have had a lack of an adequate response with, loss of response to, or was dependent on corticosteroid therapy. The patient may have previously received treatment with at least one corticosteroid (e.g., prednisone, prednisolone, budesonide, methylprednisolone, hydrocortisone) for the inflammatory bowel disease. An inadequate response to corticosteroids refers to signs and symptoms of persistently active disease despite a history of at least one 4- week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week. A loss of response to corticosteroids refers to two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally. Intolerance of corticosteroids includes a history of Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, insomnia and / or infection. An immunomodulator may be, for example, oral azathioprine, 6-mercaptopurine, or methotrexate. An inadequate response to an immunomodulator refers to signs and symptoms of persistently active disease despite a history of at least one 8-week regimen or oral azathioprine, 6-mercaptopurine, or methotrexate. Intolerance of an immunomodulator includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia. TPMT genetic mutation and / or infection. In one aspect, the subject may have had a lack of an adequate response with, loss of response to, or was intolerant to treatment with biologic therapy. In one aspect, the subject may have had a lack of an adequate response with, loss of response to, or was intolerant to treatment with a TNF-alpha inhibitor (antagonist). A TNF-alpha antagonist is, for example, an agent that inhibits the biological activity of TNF-alpha, and preferably binds TNF-alpha, such as a monoclonal antibody, e.g., infliximab, adalimumab, certolizumab pegol, golimumab, or an Fc fusion protein such as ENBREL (etanercept). An inadequate response to a TNF-alpha antagonist refers to signs and symptoms of persistently active disease despite a history, for example, of at least one 4-week induction regimen of infliximab 5 mg / kg IV, 2 doses at least 2 weeks apart; one 80 mg subcutaneous dose of adalimumab, followed by one 40 mg dose at least two weeks apart; or 400 mg subcutaneously of certolizumab pegol, 2 doses at least 2 weeks apart. A loss of response to a TNF-alpha antagonist refers to recurrence of symptoms during maintenance dosing following prior clinical benefit. Intolerance of a TNF-alpha antagonist includes, but is not limited to infusion related reaction, demyelination, congestive heart failure, and / or infection. In certain embodiments, the subject is one with moderately to severely active UC who has experienced aninadequate response, loss of response, or intolerance to no more than two prior TNF-antagonists. In one embodiment, diseases which can be treated accordingly with the methods described herein include inflammatory bowel disease (IBD), such as ulcerative colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy, and ileoanal anastomosis. In one embodiment, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. The ulcerative colitis may be moderate to severely active ulcerative colitis. Treatment may result in mucosal healing in patients suffering from moderate to severely active ulcerative colitis. Treatment may also result in a reduction, elimination, or reduction and elimination of corticosteroid use by the patient. Treatment may also result in a reduction, elimination, or reduction and elimination of immunomodulator use by the patient.III. Anti- 4 7 AntibodiesThe methods disclosed herein comprise administering an anti- 4 7 antibody and a pan-JAK inhibitor, e.g., tofacitinib, to a subject having an inflammatory disease such as IBD (e.g., ulcerative colitis or Crohn’s disease) for treatment. An anti- 4 7 antibody that may be used in the methods disclosed herein, has certaincharacteristics. An anti- 4 7 antibody used herein can bind an 4 7 integrin, and can inhibitbinding of the 4 7 integrin to one or more of its ligands (e.g. MAdCAM (e.g., MAdCAM-1), VCAM-1, fibronectin), thereby inhibiting leukocyte infiltration of tissues (including, recruitmentand / or accumulation of leukocytes in tissues). In another embodiment, an anti- 4 7 antibodyused herein can bind 4 7 integrin, and can selectively inhibit binding of the 4 7 integrin toone or more of its ligands (e.g., MAdCAM (e.g., MAdCAM-1), VCAM-1, fibronectin), thereby inhibiting leukocyte infiltration of tissues (including recruitment and / or accumulation ofleukocytes in tissues). Such anti- 4 7 antibodies can inhibit cellular adhesion of cells bearing an4 7 integrin to vascular endothelial cells ire mucosal tissues, including gut-associated tissues,lymphoid organs or leukocytes (especially lymphocytes such as T or B cells) in vitro and / or invivo. In yet another embodiment, the anti- 4 7 antibody used herein can inhibit the interactionof 4 7 with MAdCAM (e.g., MAdCAM-1) and / or fibronectin. In another embodiment, theanti- 4 7 antibody used herein can inhibit the interaction of 4 7 with MAdCAM (e.g.,MAdCAM-1) and / or fibronectin selectively, e.g., without inhibiting the interaction of 4 7 withVCAM. Thus, an anti- 4 7 antibody (e.g., vedolizumab) used in the methods disclosed herein,can be used to modulate (e.g., inhibit (reduce or prevent)) binding function and / or leukocyte(e.g., lymphocyte, monocyte) infiltration function of 4 7 integrin. For example, humanizedantibodies which inhibit the binding of 4 7 integrin to a ligand (i.e., one or more ligands) canbe administered according to the method in the treatment of diseases associated with leukocyte (e.g., lymphocyte, monocyte) infiltration of tissues (including recruitment and / or accumulation of leukocytes in tissues), particularly of tissues which express the molecule MAdCAM (e.g.,MAdCAM-1). Treatment methods using anti- 4 7 antibodies are described in publication nos.U.S.2005 / 0095238, WO2012151248 and WO 2012 / 151247, each of which is incorporated herein by reference. In one embodiment, the anti- 4 7 antibody is a humanized anti- 4 7 antibody that is anIgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6.In certain embodiments, the anti- 4 7 antibody is a humanized anti- 4 7 antibodycomprising a heavy chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprising a light chain variable domain comprising an amino acidsequence as set forth in SEQ ID NO: 5. In certain embodiments, the anti- 4 7 antibody isvedolizumab. In particular, the