Method for treating immune-related adverse event of gastrointestine in cancer immunotherapy

Abstract

To provide a method for lightening a gastrointestine immune-related adverse event in a subject receiving cancer immunotherapy.SOLUTION: A method for treating a gastrointestine immune-related adverse event in a mammal subject receiving cancer immunotherapy includes administering a therapeutically effective amount of polypeptide inhibiting MAdCAM-α4β7 integrin bond, which is an anti α4β7 integrin antibody such as Vedolizumab or a related antibody for example.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 62 / 312,671, filed March 24, 2016. The entire contents of the aforementioned application are incorporated herein by reference.

[0002] The present invention relates to a method for treating gastrointestinal immune-related adverse events (GI-IR) in subjects undergoing cancer immunotherapy. Exemplary gi-irAEs include colitis and diarrhea. Rarely, cancer immunotherapy includes anti-CTLA4 and / or anti-PD-1 antibodies, either alone or in combination. It may include treatment. [Background technology]

[0003] Cancer immunology is a growing and promising field in the fight against cancer. By countering the immunosuppressive tumor microenvironment, the subject's immune system can be turned against the cancer. Therefore, cancer immunotherapy offers the potential to treat cancer without many of the negative side effects of systemic chemotherapy or radiation therapy. Despite this, cancer immunology is associated with significant adverse events, including colitis and diarrhea. For example, cancer immunotherapy with anti-CTLA4 and anti-PD-1 antibodies 40% or more of people receiving treatment may experience treatment interruptions or discontinuations. Thus, negating many of the benefits of cancer immunotherapy. In subjects receiving immunotherapy such as rheumatoid arthritis, gi-irAEs such as colitis and diarrhea were There is a need for methods to mitigate this. Summary of the Invention

[0004] The present invention relates to a method for treating colitis, particularly in a subject undergoing immunotherapy, such as cancer immunotherapy. The present invention provides a method for reducing gi-irAEs, such as inflammatory bowel disease and diarrhea, by administering an anti-α4β7 inhibitor to a subject. Polypeptides that inhibit MAdCAM-α4β7 integrin binding, such as tegrin antibodies, , which can beneficially mitigate gi-irAEs in subjects undergoing cancer immunotherapy The present invention is based, at least in part, on the Applicant's discovery that corticosteroids or Anti-tumor necrosis factor (TNF) agents (e.g., infliximab, adalimumab, or etanercept) In contrast to other modalities for mitigating gi-irAEs with systemic effects, such as rituximab (R-Trypto), Therefore, polypeptides that inhibit MAdCAM-α4β7 integrin binding may be useful for immunotherapy. gi-irAEs with a more favorable safety profile without a significant reduction in efficacy can be alleviated.

[0005] As discussed further below, gi-irAEs are caused by spontaneous inflammatory bowel disease, such as inflammatory bowel disease (IBD). In contrast to chronic and / or chronic autoimmune diseases, which are mediated by a common mechanism of action Therefore, it is not known whether treatment for spontaneous autoimmune IBD is appropriate. Anti-CTLA4 and / or anti-IRAEs are not necessarily expected to act for gi-irAEs. We have conducted animal models of colitis induced by immunotherapy, such as anti-PD1 or anti-PD1 treatment. There is no information available on the efficacy and safety of corticosteroids or infliximab in the management of gi-irAEs. The efficacy of infliximab has not been confirmed in randomized clinical trials. It is registered to treat rheumatoid arthritis, psoriatic arthritis, plaque, and It also includes a broad spectrum of treatments including psoriasis, ankylosing spondylitis, and rheumatoid arthritis.

[0006] Thus, in one aspect, the present invention provides a method for the treatment of cancer in a mammalian subject undergoing cancer immunotherapy. Methods for treating gastrointestinal immune-related adverse events (gi-irAEs) are provided. These methods include: A therapeutically effective amount of a polypeptide that inhibits MAdCAM-α4β7 integrin binding to a subject In certain embodiments, the method includes administering a cancer immunotherapy. Of course, there are also second medical uses (e.g., as medicines) and the invention can be used in combination with Polypeptides that inhibit MAdCAM-α4β7 integrin binding corresponding to the methods provided herein Corresponding medical applications, including targeted uses of the peptides, are also encompassed. These methods, agents and uses may be referred to as "methods provided by the present invention."

[0007] In some embodiments, the cancer immunotherapy is 4-1BB, B7H3, B7H4, CCR 2, CD27, CD40, CD40L, CD244, CSF1R, CTLA4, CXCR 4. GITR, IDO, ICOS, KIR (e.g., KIR2DL1 or KIR2DL 3) NKG2A, NKG2D, OX40, RAF kinase, PD-1, PDL-1, P One or more selected from DL-2, TIM-3, VISTA, or a combination thereof In a more particular embodiment, the treatment includes treatment with a modulator of a target of a T cell co-receptor. , more specifically, inhibitory receptors, and even more specifically, inhibitory receptors such as CTLA4, P D-1, or CTLA4 and PD-1. In some cases, cancer immunotherapy targets CCR2, CTLA4, RAF kinase, or PD-1 (single Alone or in combination with, for example, one or more of CTLA4, CCR2, and RAF kinase. ) is not included.

[0008] In certain embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding The peptide is an anti-α4β7 peptide that competes with vedolizumab for binding to the α4β7 integrin. and more particularly, an anti-α4β7 integrin antibody, such as an anti-α4β7 integrin antibody. The antibody has epitope specificity for vedolizumab, and more specifically, the antibody has a and more particularly, the antibody is vedolizumab. In a more specific embodiment, the anti-α4β7 integrin antibody is about 1.25 to 8.0 mg In certain specific embodiments, the anti-α4β7 integrin The antibody is administered at approximately 1.25-4.25 mg / kg, 1.75-3.75 mg / kg, or 2.25- 3.25 mg / kg, for example, about 2.86 mg / kg, for example, about 2.8 mg / kg or In another specific embodiment, the anti-α4β7 inhibitor is administered at a dose of about 2.9 mg / kg. The doses of Glycine antibodies were approximately 5.0-8.0 mg / kg, 5.5-7.5 mg / kg, and 6.0-7. 0 mg / kg, for example, about 6.43 mg / kg, for example, about 6.4 mg / kg or about 6 In certain embodiments, the anti-α4β7 integrin The antibody is approximately 108, 150, 165, 200, 216, 250, 300, 350, 400 , 450, 500, 550, 600, 650, 700, 750 mg or more The anti-α4β7 integrin antibody is administered to a human subject at a dose of, for example, For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 doses, or For doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more or once every 12 weeks or longer, on various schedules such as In certain embodiments using multiple doses, The administration may be at the same dose or at different doses, e.g., at a dose of 200 mg. In some embodiments, the initial unit dose may be 450 mg, followed by titration in doses of 450 mg. The anti-α4β7 integrin antibody is at a concentration of about 10 μg / ml or more, for example, about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 5 Serum concentrations of 0, 60, 70, 80, 90, 93, or 100 μg / ml (e.g., serum The drug is administered, for example, for a period of at least 20 weeks to achieve a trough concentration. In one embodiment, the anti-α4β7 integrin antibody has a serum trough concentration of greater than 15 μg / ml. It is administered for at least 20 weeks to achieve efficacy.