methods disclosed herein include administration of the anti- 4 7antibody vedolizumab, or antibodies having antigen binding regions of vedolizumab. Vedolizumab is also known by its trade name ENTYVIO®(Takeda Pharmaceuticals, Inc.). Vedolizumab is a humanized antibody that comprises mutated human IgGl framework regions and antigen-binding CDRs from the murine antibody Act-1 (which is described in US Patent No. 7,147,851, incorporated by reference herein). Vedolizumab specifically binds to the 4 7 integrin and blocks the interaction of 4 7integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and fibronectin and inhibits the migration of memory T-lymphocytes across the endothelium into inflamedgastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the 4 1and E 7 integrins and does not antagonize the interaction of 4 integrins with vascular celladhesion molecule-1 (VCAM-1). The heavy chain variable region of vedolizumab is provided herein as SEQ ID NO: 1, and the light chain variable region of vedolizumab is provided herein as SEQ ID NO: 5. Vedolizumab comprises a heavy chain variable region comprising a CDR1 of SEQ ID NO: 2, a CDR2 of SEQ ID NO: 3, and a CDR3 of SEQ ID NO: 4. Vedolizumab comprises a light chain variable region comprising a CDR1 of SEQ ID NO: 6, a CDR2 of SEQ ID NO: 7 and CDR3 of SEQ ID NO: 8. Vedolizumab and the sequences of vedolizumab are also described in U.S. Patent Publication No.2014 / 0341885 and U.S. Patent Publication No.2014 / 0377251, the entire contents of each which are expressly incorporated herein by reference in their entireties. Alpha4beta7 antibodies and their corresponding amino acid sequences are described in U.S. Patent No.10143752, which is incorporated by reference herein. Antibodies useful as anti- 4 7 antibodies suitable in the methods and uses describedherein can also be identified using techniques known in the art, such as hybridoma production. Hybridomas can be prepared using, e.g., a murine system. Protocols for immunization and subsequent isolation of splenocytes for fusion are known in the art. Fusion partners and procedures for hybridoma generation are also known. In making a desired antibody, a target protein (antigen) of choice (whole protein or fragments thereof) is isolated and / or purified. Immunization of animals can be performed by any method known in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, New York: Cold Spring Harbor Press, 1990. Methods for immunizing animals such as mice, rats, sheep, goats, pigs, cattle, and horses are well known in the art. See, e.g., Harlow and Lane, supra, and U.S. Pat. No.5,994,619. A desired antigen may be administered with an adjuvant to stimulate the immune response. Adjuvants known in the art include complete or incomplete Freund's adjuvant, RIBI (muramyl dipeptides) or ISCOM (immunostimulating complexes). After immunization of an animal with a desired antigen, antibody-producing immortalized cell lines are prepared from cells isolated from the immunized animal. After immunization, the animal is sacrificed and lymph node and / or splenic B cells are immortalized by methods known in the art (e.g., oncogene transfer, oncogenic virus transduction, exposure to carcinogenic or mutating compounds, fusion with an immortalized cell, e.g., a myeloma cell, and inactivating a tumor suppressor gene. See, e.g., Harlow and Lane, supra. Hybridomas can be selected, cloned, and further screened for desirable characteristics, including robust growth, high antibody production and desirable antibody characteristics. Humananti- 4 7 antibodies can also be generated in mice, such as in the HuMAb-Mouse® orXenoMouse™. Methods for high throughput screening of antibody, or antibody fragment, libraries for molecules capable of binding a target protein (antigen) can be used to identify and affinity mature antibodies useful for the methods of the present disclosure. Such methods include in vitro display techniques known in the art, such as phage display, bacterial display, yeast display, mammalian cell display, ribosome display, mRNA display, and cDNA display, among others. The use of phage display to isolate ligands that bind biologically relevant molecules has been reviewed, for example, in Felici et al., Biotechnol. Annual Rev.1:149-183, 1995; Katz, Annual Rev. Biophys. Biomol. Struct.26:27-45, 1997; and Hoogenboom et al., Immunotechnology 4:1- 20, 1998, the disclosures of each of which are incorporated herein by reference as they pertain to in vitro display techniques. Randomized combinatorial peptide libraries have been constructed to select for polypeptides that bind cell surface antigens as described in Kay, Perspect. Drug Discovery Des.2:251-268, 1995 and Kay et al., Mol. Divers.1:139-140, 1996, the disclosures of each of which are incorporated herein by reference as they pertain to the discovery of antigen- binding molecules. Proteins, such as multimeric proteins, have been successfully phage- displayed as functional molecules (see, for example, EP 0349578; EP 4527839; and EP 0589877, as well as Chiswell and McCafferty, Trends Biotechnol.10:80-841992, the disclosures of each of which are incorporated herein by reference as they pertain to the use of in vitro display techniques for the discovery of antigen-binding molecules). In addition, functional antibody fragments, such as Fab and scFv fragments, have been expressed in in vitro display formats (see, for example, McCafferty et al., Nature 348:552- 554, 1990; Barbas et al., Proc. Natl. Acad. Sci. USA 88:7978-7982, 1991; and Clackson et al., Nature 352:624-628, 1991, the disclosures of each of which are incorporated herein by reference as they pertain to in vitro display platforms for the discovery of antigen-binding molecules). These techniques, among others, can be used to identify and improve the affinity of antibodies that bind to a target antigen. In addition to in vitro display techniques, computational modeling techniques can be used to design and identify antibodies, or antibody fragments, in silico that bind a target antigen. For example, using computational modeling techniques, one of skill in the art can screen libraries of antibodies, or antibody fragments, in silico for molecules capable of binding specific epitopes, such as extracellular epitopes of the target antigen. IV. JAK Inhibitors Provided herein is a combination therapy comprising an anti- 4 7 antibody (e.g.,vedolizumab) and