[0009] In certain embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding The peptide will be administered at least once prior to cancer immunotherapy.

[0010] In some specific embodiments, MAdCAM-α4β7 integrin binding is inhibited The polypeptide is administered at least four times, with the second dose being administered approximately two weeks after the first dose. the third dose is administered about four weeks after the first dose, and the fourth dose is administered about two weeks after the first dose. It is administered after 12 weeks.

[0011] In certain embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding The peptide is intended to be administered prior to the appearance of one or more symptoms of gi-irAEs, in the setting of immunotherapy, e.g., cancer immunotherapy. In another embodiment, the MAdCAM-α Polypeptides that inhibit β4β7 integrin binding suppress gi-irAE after cancer immunotherapy It is administered in a therapeutic setting in response to one or more symptoms.

[0012] In some embodiments, the subject is administered an antibody that competes with nivolumab for binding to PD-1. PD-1 antibody therapy (or certain specific In a specific embodiment, the antibody is administered to a subject. The antibody has epitope specificity or, more specifically, the antibody is directed to the complementarity determining region of nivolumab. or more specifically, the antibody is nivolumab. In this embodiment, the anti-PD-1 antibody treatment is at a dose of about 0.5-6.0 mg / kg. In particular embodiments, the dose is about 0.5-2.0 mg / kg, 0.5-1.5 mg / kg In another specific embodiment, the amount is 0.75 to 1.25 mg / kg, for example, about 1.0 mg / kg. In embodiments, the dose is about 1.5-6.0 mg / kg, 2.0-5.0 mg / kg, 2.0 ~4.0 mg / kg, 2.5 to 3.5 mg / kg, for example, about 3.0 mg / kg. In another embodiment, the anti-PD-1 antibody treatment is administered at a fixed dose, e.g., about 200 mg, 220 mg g, 240 mg, 250 mg, 260 mg, or 280 mg. , including the use of no predefined end points, e.g., 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10 or more doses, 1, 2, 3, 4, 5, 6, Various doses, such as once every 7, 8, 9, 10, 11, or 12 weeks, or once every longer The doses may be administered at any of the aforementioned doses on any schedule. The anti-PD-1 antibody is administered at a dose of approximately 1 mg / kg once every 2 weeks or once every 3 weeks. In a specific embodiment, the anti-PD-1 antibody is administered at a dose of about 3 mg / kg every 2 weeks. It is administered once every 24 hours.

[0013] In certain embodiments, the subject is a subject with a cytotoxic T cell that competes with ipilimumab for binding to CTLA4. are receiving treatment with anti-CTLA4 antibodies, such as anti-CTLA4 antibodies that In certain embodiments, the antibody is administered to a subject, or more specifically, the antibody is ipilimumab. More specifically, the antibody has epitope specificity for the complementarity determining region of ipilimumab. and even more specifically, the antibody is ipilimumab. In a typical embodiment, the anti-CTLA4 antibody is administered at a dose of about 1.5 to 10.0 mg / kg (e.g., about 1 0mg / kg), 2.0-5.0mg / kg, 2.0-4.0mg / kg, 2.5- The anti-CTLA4 antibody is, for example, Includes use without a specific end point, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times For doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, or more, Various schedules, such as once every 10, 11, or 12 weeks or longer In a specific embodiment, the anti-CTL The A4 antibody is administered at a dose of approximately 1 mg / kg once every 3 weeks, once every 6 weeks, or once every 12 weeks. It is administered once every 24 hours.

[0014] In certain embodiments, the subject treated by the methods provided herein is a human , for example an adult human.

[0015] In certain embodiments, the subject treated by the methods provided by the present invention is Melanoma (including unresectable or metastatic melanoma), non-small cell lung cancer (squamous and non-squamous) squamous cell carcinoma, renal cell carcinoma, head and neck cancer, bladder cancer, small cell lung cancer, colorectal cancer (metastatic (including metastatic hormone-refractory prostate cancer), Hodgkin's lymphoma, In some embodiments, the patient has a cancer selected from Hodgkin's lymphoma and myeloma. Subjects treated by the methods provided herein are those with melanoma (unresectable or including metastatic melanoma), non-small cell lung cancer (both squamous and non-squamous), and renal cell carcinoma , head and neck cancer, bladder cancer, small cell lung cancer, prostate cancer (including metastatic hormone refractory prostate cancer), The patient has a cancer selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, and myeloma. In a specific embodiment, the subject has melanoma or non-small cell lung cancer. In certain embodiments, the subject has melanoma, including unresectable or metastatic melanoma. In another specific embodiment, the subject has both squamous and non-squamous non-small cell lung cancer. He has non-small cell lung cancer.

[0016] In some embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding. Following at least one administration of the peptide, the subject may be administered, for example, a 2-week dose of about 3 mg / kg. The patient is currently being treated with PD-1 antagonists, such as anti-PD-1 antibodies administered every 24 hours. In one embodiment, a small amount of a polypeptide that inhibits MAdCAM-α4β7 integrin binding is Following at least one administration, the subject is treated with a CTLA4 antagonist, such as an anti-CTLA4 antibody. For example, patients are receiving treatment with PD-1 antagonist at a dose of about 1 mg / kg for 3 weeks. In yet another embodiment, the subject is administered a dose of about 3 mg / kg every 10 minutes. For example, you have been treated with a CTLA4 antagonist, such as an anti-CTLA4 antibody (e.g. Concomitantly with a PD-1 antagonist, such as an anti-PD-1 antibody at a dose of about 1 mg / kg, e.g. , administered every 3 weeks at a dose of about 3 mg / kg, where four doses of a CTLA4 antagonist are Following administration of 100 mg ... The antagonist is administered every two weeks (e.g., at a dose of about 3 mg / kg). In this study, both anti-PD-1 and anti-CTLA4 antibodies were administered at a dose of approximately 1 mg / kg for 3 weeks. In some specific embodiments, the anti-PD-1 antibody is administered at a dose of about 1 mg / kg. g once every 2 weeks, and anti-CTLA4 antibodies were administered at a dose of approximately 1 mg / kg every 6 weeks. In another specific embodiment, the anti-PD-1 antibody is administered at about 3 mg / kg. The anti-CTLA4 antibody is administered once every 2 weeks at a dose of approximately 1 mg / kg for 12 weeks. In yet another specific embodiment, the anti-PD-1 antibody is administered at a dose of about 3 mg / kg. g once every 2 weeks, and anti-CTLA4 antibodies were administered at a dose of approximately 1 mg / kg every 6 weeks. In any of the embodiments described herein, the medicament is administered once every 10 minutes, such as ipilimumab. The anti-CTLA4 antibody is administered in an adjuvant dose, e.g., at about 10 mg / kg, for example, for 3 weeks. For example, four doses may be administered every four doses. In either case, anti-PD-1 antibody, anti-CTLA4 antibody, or anti-PD-1 antibody and anti-CTLA Both of the four antibodies are polypeptides that inhibit MAdCAM-α4β7 integrin binding. The dose may be administered on the same day that the drug is administered.

[0017] In certain embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding The subjects receiving the peptide were treated with a polypeptide that inhibits MAdCAM-α4β7 integrin binding. Compared with appropriate controls receiving non-peptide cancer immunotherapy, subjects will receive one of the following: Improved compliance (e.g., treatment interruption, discontinuation, or dosage reduction) (reduction in incidence of pulmonary embolism, higher treatment completion rate, longer treatment duration) for example, at least 5, 1 0, 15, 20, 25, 30, 35, 40, 45, 50% or more improved con Priority: There is no significant decrease in the efficacy of cancer immunotherapy (e.g., 30% or more of efficacy). a decrease of less than 25, 20, 15, 10, or 5%; or in some embodiments, a decrease of less than 5 , 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%; or increased efficacy (e.g., increased efficacy beyond that); reduction in the grade of gi-irAEs (e.g., For example, a mean grade reduction of at least 1, 2, 3, 4, or 5 grades; or Decreased incidence of certain grades (as determined by NCI CTCAE 4.03) ), shortening the duration of gi-irAEs (e.g., at least 5, 10, 15, 20, 25 , 30, 35, 40, or 50% reduced duration, e.g. 1, 2, 3, 4, 5, or for 6 weeks; or for 1, 2, 3, 4, 5, or 6 months or longer), Delay in onset of gi-irAEs (1, 2, 3, 4, 5, or 6 weeks; or delayed for 6 months or longer), corticosteroids (oral or systemic), antibiotics (oral or parenteral), noncorticosteroid immunosuppressants (e.g. Reduced use of anti-TNF-α agents, colonoscopies, hospitalizations, or a combination of these or resolved (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, or 99% reduction); or any combination thereof .

[0018] In a related aspect, the invention also provides a method for treating cancer, e.g., a cancer subject, e.g., a cancer immunotherapy Polypeptides for treating or preventing gi-irAE in a subject receiving a therapeutic An effective amount of a polypeptide that inhibits MAdCAM-α4β7 integrin binding, together with instructions for use. For carrying out any of the methods provided by the present invention, a container containing the peptide is provided. Useful kits are also provided. In some embodiments, the kits include, for example, an anti-PD-1 and / or anti-CTLA4 antibodies. It may include. [Brief description of the drawings]

[0019] [Figure 1] 1 is a schematic depiction of a dosing schedule for a treatment consistent with the methods provided by the present invention, illustrating administration of an anti-α4β7 antibody (vedolizumab) along with an anti-CTLA4 antibody (ipilimumab) and anti-PD-1 antibody (nivolumab) combination treatment. [Diagram 2] 1 is a schematic depiction of an alternative dosing schedule of treatment consistent with the methods provided by the present invention, depicting administration of an anti-α4β7 antibody (vedolizumab) with an anti-CTLA4 antibody (ipilimumab) and an anti-PD-1 antibody (nivolumab) combination treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention relates to, inter alia, a PD-1 antagonist, a CTLA4 antagonist, or a PD-1 antagonist and In mammalian subjects undergoing cancer immunotherapy, such as treatment with both CTLA4 antagonists Provides treatment for gastrointestinal immune-related adverse events (gi-irAEs) such as colitis and diarrhea in patients with These treatments consist of therapeutically effective amounts of MAdCAM-α4β7 integrin binding inhibitors. "Treatment" includes therapeutic treatment, i.e. , for those already with gi-irAEs, and before the appearance of gi-irAEs A subject is administered a polypeptide that inhibits MAdCAM-α4β7 integrin binding. Both therapeutic and prophylactic treatment refer to the absence or improvement of the severity of an adverse event. This could result in "prevention" of gi-irAEs, which refers to treatment that results in the alleviation or amelioration of gi-irAEs. In elephant populations, treatments typically result in a certain percentage of adverse events, or Although it may result in a certain percentage of serious adverse events, it is more likely to be administered for preventative purposes. The treatment being used is associated with a lower percentage of adverse events (i.e., lower or mitigated risk of adverse events) or a lower percentage of serious adverse events (i.e., If a low or reduced adverse event poses a serious risk, the population is considered GI-IR. Includes subjects in whom AEs are prevented.

[0021] "Immune-related adverse events" (irAEs) are events that occur when the intended target effect of immunotherapy, such as cancer immunotherapy, is not achieved. Desirability induced or exacerbated by on-target effects Exemplary irAEs include colitis, diarrhea, dermatitis, hepatitis, and endocrine disorders. IrAEs include glaucoma, uveitis, nephritis, and combinations thereof. IrAEs are serious and include: In certain embodiments, the immune-related The adverse events were classified as "gastrointestinal immune-related adverse events" (gi-irAEs), which are gastrointestinal irAEs. That is, is it induced by the inherent target effect of immunotherapy such as cancer immunotherapy? This is an undesirable acute disorder of the gastrointestinal system that is either severe or aggravated by gi-irAEs. The infection may be caused by an infectious agent (e.g., a virus, bacteria, fungus, or protozoan), or by spontaneous and and / or chronic autoimmune diseases, e.g. inflammatory bowel disease such as ulcerative colitis or Crohn's disease Specific gi-irAEs include colonic inflammatory disease. In some embodiments, the cause is an existing infectious agent or autoimmune disease. IBD, such as ulcerative colitis or Crohn's disease, is a cancer immunotherapy. It will be significantly worsened by treatment and in these embodiments is a gi-irAE. In certain specific embodiments, the gi-irAE is a PD-1 antagonist and a CTLA4 antagonist. It is induced by cancer immunotherapy, such as in combination with drugs.