a pan-Janus kinase (JAK) inhibitor, for the treatment of an IBD (e.g., ulcerative colitis) in a human patient in need thereof. In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is tofacitinib. Tofacitinib is also known as XELJANZ. Tofacitinib is a potent inhibitor of the JAK family of enzymes that consists of intracellular tyrosine kinases JAK 1, 2, and 3 and the related kinase tyrosine kinase 2 (TYK2). Upon binding of cytokines to their cell surface receptors, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) a family of DNA-binding proteins that regulates the expression of genes relevant to immune and inflammatory cellular responses. This includes the synthesis of inflammatory proteins, primarily members of the interleukin (IL) family, including IL-2, -4, -6, -7, -9, -12, -15, -21, -23, and -27. Among these, IL-6, IL-12, and IL-23 are important drivers of disease activity in inflammatory bowel disease (IBD). Tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TYK2, phosphorylation, thus preventing STAT activation, thereby restricting intracellular growth factor and cytokine-mediated signals to be transduced by the JAK-STAT pathway and downregulating a number of inflammatory mediators. Other exemplary pan-JAK inhibitors suitable for use in the combination therapy disclosed herein include, but are not limited to, baricitinib, cerdulatinib, delgocitinib, gusaticinib, izencitinib, momelotinib, and peficitinib. In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is baricitinib. Baricitinib inhibits Jak 1 and Jak 2 and additionally has moderate activity against TYK2 and minimal activity against JAK3 (Harrington, Robert et al. “JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical Data.” Journal of inflammation research vol.13519-531.14 Sep.2020). Baricitinib is also in combination with dosing regimens described herein for the anti- 4 7 antibody, baricitinib is orally administered at 2 mg once daily or 4 mgonce daily to a subject. In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is cerdulatinib. Cerdulatinib is an investigational oral, dual spleen tyrosine kinase (Syk) and janus kinase (JAK) 1 / 2 / 3 inhibitor. In some embodiments in combination with dosing regimens described herein for the anti- 4 7 antibody, cerdulatinib isorally administered at 30, 25, 20, or 15 milligrams twice daily to a subject. In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is delgocitinib. Delgocitinib is also known as CORECTIM®, and inhibits Jak 1, Jak 2, Jak 3, and Tyk2 (Shih, Pei-Yun, Chia-Jung Li, and Su-Boon Yong. "Emerging trends in clinical research on Janus kinase inhibitors for atopic dermatitis treatment." International Immunopharmacology 124 (2023): 111029). Topical delgocitinib is currently approved in Japan for treating atopic dermatitis. In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is gusaticinib. Gusaticinib is an oral spleen tyrosine kinase / Janus Kinase (JAK 1, 2, 3, and TYK2) inhibitor (Jimenez, Pablo A., et al. "Oral spleen tyrosine kinase / Janus Kinase inhibitor gusacitinib for the treatment of chronic hand eczema: Results of a randomized phase 2 study." Journal of the American Academy of Dermatology (2023).). In someembodiments in combination with dosing regimens described herein for the anti- 4 7 antibody,gusaticinib is orally administered at 80 mg once daily to a subject (e.g., for 12 weeks). In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is momelotinib (Desai, Jigar, et al. "Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor." Bioorganic & Medicinal Chemistry Letters 66 (2022): 128728). Momelotinib is also known as OJJAARA®. In some embodimentsin combination with dosing regimens described herein for the anti- 4 7 antibody, momelotinibis orally administered at 100 mg, 150 mg, or 200 mg once daily to a subject (e.g., for 24 weeks, 48 weeks or longer). In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is peficitinib (Kaneko, Yuko. "Efficacy and safety of peficitinib in rheumatoid arthritis." Modern rheumatology 30.5 (2020): 773-778.; Markham, Anthony, and Susan J. Keam. "Peficitinib: first global approval." Drugs 79.8 (2019): 887-891.). Peficitinib is also known as SMYRAF®. Peficitinib is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor currently approved in Japan for the treatment of rheumatoid arthritis. In some embodiments in combination with dosing regimens described herein for theanti- 4 7 antibody, peficitinib is orally administered at 100 mg or 150 mg once daily to asubject. In certain embodiments, a pan-JAK inhibitor, which can be used in the combination therapy disclosed herein, is izencitinib. In some embodiments in combination with dosingregimens described herein for the anti- 4 7 antibody, izencitinib is orally administered at 80 mgor 200 mg once daily to a subject (Schreiber, S., et al. "P375 Izencitinib induction treatment in patients with moderately-to-severely-active Crohn’s Disease: A phase 2 double-blind, randomized, placebo-controlled study." Journal of Crohn's and Colitis 17.Supplement_1 (2023): i505-i507). The following examples exemplify improved methods and compositions described herein. The following examples are offered for illustrative purposes only and are not intended to limit the scope of the present invention in any way. EXAMPLES EXAMPLE 1. A Study of Vedolizumab with Tofacitinib in Adults with Ulcerative Colitis (UC) Overview This study is a phase 4, open-label, single-arm, multicenter study to evaluate the induction of response and remission of dual targeted therapy with an anti-integrin (vedolizumab [VDZ]) and a Janus kinase (JAK) inhibitor (tofacitinib [TOF]) in adult patients with moderately to severely active ulcerative colitis (UC) who have failed no more than two prior tumor necrosisfactor–alpha (TNF- ) antagonists.The study will enroll approximately 65 patients. All participants will be enrolled in a single treatment group to receive dual targeted treatment with vedolizumab and tofacitinib (Vedolizumab 300 mg + Tofacitinib 10 mg) for the first eight weeks. Only those participants who show a clinical response at Week 8 will transition to vedolizumab monotherapy for 44 weeks. The overall duration of the study is up to 76 weeks. Participants will be followed up for 26 weeks after the last dose of the study drug for safety. Study Design For a schematic of the study design, see Fig.1. This is a phase 