[0022] "Immunotherapy(s)" refers to, for example, one or more biologics (antibodies, therapeutic proteins, or modified cells, including, for example, chimeric antigen receptor (CAR)-T cells, 1 One or more small molecules, or a combination of these, that activate the immune system to ameliorate disease Immunotherapy is a therapeutic intervention that aims to improve the immune system. and antagonizing immune system inhibitors (e.g., checkpoint inhibitors) or stimulating immune system activators and antagonizing immune system suppressors. "Cancer immunotherapy" is a treatment that activates the immune system, for example, which can result in tumors evading the immune system. This is an example of an anti-cancer immunotherapy to combat the immunosuppressive tumor microenvironment. Therapeutic options include anti-PD-1 antibodies, such as PD-1 (OMIM 600244, human gene ID 5133, Homologene 3681) antagonists, anti-CTLA4 antibodies, etc. 4 (OMIM123890, Human Gene ID 1493, Homologene3820) These include treatment with antagonists, or both PD-1 and CTLA4 antagonists. Other cancer immunotherapies include CCR2 antagonists (e.g., prosalizumab and related antibodies). anti-CCR2 antibodies, such as BRAF(wt) and / or kinase inhibitors that inhibit more than the BRAFV600 isoform, e.g. International Publication No. 2009 / 006389, International Publication No. 2015 / 148828, International Publication See, for example, about 300 to about 600 mg per week. MLN2480, CAS 1096708-71-2), if and combinations of these with PD-1 antagonists and / or CTLA4 antagonists. In certain embodiments, the cancer immunotherapy includes a combination of surgery, chemotherapy, and It can be combined with other anti-cancer treatments, such as radiation.

[0023] The "polypeptide that inhibits MAdCAM-α4β7 integrin binding" is an α4β7 integrin Between integrin and MAdCAM (OMIM102670, human GeneID8174) These polypeptides include those that inhibit the interaction of α4 integrin (OMIM192 975, Human GeneID3676, Homologene37364), β7 integrin Phosphorus (OMIM147559, Human GeneID3695, Homologene202 47) or binds to integrin protein complexes, including the α4β7 integrin complex These include antibodies that inhibit MAdCAM-α4β7 integrin binding and inhibit α4β7 Administering a polypeptide that inhibits integrin activity is an "anti-α4β7 integrin In certain specific embodiments, the MAdCAM-α4β7 integrin The polypeptide that inhibits binding is an anti-α4β7 integrin antibody, e.g., Vedoliz Mabs or related antibodies, or antigen-binding fragments thereof, directed only to α4 or β7 In another embodiment, the anti-α4β7 integrin antibody is an antibody that binds in the presence of the other. The antibody is AMG181 (specific for α4β7, see e.g., U.S. Pat. No. 8,444,981). and etrolizumab (β7 specific, CAS1044758-60-2, KEGG D09901, PubChem 24490613; see, e.g., U.S. Pat. No. 7,528,236 see No. 1), natalizumab (specific for α4, TYSABRI®, CAS189 261-10-7, KEGG D06886, PubChem 49661786, e.g. (See, e.g., U.S. Pat. No. 5,840,299), any of the above related antibodies, any of the above The anti-α4β7 integrin antibody is an antibody that binds to the α4β7 integrin. The treatment methods used are described in U.S. Patent Application Publication No. 2005 / 0095238 and International Patent Publication No. 2012 151248, and WO2012151247.

[0024] Inhibits MAdCAM-α4β7 integrin binding and may be used in accordance with the present invention. Other polypeptides that can be used include anti-MAdCAM antibodies (see, e.g., U.S. Patent No. 8,277, ,808, PF-00547659 or WO 2005 / 067620 see Antibodies for the current invention); fusion proteins, such as Fc fusions, that contain soluble integrin subunits; soluble α4 integrin, soluble β7 integrin, or soluble α4β7 Soluble integrin subunits, such as integrin complexes (e.g., those that contain a transmembrane domain) complexes containing α4 and / or β7 lacking or lacking the transmembrane and intracellular domains); and MAdCAM, as described, for example, in U.S. Pat. No. 7,803,904. -Soluble MAdCAM, including fusion proteins containing MAdCAM, such as Fc chimeras (e.g. For example, they lack a transmembrane domain or they lack a transmembrane domain and an intracellular domain. Can be obtained.

[0025] The methods provided by the present invention, in certain embodiments, involve the use of antibodies. "Antibody" refers to an immunoglobulin or a portion thereof, and may be any of the following: source, species origin, method of production, and The term encompasses any polypeptide that contains an antigen-binding site, regardless of its structure and characteristics. The term "antibody" refers to antibodies derived from human, orangutan, mouse, rat, rabbit, goat, Includes sheep and chicken antibodies. The term refers to polyclonal, monoclonal, single-specific isomeric, polyspecific, nonspecific, humanized, camelized, single-stranded, chimeric, synthetic, recombinant, hybrid These include, but are not limited to, lid, mutant, and CDR grafted antibodies. For the purposes of this invention, unless otherwise specified, Fab, F(ab')2, Fv, sc Antibody fragments such as Fv, Fd, dAb, VHH (also called nanobodies), and antigens Other antibody fragments that retain binding function are also included. The term "antigen-binding domain" refers to Refers to the portion of an antibody that contains the region that specifically binds to or is complementary to part or all of an antigen. If an antigen is large, the antibody can only bind to a specific part of the antigen. An "antigenic determinant" is a part of an antigen molecule that is responsible for specific interactions with the antigen-binding domain of an antibody. An antigen-binding domain is one or more antibody variable domains (e.g., a VH domain or The antigen-binding domain can be provided by an antibody light chain (so-called Fd antibody fragment). The antibody variable region may include a variable region (VL) and an antibody heavy chain variable region (VH). It contains complementarity determining regions (CDRs) that together determine the specificity of the antibody. melidae, camelids) have only heavy chains and no light chains. The antigen-binding site of such an antibody is expressed as a VHH. The topology of the endothelial cell is a single domain called the endothelial cell. Such antibodies are called "camelized antibodies" or "nanobodies." See, e.g., Nos. 5,800,988 and 6,005,079, which are incorporated herein by reference. See WO 94 / 04678 and WO 94 / 25591. In certain embodiments, the antibodies for use in the methods provided by the invention are human The antibodies for use in the methods provided by the present invention are humanized or chimeric. The antibody may, in different embodiments, be human: IgG1, IgG2, IgG3, or IgG4; Different framework regions can be used, including these chimeras.

[0026] In some embodiments, the specific antibodies discussed in this application, or related antibodies, are The present invention relates to a method for detecting a marker for a specific antigen-binding fragment of a reference antibody. An antibody that is a "related antibody" (including but not limited to a reference antibody) competes with a reference antibody for binding to a target antigen. or (e.g., in some embodiments, to the same, overlapping, or adjacent epitopes). competition for the reference antibody), has the epitope specificity of the reference antibody, or has the complementarity determining region (C DR) (in some embodiments, 1, 2, 3, 4, or 5 across all CDRs) There may be conservative amino acid substitutions in each CDR, or up to one or two conservative substitutions in each CDR. ) or comprises the variable heavy and variable light domains of the reference antibody (or comprises the variable domains At least 80, 85, 90, 95, 96, 97, 98, 99% or more and any amino acid changes may be in the framework regions. , and which may be conservative or non-conservative), antibodies (and antigen-binding fragments thereof). In some embodiments, conservative substitutions are determined by the default parameters of BLASTp. In other embodiments, conservative mutations fall within the class substitutions, The classes are aliphatic (glycine, alanine, valine, leucine, isoleucine), hydroxyl Sulfur- or sulfur / selenium-containing (serine, cysteine, selenocysteine, threonine, thionine), cyclic (proline), aromatic (phenylalanine, tyrosine, tryptophan ), basic (histidine, lysine, arginine), and acidic and amide (asparagine Those skilled in the art will generally recognize that: Single amino acid substitutions in non-essential regions of a polypeptide can substantially alter biological activity. (e.g., Watson et al. (1987) Molecular lar Biology of the Gene,The Benjamin / Cum (See Mings Pub. Co., p. 224 (4th Ed.)). Substitution of structurally or functionally similar amino acids is unlikely to interfere with biological activity. Thus, for example, antibodies related to vedolizumab may be used in different embodiments, e.g. , an epitope of vedolizumab that competes with vedolizumab for binding to α4β7 integrin. or containing the complementarity determining regions (CDRs) of vedolizumab with vedolizumab specificity It may comprise the variable heavy and variable light domains of lizumab.

[0027] In some embodiments of the methods provided by the present invention, the antibody is an immunoglobulin other than The antigen-binding molecules may be replaced with other scaffold-based antigen-binding molecules. Known non-immunoglobulin scaffolds in the field include small modular immunopharmaceuticals (e.g. See, for example, U.S. Patent Application Publication Nos. 20080181892 and 20080227958. ), tetranectin, fibronectin domains (see, e.g., AdNect ins, U.S. Patent Application Publication No. 2007 / 008, published April 12, 2007 2365), protein A, lipocalin (see, e.g., U.S. Pat. No. 7,111, 8,915), ankyrin repeats, and thioredoxin. Molecules based on non-immunoglobulin scaffolds are generally expressed using phage display. Methods (e.g., Hoogenboom, Method Mol. Biol. 178:1-3 7 (2002)), ribosome display methods (see, for example, Hanes et al. t al., FEBS Lett. 450:105-110(1999) and He an d Taussig, J. Immunol. Methods 297:73-82(20 05) or methods in the art for identifying high affinity binding sequences. Other known techniques (Binz et al., Nat. Biotech. 23:1257- 68(2005), Rothe et al.,FASEB J.20:1599-16 10 (2006), and U.S. Patent Nos. 7,270,950 and 6,518,018, and 6,281,344 (see also US Pat. No. 6,281,344). Generated by selection.

[0028] Cancer immunotherapy In certain embodiments, the cancer immunotherapy is an anti-PD-1 antibody, such as nivolumab or PD-1 antagonists such as pembrolizumab, anti-CTLA4 antibodies, e.g., ipilimumab, with CTLA4 antagonists such as temafibrin or tremilimumab, or with PD-1 antagonists and Other cancer immunotherapies include treatment with both CCR2 (human Gen eID 729230) antagonists (e.g., anti-CCR2 antibodies), pan-RAF kinase inhibitors anti-PD-1 agents (e.g., MLN2480, CAS1096708-71-2), and PD-1 antagonists These include combinations of drugs and / or CTLA4 antagonists. In embodiments, cancer immunotherapy is used in combination with other anti-cancer treatments, such as surgery, chemotherapy, and radiation. It is possible.

[0029] In certain embodiments, the cancer immunotherapy comprises modulating a T cell co-receptor. In some embodiments, this can be achieved by using soluble mediators (e.g., CD28, 41 BB, OX40, CD27, GITR, CD137, HVEM or a combination of these stimulating one or more activating receptors or immunomodulators, including soluble mediators ( For example, CTLA4, BTLA-4, PD-1, PDL-1, PDL-2, IDO, LA G3, ICOS, VISTA, TIM3, CSF-1R or a combination of these) antagonizing one or more inhibitory receptors or immunomodulators, or a combination of both, For example, activating one or more activating receptors or inhibiting one or more inhibitory receptors. In some embodiments, the cancer immunotherapy involves antagonizing B7 and CD2 8-related (e.g., PDL-1, B7H3, B7H4, PD-1, CTLA4, or combinations), TNF / TNFR-related (e.g., VISTA, CD40, CD40L , 4-1BB, OX40, CD27, GITR, or a combination of these), suppressed bone marrow (e.g., CSF1R), soluble mediators (e.g., IDO, CXCR4, or combinations), NK cells (e.g., KIR's, NKG2A / D, CD244, or combinations thereof), Ig superfamily (e.g., LAG3, TIM3, or These combinations), and combinations of the above, and the like. Thus, in certain embodiments, the cancer immunotherapy comprises 4-1BB (human GeneID36 04), B7H3 (human GeneID 80381), B7H4 (human GeneID 79 679), CD27 (human GeneID 939), CD40 (human GeneID 95 8), CD40L (human GeneID 959), CD244 (human GeneID 51 744), CSF1R (human GeneID 1436), CTLA4, CXCR4 (human GeneID 7852), GITR (human GeneID 8784), IDO (human G eneID 3620), ICOS (human GeneID 29851), KIR's (K IR2DL1 Human GeneID 3802, KIR2DL3 Human GeneID 3804 ), NKG2A (human GeneID 3821), NKG2D (human GeneID 229 14), OX40 (human GeneID 7293), PD-1, PDL-1 (human Gen eID 29126), PD-L2 (human GeneID 80380), TIM-3 (human GeneID 84868), VISTA (human GeneID 64115), or Providing one or more of these combinations of modulators, e.g., for a single target, or one or more modulators for two or more targets. This includes:

[0030] In some embodiments, for example, MAdCAM-α4β7 integrin binding is inhibited. Cancer immunotherapy according to the present invention, directed to polypeptides that inhibit the expression of OX40, CD2 Immune activating agents such as 7 agonists, GITR agonists, 4-1BB agonists, or CD40 agonists Cancer immunotherapy that activates PD-1 or PD-L1 antagonists, ICOS antagonists, L One or more negative checkpoints, such as AG3 antagonist, IDO1 antagonist, or TIM3 antagonist or combinations of GITR agonists and PD1 antagonists, for example Such molecules can include, for example, OX4 Antibodies or antibodies for cell surface receptors such as CD40, CD134, CD27, and CD40. Larger ones, such as related substances, or for intracellular or enzymatic targets, such as IDO1 The size of the gap can be as small as 10 mm.