4, interventional, open- label, single-arm, multicenter study in adult participants with moderately to severely active UC who have experienced an inadequate response, loss of response, or intolerance to no more than 2prior TNF- antagonists.This study will evaluate the efficacy and safety of a dual targeted therapy (300 mg VDZ IV and 10 mg TOF PO) (VDZ + TOF) over an 8-week treatment period, followed by VDZ IV monotherapy for 44 weeks, for a total treatment period of 52 weeks. Participants will be followed for a further 20-week safety / long-term follow-up period to Week 72 (or at 26 weeks post-last dose of any study intervention administered in the study, including VDZ or TOF). • VDZ + TOF Dual Targeted Therapy: VDZ 300 mg intravenous infusion (IV) at Weeks 0 (Day 1), 2, and 6; TOF 10 mg tablet orally (PO) will be started on Day 1 and given twice daily (BID) for 8 weeks. • VDZ Monotherapy: VDZ 300 mg IV every 8 weeks (Q8W) from Week 14 through Week 46. Participants will be assessed for clinical response at Week 8 upon completion of dual targeted therapy. Participants with clinical response at Week 8 will transition to VDZ 300 mg monotherapy Q8W until Week 46. Participants who do not achieve clinical response at Week 8 will not continue to VDZ monotherapy treatment; they will immediately transition to the safety follow-up period and receive standard of care. Scientific Rational for Study Design Advanced treatments typically result in clinical remission rates at 1 year of 30% to 50%,suggesting there may be a therapeutic ceiling for the use of single agents (Danese et al., 2022). This raises the question of whether using a combination of a biologic with a drug of different mechanism of action, like a small molecule JAK inhibitor, may improve outcomes and provide a suitable option for patients who have failed treatment with 1 prior biologic. Several different inflammatory pathways orchestrate the development and progression of UC and other immune-modulated conditions. Based on the prior studies demonstrating that a combination of a biologic with immunomodulator is more effective than immunomodulator alone, there has been an increasing attempt to explore the therapeutic potential of combining mechanistically different biologics and / or small molecules in patients with refractory IBD. The safety profile of VDZ combined with its gut selectivity makes it an ideal combination agent with a small molecule drug such as TOF. This study will consist of an 8-week VDZ + TOF dual targeted therapy induction period followed by a VDZ 44-week monotherapy phase. The duration of the dual targeted therapy induction period is thought to provide sufficient time to evaluate the effect of combination therapy in inducing clinical remission, while minimizing the potential immunosuppressive risks associated with longer duration dual targeted therapy. The 44 weeks for the VDZ monotherapy phase are anticipated to provide sufficient time to provide data on participant response following transition from combination treatment to VDZ monotherapy. The study population, adults with moderately to severely active UC, with inadequateresponse, loss of response, or intolerance to no more than 2 prior TNF- antagonists, isconsidered appropriate given the study interventions being evaluated. The primary endpoint of the study is the proportion of participants achieving clinical remission at Week 8, as defined a complete Mayo score (stool frequency, rectal bleeding, PGA, and endoscopic subscores) of 2 points and no individual subscore >1 point. The Mayo score is a standardized instrument that assesses the current severity of UC. Dose Rationale The planned VDZ and TOF doses are consistent with their approved dosing regimen as monotherapy. End of Study / Study Completion Definitions The end of the study is defined as the date of the last visit of the last participant undergoing the study, unless the study is stopped earlier by the sponsor (or DSMB) due to futility or for safety reasons. The final analysis for the primary endpoint of the study will be conducted when the last participant has completed the Week 8 visit in the dual targeted therapy treatment period (primary completion date). The participant’s maximum duration of participation is expected to be approximately 76 weeks. Table 1. Objectives and Endpoints Objectives: Endpoints: Prim r Ob tiv Prim r End int s To determine the effect of dual targeted Proportion of participants achieving clinical therapy and dual targeted therapy followed remission (defined as a partial Mayo score e t e o To determine the effect of dual targeted Proportion of participants achieving clinical therapy followed by VDZ monotherapy on response at Week 8 and with mucosal healing at o c - s 0 t To assess participant satisfaction with dual Treatment Satisfaction Questionnaire for targeted therapy. Medication-9 (TSQM-9) score at Week 8. Study Population Inclusion Criteria Participants must meet all of the following criteria to be eligible for inclusion in the study: 1. Is an adult, aged 18 to 65 years, inclusive, at screening. 2. Has provided informed consent (that is, in writing, documented via a signed and dated informed consent form or electronically) and any required privacy authorization before the initiation of any study procedures. 3. Has a confirmed diagnosis of UC established at least 3 months prior to screening, by clinical and endoscopic evidence and corroborated by a histopathology report. 4. Has moderately to severely active UC at screening as determined by a complete Mayo score (including PGA) of 6 to 12 with a rectal bleeding subscore 1 and a centrally assessed endoscopic subscore 2. 5. Has evidence of UC extending proximally to the rectum ( 15 cm of involvedcolon). 6. Participants with extensive colitis or pancolitis of >8 years duration or left-sided colitis >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial Screening Visit (if not performed in previous 12 months, may be performed during screening). 7. Participants with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factors must be up to date on colorectal cancer surveillance (may be performed during screening). 8. Has demonstrated an inadequate response to, loss of response to, or intolerance tono more than 2 TNF- antagonists. Participants without prior failure or intolerance to biologicsare not eligible. Participants who discontinued TNF antagonist therapy for reasons other thanfailure or intolerance (e.g., pregnancy) may be eligible after discussion with the Medical Monitor. 9. If taking oral corticosteroids, must be on a stable dose up to a maximum of 40 mg / d of prednisone or equivalent for at least 2 weeks prior to first dose and must be willing to follow a mandatory taper of corticosteroids. 10. A male participant who is non-sterilized, capable of producing viable sperm, and sexually active with a female partner of childbearing potential agree to use highly effective contraception (ie, dual contraception) and to avoid donating sperm from signing of informed consent throughout the duration of the study and for 18 weeks, and for later enrolled subjects throughout the duration of the study and for 26 weeks, after last dose of any study intervention. 11. A female participant of childbearing potential must: a. Have a negative serum pregnancy test at screening. b. Agree to use highly effective contraception (as defined in this protocol) and to avoid donating ova from signing of the ICF throughout the duration of the study and for 18 weeks, and for later enrolled subjects throughout the duration of the study and for 26 weeks, after last dose of any study intervention. c. If capable of breastfeeding, must agree to forego breastfeeding for the period from signing of the ICF until 18 weeks, and for later enrolled subjects for the period from signing of the ICF until 26 weeks, after last dose of any study intervention. 12. The participant is willing and able to understand and fully comply with study procedures and requirements (including digital tools and applications), in the opinion of the investigator. Exclusion Criteria The participant will be excluded from the study if any of the following exclusion criteria are met: GI Exclusion Criteria 1. Has any of the following UC-related complications: a. Acute severe UC, defined by 6 bloody diarrhea / d and any signs of systemic toxicity (pulse >90 beats / min, temperature >37.8°C, hemoglobin <10.5 g / dL, erythrocyte sedimentation rate >30 mm / h, or CRP >30 mg / L); a. Acute severe UC, defined by >6 bloody diarrhea / day AND 1 or more of the following criteria; pulse >90 beats / min, temperature >37.8°C, hemoglobin <10.5 g / dL, erythrocyte sedimentation rate >30 mm / h, or CRP >30 mg / L; or in the investigator’s opinion, hospitalization for the treatment of UC may be imminent. b. The participant has had extensive colonic resection, subtotal or total colectomy. c. The participant has clinical evidence of abdominal abscess or toxic megacolon. d. The participant has an ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine. e. Short bowel syndrome. 2. Has Crohn’s, colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti- inflammatory drug (NSAID) induced colitis, idiopathic colitis (ie, colitis not consistent with UC), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption. Participants with a history of colonic mucosal dysplasia are also excluded. 3. Has uncontrolled primary sclerosing cholangitis. Infectious Disease Exclusion Criteria 4. Has evidence of an active infection during screening. Patients with nonsystemic infections (e.g., active fungal infection of nail beds) may be included, if in the opinion of the investigator, inclusion of the participant will not interfere with the collection or interpretation of the study results and poses no risk to the participant. 5. Has active or latent TB, regardless of treatment history, as evidenced by any of the following: a. History of TB. b. A diagnostic TB test performed during screening that is positive, as defined by: i. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, or ii. A tuberculin skin test reaction 10 mm ( 5 mm in participants receivingthe equivalent of >15 mg / d prednisone). 6. Personal history of congenital or acquired immunodeficiency (eg, common variable immunodeficiency, HIV infection, organ transplantation) excluding pharmacologic immunosuppressant. 7. A positive test for hepatitis B virus (HBV), as defined by the presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) test. If a participant tests negative for HBsAg, but positive for HBcAb, the participant would be considered eligible if no HBV DNA is present, confirmed by HBV DNA polymerase chain reaction reflex testing performed by the central laboratory. 8. A positive test for hepatitis C virus (HCV), as defined by a positive HCV antibody test and detectable HCV RNA. Participants who are HCV antibody positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured [defined as no evidence of HCV RNA at least 12 weeks prior to screening]). 9. Has evidence of active C. difficile infection or is receiving treatment for C. difficile or other intestinal pathogens during screening. Participants who test positive for C. difficile or other intestinal pathogens at screening and receive treatment may be enrolled or rescreened (if required) following confirmation of infection resolution. 10. Evidence of active Cytomegalovirus (CMV) infection at screening. Medication Exclusion Criteria 11. Has received any approved or investigational biologic therapy, other than a TNF- antagonist. 12. Has had previous exposure to approved or investigational anti-integrins (eg, VDZ, natalizumab), or JAK inhibitors (eg, TOF, upadacitinib), or anti-interleukins (ustekinumab), or S1P receptor agonists (eg, ozanimod). 13. Has received any investigational product within 60 days or 5 half-lives prior to screening, whichever is longer. 14. Has received any live vaccine within 4 weeks prior to first dose. 15. Has received any medicinal product, herbal medication, or natural health product that might interfere with CYP3A4 within 2 weeks before first dose, except for any CYP3A4 modulator used to treat a C. difficile or an intestinal pathogen infection at screening. 16. Has received the following medical therapies for UC: a. Immunomodulators (eg, 6-MP, azathioprine, and MTX) within 4 weeks prior to first dose b. Immunosuppressants (eg, cyclosporine, tacrolimus) within 8 weeks prior to first dose. c. IV antibiotics within 8 weeks prior to first dose. d. Any rectal therapy within 2 weeks prior to screening endoscopy. e. Chronic NSAID use defined as daily use for >2 consecutive weeks (Note: occasional use [< 2 consecutive weeks] of NSAIDs and acetaminophen [<100 mg daily] for headache, arthritis, myalgias, or menstrual cramps and chronic low dose aspirin use [81-162.5 mg daily] for cardiovascular prophylaxis are permitted). 