[0031] In certain embodiments, for example, MAdCAM-α4β7 integrin binding is inhibited. Cancer immunotherapy according to the present invention, directed to a polypeptide that inhibits CTLA4, is a CTLA4 antagonist (i.e., limumab), PD-1 antagonists (e.g., nivolumab), and OX40 agonists (MEDI 6469 antibody, Powderly et al., J. Clin. Oncol. 3 3,2015(suppl;abstr TPS3091),Eggermont an d Robert,Nat.Rev.Clin.Oncol.11:181-2(201 4)), CD27 agonists (e.g., varlilumab, CELLDEX Th erapeutics, for example, Ramakrishna et al., JI mmunother.Cancer3:27(2015), U.S. Patent No. 9,169,325 ), KIR antagonists (e.g., lirilumab, see, e.g., CAS:100 0676-41-4, KEGG:D10444, PubChem:172232537 see ), or IDO antagonists (e.g., INCB024360 (epacadostat (see, for example, PubChem914471-09-3) Combination of PD-1 antagonists (e.g., nivolumab) and CTLA4 antagonists (e.g., ipilimumab) in combination with 41BB agonists (e.g., PF05082566); or a combination thereof.

[0032] In certain embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding The peptide, e.g., an antibody containing the CDRs of vedolizumab, can be used to treat one or more symptoms of gi-irAEs. It is administered as primary prophylaxis to patients being treated with cancer immunotherapy before the emergence of In embodiments, a polypeptide that inhibits MAdCAM-α4β7 integrin binding, e.g. Antibodies containing the CDR of vedolizumab inhibit gi-irA after or during cancer immunotherapy. It is administered in a therapeutic setting in response to one or more symptoms of E. Polypeptides that inhibit AdCAM-α4β7 integrin binding, e.g., vedolizumab The decision to use an antibody containing the CDRs of may arise from the behavior of the cancer immunotherapy alone. For example, if a cancer immunotherapy causes gi-irAEs in <30% of patients, MAdC Polypeptides that inhibit AM-α4β7 integrin binding, e.g., CD of vedolizumab Antibodies containing R are administered in a therapeutic setting. Cancer immunotherapy is gi- In causing irAEs, polypeptides that inhibit MAdCAM-α4β7 integrin binding Antibodies that contain the CDRs of peptides such as vedolizumab can be used in either prophylactic or therapeutic settings. Cancer immunotherapy may cause gi-irAEs in more than 50% of patients. In this case, a polypeptide that inhibits MAdCAM-α4β7 integrin binding, e.g., Antibodies containing the CDRs of izumab are administered in a prophylactic setting.

[0033] Polypeptides that inhibit MAdCAM-α4β7 integrin binding, e.g., vedolizumab Antibodies containing the CDRs of the mab may be administered in a prophylactic or, optionally, therapeutic setting to treat cancer. Examples of treatments include CTL Cancer immunotherapy including A4 antagonists. For example, melanoma, non-small cell lung cancer, Combination of CTLA4 antagonists and PD1 antagonists in head and neck cancer; e.g., metastatic CTLA4 antagonists such as tremelimumab and MED in solid tumor cancers such as colorectal cancer In combination with OX40 agonists, such as the I6469 antibody; for example, in solid tumor cancers or lymphomas Combining CTLA4 antagonists with KIR antagonists, such as lirilumab, in patients with bronchial tumors; For example, in melanoma, CTLA4 antagonists such as ipilimumab and varlilumab Combination with CD27 agonists; e.g., CT, such as ipilimumab, in melanoma Combination of LA4 antagonists with IDO antagonists such as INCB024360 (epacadostat) or, for example, in EGFR-mutated non-small cell lung cancer, tremelimumab and epidermal growth factor receptor antagonists such as erlotinib or gefitinib. Combination with (EGFR) antagonists inhibits MAdCAM-α4β7 integrin binding A polypeptide that binds to the VEDOLIZUMAB CDR can be used, for example, an antibody that contains the VEDOLIZUMAB CDR. The therapeutic agent may be administered in a preventive setting or, optionally, in a therapeutic setting.

[0034] Polypeptides that inhibit MAdCAM-α4β7 integrin binding, e.g., vedolizumab Examples of cancer immunotherapy in which antibodies containing the CDRs of mabs are administered in a therapeutic setting are PD-1 antagonists, For example, cancer immunotherapy including anti-PD-1 antibodies such as nivolumab or pembrolizumab For example, the efficacy and safety of nivolumab in solid tumor cancers such as head and neck cancer (e.g., HNSCC) has been Which PD-1 antagonists can be combined with KIR antagonists such as lirilumab; head and neck cancer, ovarian cancer, PD such as nivolumab in solid tumor cancers such as colorectal cancer, renal cell carcinoma or glioblastoma or in combination with a CD27 agonist, such as varlilumab; or in combination with a CD27 agonist, such as varlilumab; and PD-1 antagonists such as pembrolizumab in solid tumor cancers such as small cell lung cancer. Combination with 4-1BB agonists such as PF-05082566 (utomirumab) is Polypeptides that inhibit AM-α4β7 integrin binding, e.g., CD of vedolizumab R-containing antibodies can be used and administered in a therapeutic setting. A polypeptide that inhibits integrin binding, such as an antibody containing the CDR of vedolizumab, is a therapeutic agent. Additional examples of cancer immunotherapies administered in therapeutic settings include agents such as TIM3, 4-1BB, B7H3, B7H4, CCR2, CD27, CD40, CD40L, CD244, CSF 1R, CXCR4, GITR, IDO, ICOS, KIR (e.g., KIR2DL1 or KIR2DL3), NKG2A, NKG2D, OX40, RAF kinase, or VI Cancer immunotherapy includes single agents that target STA. For example, PD-1 A combination of an antagonist and a GITR activator may be used, for example, to treat ovarian cancer.

[0035] PD-1 antagonists Programmed death 1 protein (PD-1) plays an important role in immune regulation and the maintenance of peripheral tolerance. PD-1 is recognized to play an important role in naive T cells, B cells, and NKT It is moderately expressed in cells and mediates T / B cell receptor signaling on lymphocytes, monocytes, and myeloid cells. (Sharpe, AH, et al. (2007) Nature 43:1311-1322) re Immunology;8:239-245).