17. Medical history or known allergy, hypersensitivity, or intolerance to VDZ, TOF, or their excipients. General Exclusion Criteria 18. Has any of the following cardiovascular or thrombotic conditions: a. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting. b. Recent (within past 6 months) moderate to severe congestive heart failure (New York Heart Association class III or IV). c. Prior history of thrombotic events, including deep vein thrombosis and pulmonary embolism. d. Known inherited conditions that predispose to hypercoagulability. 19. History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and / or splenomegaly. 20. History of malignancy, except for the following: adequately treated nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to Screening; and history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to screening. Participants with a remote history of malignancy (eg, >10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received; this must be discussed with the sponsor on a case by-case basis prior to enrollment. 21. History of any major neurological disorders, including stroke, multiple sclerosis, epilepsy, or demyelinating or neurodegenerative disease. 22. History or symptoms of progressive multifocal leukoencephalopathy (PML) at screening or prior to first dose, in the investigator’s discretion. 23. Any of the following laboratory abnormalities during the screening period: a. Hemoglobin level <9 g / dL. b. White blood cell count <3 × 109 / L. c. Lymphocyte count <0.5 × 109 / L. d. Platelet count <100 × 109 / L or >1200 × 109 / L. e. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN). f. Alkaline phosphatase >3 × ULN. g. Serum creatinine >2 × ULN or creatinine clearance <30mL / min. h. Serum albumin <2.5 g / dL. 24. Participant has other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation, study treatment administration, study participation, or may interfere with the interpretation of study results, as determined by the investigator. 25. A surgical procedure requiring general anesthesia within 3 months prior to screening or is planning to undergo major surgery during the study period. 26. Any investigational procedure 4 weeks prior to screening that, in the investigators opinion may interfere with interpretation of study results. 27. Prior enrollment in this study and had received study intervention. 28. Unwilling to withhold protocol-restricted interventions during the study. 29. History of excessive alcohol or drug abuse that in the opinion of the investigator may interfere with the participant’s ability to comply with the study procedures. 30. Participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, or sibling). Lifestyle Considerations Any medicinal product, herbal medication, or natural health product that might interfere with (e.g., inhibit or induce) a cytochrome P450 (CYP) enzyme, such as inhibitors of CYP3A4, is prohibited within 2 weeks prior to first dose and must not be administered concurrently with TOF administration during the dual targeted therapy treatment period. Examples of CYP3A4 inhibitors include, but are not limited to Amprenavir, Amiodarone, Aprepitant, Atazanavir, Boceprevir, Casopitant, Cimetidine, Ciprofloxacin, Clarithromycin, Cobicistat, Conivaptan, Darunavir, Diethyldithiocarbamate, Diltiazem, Dronedarone, Elvitegravir, Erythromycin, Fluconazole, Fluvoxamine, Imatinib, Indinavir, Itraconazole, Ketoconazole, Lopinavir, Mibefradil, Mifepristone (RU486), Nefazodone, Nelfinavir, Norfloxacin, Posaconazole, Ritonavir, Saquinavir, Schisandra sphenanthera, Telaprevir, Telithromycin, Tipranavir, Tofisopam, Troleandomycin, Verapamil, or Voriconazole. Examples of CYP3A4 iinducers include, but are not limited to, Avasimibe, Bosentan, Barbiturates, Carbamazepine, Efavirenz, Etravirine, Mitotane, Modafinil, Nafcillin, Phenobarbital, Phenytoin, Rifabutin, Rifampin, St. John’s Wort, or Talviraline. Permitted Concomitant Medications and Procedures The following medications for UC are permitted during the study: 1. Oral corticosteroid therapy for UC (up to a maximum of 40 mg prednisone / d, 9 mg budesonide / d, or equivalent) with a stable dose for at least 2 weeks prior to first dose of study intervention and with mandatory tapering. 2. Oral 5-aminosalicylate drugs or sulfasalazine, not exceeding 4.8 g per day, with stable dose for at least 4 weeks prior to first dose of study intervention and during the study. 3. Antidiarrheal drugs, with stable dose for at least 8 weeks prior to first dose of study intervention and during the study. 4. Bile-salt sequestrants (eg, cholestyramine), with stable dose for at least 4 weeks prior to first dose of study intervention and during the study. 5. Occasional use (< consecutive 2 weeks) of NSAIDs and acetaminophen (<100 mg daily) for headache, arthritis, myalgias, or menstrual cramps and chronic use of low dose aspirin (<100 mg daily) for cardiovascular prophylaxis. Study Intervention(s) The interventions administered in this study are described in Table 2. Table 2. Study Intervention(s) Administered: VDZ IV, TOF PO Intervention Entyvio Xeljanz Label e, , e Use Intervention, as part of dual targeted Intervention, as part of dual targeted therapy with TOF, and as therapy with VDZ tumor necrosis factor–alpha; UC: ulcerative colitis; US: United States; VDZ, vedolizumab. Administration All VDZ infusions will be administered IV over approximately 30 minutes. Longer infusion times of up to 60 minutes may be used based on participant observations. Participants should be observed for 2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion in a room where appropriate treatment for infusion-related reactions is available. The participant should be considered clinically stable by the investigator or designee prior to discharge. Additional information on administration procedures can be found in the pharmacy manual. TOF will be self-administered. Participants will be given clear dosing instructions and will be instructed to take 1 tablet from the bottle in the morning and 1 tablet in the evening, approximately 12 hours apart, for a total of 2 tablets taken per day. TOF may be taken with or without food. Participants should swallow the tablet whole. If a TOF dose is missed and the interval to the next scheduled dose is less than 6 hours, the missed dose of TOF should not be administered.