[0036] "PD-1 antagonists" target T cells, cancer cells, macrophages, and antigen-presenting cells (APCs) ) and its cognate ligands (e.g. For example, regulating the interaction with PD-L1 and / or PD-L2 (in certain embodiments, means any compound or biological molecule that blocks or inhibits PD-1 (human Alternative names or synonyms for its ligands include PD-1 and PD-2. For PD-L1, PDCD1, PD1, CD279, and SLEB2 are listed. Examples of these include PDCD1L1, PD-L1, B7H1, B7-4, CD274, and B7-H. For PD-L2, PDCD1L2, PDL2, B7-DC, Btdc and P Any of the therapeutic methods, medicaments and uses of the invention in which a human subject is treated. In this study, PD-1 antagonists inhibited or blocked the binding of human PD-L1 to human PD-1. and preferably inhibits or blocks the binding of human PD-L1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 is located at NCBI Locus No.: NP00500. 9. The human PD-L1 and PD-L2 amino acid sequences are available from NCBI Lo cus No.: NP_054862 and NP_079515, respectively. do.

[0037] PD-1 antagonists useful in any of the methods, medicaments and uses of the invention include PD- 1 or PD-L1, preferably human PD-1 or human PD-L1 The present invention includes a monoclonal antibody (mAb), or an antigen-binding fragment thereof, that specifically binds to m The Ab may be a human antibody, a humanized antibody, or a chimeric antibody, and may contain a human constant region. In some embodiments, the human constant region is an IgG1, IgG2, IgG3, or I and in some embodiments the human constant region is selected from the group consisting of an IgG4 constant region. In some embodiments, the antigen-binding fragment is a FabG1 or IgG4 constant region. , Fab'-SH, F(ab')2, scFv and Fv fragments. Inhibiting PD-1 activity by administering a PD-1 antagonist is "anti-PD-1 therapy."

[0038] Examples of mAbs that bind to human PD-1 and are useful in the therapeutic methods, medicaments and uses of the present invention are described in US Pat. Patent No. 7521051, U.S. Patent No. 8779105, U.S. Patent No. 8008449, U.S. Patent No. 8,900,587, U.S. Patent No. 8,952,136, U.S. Patent No. 8,354,509 No. 8,735,553, No. 9,102,728, No. 89,937 No. 31, U.S. Patent No. 9,102,727, U.S. Patent No. 9,181,342, U.S. Patent No. 892 7697, U.S. Patent No. 8945561, U.S. Patent No. 748802, U.S. Patent No. 73 No. 22582, U.S. Pat. No. 7,524,498 and U.S. Pat. No. 9,205,148. The therapeutic methods, medicaments and uses of the present invention are useful as specific anti-human PD-1 antagonists. D-1mAb is commercially available in the United States under the trade name KEYTRUDA®. Pembrolizumab (formerly MK-3475 and lambrolizumab, CAS:13 74853-91-4, KEGG:D10574), WHO Drug Information,Vol.27,No.2,pages161-162(201 3) A humanized IgG4 mAb having the structure described above or a related antibody, trade name OPDI Nivolumab (formerly ONO-4538, M DX1106 or BMS-936558, CAS:946414-94-4, K EGG:D10316, PubChem:163312346), WHO Drug Information,Vol.27,No.1,pages 68-6 9 (2013) or a related antibody, Lizumab (CT-011, also known as hBAT or hBAT-1, CAS: 1036730-42-3, PubChem:172232483, KEGG:D103 90), WHO Drug Information, Vol. 26, N o.4, page 434 (2012) or Related antibodies and humanized antibodies described in WO 2008 / 156712 409A11, h409A16 and h409A17 or related antibodies, PDR-100 , SHR-1210, REGN-2810, MEDI-0680, BGB-108, PF -06801591, but are not limited to these.

[0039] Examples of mAbs that bind to human PD-L1 and are useful in the therapeutic methods, medicaments and uses of the invention are described in International Publication No. 2013 / 019906, International Publication No. 2010 / 077634, and The therapeutic methods, medicaments and uses of the present invention are described in U.S. Patent No. 8,383,796. Atezolizumab is a specific anti-human PD-L1 mAb that can be used as a PD-1 antagonist. (MPDL3280A), BMS-936559, durvalumab (MEDI4736) , avelumab (MSB0010718C) and the sequences disclosed in International Publication No. 2013 / 019906 SEQ ID NO: 24 and SEQ ID NO: 21, respectively, or Antibodies comprising the CDRs of the variable domains are included.

[0040] Other PD-1 antagonists useful in any of the methods, medicaments and uses of the invention include specifically binds to PD-1 or PD-L1, preferably human PD-1 or human PD-L1, e.g., PD-L fused to a constant region, such as the Fc region, of an immunoglobulin molecule Specific for fusion proteins containing the extracellular or PD-1-binding portion of PD-L2 or PD-L2 Immunoadhesins that specifically bind to PD-1 include Examples of amine molecules are described in WO 2010 / 027827 and WO 2011 / 0663. The PD-1 antagonists in the methods, medicaments and uses of the present invention are described in US Pat. A specific fusion protein useful in this regard is the PD-L2-FC fusion protein, which is a fusion protein that expresses human PD-L2. AMP-224 (also known as B7-DCIg), which binds to -1.

[0041] In some embodiments, the PD-1 antagonist is nivolumab, pembrolizumab, PDR -001, SHR-1210, AMP-224, REGN-2810, MEDI-068 0, BGB-108, PF-06801591, atezolizumab, durvalumab, and BMS-936559, and AMP-224.

[0042] In some embodiments, the PD-1 antagonist is nivolumab, pembrolizumab, PDR -001, SHR-1210, AMP-224, REGN-2810, MEDI-068 0, BGB-108, and PF-06801591, and AMP-224 can be.

[0043] In some embodiments, the PD-1 antagonist is selected from pembrolizumab and nivolumab. It is selected.

[0044] In some embodiments, the PD-1 antagonist is nivolumab.

[0045] In some embodiments, the PD-1 antagonist is pembrolizumab.

[0046] In some embodiments, the PD-1 antagonist is atezolizumab, durvalumab, and B MS-936559.

[0047] In some embodiments of the methods, medicaments and uses of the invention, the PD-1 antagonist is nivolumab. A monoclonal antibody or an antigen-binding fragment thereof, including an antigen-binding fragment of lumab.

[0048] In some embodiments of the methods, medicaments and uses of the invention, the PD-1 antagonist is In some embodiments of the disclosed methods of treatment, medicaments and uses, the antigen-binding fragment of pembrolizumab is The antibody is a monoclonal antibody or an antigen-binding fragment thereof, including a fragment thereof.

[0049] In another embodiment of the methods, medicaments and uses of the invention, the PD-1 antagonist is a human PD- (a) a monoclonal antibody or antigen-binding fragment thereof that specifically binds to the antibody of the present invention; and (b) a heavy chain variable region of an antibody or variant thereof described herein. In some embodiments, the variant heavy chain variable region sequence comprises the variant light chain variable region. The columns contain up to 17 conservative amino acid substitutions in the framework regions (i.e., outside the CDRs). It is identical to the reference sequence except for having substitutions, preferably 10 in the framework regions. In certain embodiments, the amino acid sequence has fewer than 9, 8, 7, 6, or 5 conservative amino acid substitutions. The variant light chain variable region sequence has 5 amino acids in the framework regions (i.e., outside the CDRs). Identical to a reference sequence except for up to 1 conservative amino acid substitution, preferably There are less than 4, 3, or 2 conservative amino acid substitutions in the framework regions.