[0002] SEQUENCE TABLE SEQ SEQUENCE AMINO ACID SEQUENCE ID DESCRIPTION Y C G P EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference.

Claims

CLAIMS What is claimed is:

1. A method of treating a human patient having an inflammatory bowel disease (IBD), said method comprising administering a humanized anti- 4 7 antibody and a pan-Januskinase (JAK) inhibitor to the human patient, wherein the humanized anti- 4 7 antibodyis an IgG1 antibody; comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO:

6.

2. The method of claim 1, wherein the IBD is ulcerative colitis (UC).

3. The method of claim 2, wherein the UC is moderately to severely active UC.

4. The method of claim 1, wherein the IBD is Crohn’s disease.

5. The method of claim 4, wherein the Crohn’s disease is moderately to severely active Crohn’s disease.

6. The method of any one of the preceding claims, wherein the human patient had an inadequate response or intolerance to at least one TNF-alpha inhibitor.

7. The method of any one of the preceding claims, wherein the human patient had an inadequate response or a lack of remission after initial treatment with an anti- 4 7antibody, optionally with vedolizumab; an inadequate response with, loss of response to, or was dependent on corticosteroid therapy; an inadequate response with, loss of response to, or was dependent on an immunomodulator; and / or an inadequate response with, loss of response to, or was intolerant to treatment with biologic therapy.

8. The method of claim 7, wherein the human patient had an inadequate response, treatment failure, lack of remission, loss of response, or was intolerant to treatment with two agents selected from an anti- 4 7 antibody (optionally with vedolizumab); corticosteroidtherapy; an immunomodulator; or a biologic therapy.

9. The method of any one of the preceding claims, wherein the treating of the human patient results in a reduction, optionally an elimination, of corticosteroid use or immunomodulator use.

10. The method of any one of the preceding claims, wherein the human patient has not been previously exposed to at least one of, optionally has not been previously exposed to any of, approved or investigational anti-integrins (e.g., vedolizumab or natalizumab), JAK inhibitors (e.g., TOF, upadacitinib), interleukin 12 / 23 inhibitors (e.g., ustekinumab), or S1P receptor agonists (e.g., ozanimod).

11. The method of any one of claims 1-10, wherein the anti- 4 7 antibody and the pan-JAKinhibitor are administered to the human patient during an induction phase.

12. The method of claim 11, wherein the induction phase is eight weeks.

13. The method of any one of claims 1-2, wherein the pan-JAK inhibitor is selected from the group consisting of tofacitinib, baricitinib, cerdulatinib, delgocitinib, gusaticinib, izencitinib, momelotinib, and peficitinib.

14. The method of any one of claims 1-2, wherein the pan-JAK inhibitor is tofacitinib.

15. The method of claim 13 or 14, wherein 10 mg of tofacitinib is orally administered twice daily.

16. The method of any one of claims 11-15, wherein 300 mg of the anti- 4 7 antibody isintravenously administered to the human patient at Weeks 0, 2, and 6.

17. The method of any one of claims 11-16, wherein the induction phase is followed by a maintenance phase comprising administration of the anti- 4 7 antibody as amonotherapy.

18. The method of claim 17, wherein the maintenance phase begins when the human patient achieves clinical remission and / or a clinical response.

19. The method of claim 17, wherein the human patient achieves an improvement in a health- related quality of life measure as compared to a baseline level.

20. The method of 19, wherein the health-related quality of life measure is measured by an assessment tool selected from Inflammatory Bowel Disease Questionnaire (IBDQ), Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items); a Functional Assessment of Chronic Illness Therapy—Fatigue Scale (FACIT-F), or a Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).

21. The method of claim 17, wherein the human patient has an improvement in bowel urgency.

22. The method of any one of claims 18-21, wherein the human patient achieves a reduction in C-reactive protein (CRP) level or a reduction in fecal calprotectin concentrations.

23. The method of claim 17, wherein the maintenance phase begins at Week 14.

24. The method of any one of the preceding claims, wherein the human patient is intravenously administered a first dose of 300 mg of the anti- 4 7 antibody at Week 0,followed by a second dose of 300 mg of the anti- 4 7 antibody at Week 2.

25. The method of claim 24, further comprising intravenously administering a third dose of 300 mg of the anti- 4 7 antibody at Week 6.

26. The method of claim 24 or 25, wherein 10 mg of tofacitinib is orally administered twice daily for eight weeks.

27. The method of claim 26, wherein 300 mg of the anti- 4 7 antibody is intravenouslyadministered to the human patient every eight weeks starting at Week 14.

28. The method of claim 27, wherein the human patient achieves a clinical remission.

29. The method of claim 28, wherein the clinical remission is defined by a complete Mayo score of 2 points and no individual subscore >1 point.

30. The method of claim 28 or 29, wherein the human patient achieves the clinical remission by week eight.

31. The method of any one of claims 28-30, wherein clinical remission is achieved at week 52.

32. The method of any one of claims 28-31, wherein the clinical remission is achieved at week 8 and at week 52.

33. The method of any one of claims 28-32, wherein the clinical remission is corticosteroid- free clinical remission.

34. The method of claim 24, wherein the human patient is subcutaneously administered a dose of 108 mg of the anti- 4 7 antibody at week 6, followed by a 108 mg dose everytwo weeks thereafter.

35. The method of claim 25, wherein the human patient is subcutaneously administered a dose of 108 mg of the anti- 4 7 antibody at week 14, followed by a 108 mg dose everytwo weeks thereafter.

36. The method of claim 34 or 35, wherein the 108 mg dose is self-administered.

37. The method of any one of the preceding claims, wherein the anti- 4 7 antibodycomprises a heavy chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5.

38. The method of any one of claims 1-36, wherein the anti- 4 7 antibody is vedolizumab.

39. A method of treating a human patient having an inflammatory bowel disease (IBD), said method comprising administering a humanized anti- 4 7 antibody and tofacitinib to thehuman patient, wherein the humanized anti- 4 7 antibody is an IgG1 antibody;comprises a heavy chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 4, a CDR2 domain as set forth in SEQ ID NO: 3, and a CDR1 domain as set forth in SEQ ID NO: 2; and comprises a light chain variable region comprising a CDR3 domain as set forth in SEQ ID NO: 8, a CDR2 domain as set forth in SEQ ID NO: 7, and a CDR1 domain as set forth in SEQ ID NO: 6, wherein the human patient is intravenously administered a first dose of 300 mg of the anti- 4 7 antibody at week 0, followed by a second dose of 300 mg of the anti- 4 7antibody at week 2; and wherein 10 mg of tofacitinib is orally administered twice daily for eight weeks.

40. The method of claim 39, further comprising intravenously administering a third dose of 300 mg of the anti- 4 7 antibody at week 6.

41. The method of claim 39 or 40, wherein 300 mg of the anti- 4 7 antibody isintravenously administered to the human patient every eight weeks starting at week 14.

42. The method of claim 41, wherein the human patient achieves a clinical remission by week 8.

43. The method of any one of claims 39-42, wherein clinical remission is achieved at week 52.

44. The method of any one of claims 39-43, wherein the clinical remission is achieved at week 8 and at week 52.

45. The method of any one of claims 39-44, wherein the clinical remission is corticosteroid- free clinical remission.

46. The method of any one of claims 42 to 45, wherein the clinical remission is defined by a complete Mayo score of 2 points and no individual subscore >1 point.

47. The method of any one of claims 39-46, wherein the human patient achieves an improvement in health-related quality of life measure as compared to a baseline level.

48. The method of 47, wherein the health-related quality of life measure is measured by an assessment tool selected from Inflammatory Bowel Disease Questionnaire (IBDQ), Health-Related Quality-of-Life (HRQOL): Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic Function Function (5 items); a Functional Assessment of Chronic Illness Therapy—Fatigue Scale (FACIT-F), or a Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).

49. The method of any one of claims 39-46, wherein the human patient has an improvement in bowel urgency.

50. The method of claim 39, wherein the human patient is subcutaneously administered a dose of 108 mg of the anti- 4 7 antibody at week 6, followed by a 108 mg dose everytwo weeks thereafter.

51. The method of claim 40, wherein the human patient is subcutaneously administered a dose of 108 mg of the anti- 4 7 antibody at week 14, followed by a 108 mg dose everytwo weeks thereafter.

52. The method of claim 50 or 51, wherein the 108 mg dose is self-administered.

53. The method of any one of claims 39-52, wherein the anti- 4 7 antibody comprises aheavy chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 1, and comprises a light chain variable domain comprising an amino acid sequence as set forth in SEQ ID NO: 5.

54. The method of any one of claims 39-53, wherein the anti- 4 7 antibody is vedolizumab.

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