[0050] CTLA4 antagonists Human CTLA4(CYTOTOXIC T LYMPHOCYTE-ASSOCIAT ED4 (also known as CD152) is an immunoglobulin superfamily member expressed on activated T cells. The human CTLA4 gene was discovered in the late 1980s and 1990s. It was cloned in the early 1990s. The sequence of CTLA4 and its homologs are well known and readily available. See, e.g., OMIM 123890, Human Gene ID 1, incorporated by reference. See Homologene 3820 for reference sequence. , which acts, at least in part, to block CD28-mediated T cell activation, thereby By blocking CTLA4, it suppresses T cell activation and activates the immune system, among other things. In turn, they can attack cancer cells. The method is to use an anti-CTLA4 antibody or antigen-binding fragment thereof. The use of CTLA4 antagonists to inhibit CTLA4 is "anti-CTLA4 therapy." Antagonists include anti-CTLA4 antibodies.

[0051] In certain embodiments, anti-CTLA4 antibodies for use in the methods provided herein ipilimumab (Bristol-Myers Squibb Company) and sold under the registered trade name YERVOY® or related antibodies. or antigen-binding fragments thereof. No. 238 provides the sequence of ipilimumab, which is incorporated by reference. 77202-00-9, PubChem47206447, and Kegg D04603 See also

[0052] Other antibodies for anti-CTLA4 treatment in the methods provided by the present invention include U.S. US Patent Nos. 6,682,736 and 8,883,984 (Pfizer, Amgen n: Tremelimumab / ticilimumab) and related Related antibodies; U.S. Patent No. 7,034,121 (Genetics Institute, ) and related antibodies; U.S. Patent Application Publication No. 20030086930 A1 and related antibodies; Patent Application Publication No. WO200602921 9A2 and related antibodies; binding of CTLA4 to B7 ligands The method described in U.S. Pat. No. 8,263,073 increases T cell responses without inhibiting cell proliferation. and related antibodies; U.S. Patent No. 8,699,366, which are specific for a soluble form of CTLA4. No. 7,845 and related antibodies; humanized U.S. Pat. 20140105914 and related antibodies; WO 2016 These publications include those described in US Pat. No. 5,333,675 and related antibodies. Anti-CTLA4 antibodies useful in the methods provided herein, as well as combinations of the antibodies with each other, For a description of the combinations and combination regimens described in the publications, reference is made to the present application. will be incorporated into the subsection.

[0053] No. 9,084,776, which is incorporated by reference, is a general description of the present invention. i.e., to induce gi- One or more agents that inhibit MAdCAM-α4β7 integrin binding to ameliorate irAEs The present invention relates to an anti-PD-1 antibody for cancer treatment, which can be administered by administering a polypeptide of The authors describe a combination method for use in conjunction with TLA4 antibodies. Combination methods using anti-CTLA4 antibodies with chemotherapeutic agents described in the above patents are also included in the present invention. For use in, optionally, for example, anti-PD-1 therapy, e.g. For example, MAdCAM-α4 may be used to ameliorate gi-irAEs from anti-CTLA4 combination therapy. The method is adapted for administering one or more polypeptides that inhibit β7 integrin binding. Also, the anti-CTLA4 antibody described in U.S. Pat. No. 8,226,946 can be used. Methods of combining antibodies with photoactivation therapy are similarly compatible with the methods provided by the present invention. For example, the photoactivated therapy can be combined with an anti-CTLA4 therapy and / or an anti-PD-1 therapy. 1, which can be combined and inhibits MAdCAM-α4β7 integrin binding One or more polypeptides are provided to improve gi-irAE. No. 0100330093 discloses combinations of various CTLA4 antibodies and thymosin peptides. These and related antibodies may be used alone or in combination with other antibodies consistent with the present invention. The thymosin peptides may be used in combination with the thymosin peptides listed in U.S. Patent No. 8,475,790. The combination therapy of anti-CTLA4 antibody and anti-CD137 (agonist) described in the present invention is also For example, MAdCAM-α4β7 integrin binding can be detected by the method provided by and administering one or more polypeptides that inhibit gi-irAEs to ameliorate gi-irAEs from the combination. The method provided by the present invention can also be enhanced by, for example, One or more drugs that inhibit MAdCAM-α4β7 integrin binding to ameliorate gi-irAEs Additional anti-CTLA4 therapy that may benefit from administration of the polypeptide of Combination therapy is disclosed in U.S. Patent No. 20130156768A1 (anti-CTLA4 therapy and BRAF WO 2013019620A2 (which describes combination therapy with an anti-cancer drug); Combination therapy with CTLA4 therapy, a BRAF inhibitor, and a MEK inhibitor is described. ); U.S. Patent No. 20150283234A1 (combination of anti-CTLA4 and anti-KIR therapy) U.S. Patent No. 20140323533A1 (antibodies used in combination with tubulin regulators) CTLA4); International Publication No. 2015058048A1 (Describes combination with VEGF antagonists) ); U.S. Patent No. 20150328311 (discloses use in combination with MEDI4736) WO 2015125159A1 (combination with IL-2RP agonist, optional (Described in combination with anti-PD-1 therapy in

[0054] Anti-CTLA4 Therapeutic Dosing Schedules Described in U.S. Patent No. 9,062,111 The present invention relates to a method for reducing the clearance of anti-CTLA4 antibodies from a subject, the disclosure of which is incorporated herein by reference in its entirety. The method provided by the present invention is similar to the method described in US Pat. No. 5,007,910,000. and is incorporated by reference.

[0055] Polypeptides that inhibit MAdCAM-α4β7 integrin binding The cell surface molecule "α4β7 integrin" or "α4β7" is a integrin that binds the α4 chain (CD49D, It is a heterodimer of the β7 chain (ITGA4) and the β7 chain (ITGB7). Each chain is an alternative interleukin-1 (IL-1) It forms a heterodimer with the α4β1 or α E Able to form β7 Human α4 and α7 genes (GenBank (National Center for Biotechnology Information (N ational Center for Biotechnology Informa tion), Bethesda, MD) RefSeq accession numbers are NM_0008, respectively. 85 and NM_000889) are involved in the differentiation of B and T lymphocytes, specifically memory CD4 α4β7, which is specific to many integrins, is expressed by 4+ lymphocytes in the resting state. Ligands for the α4β7 integrin can exist in either a neutral or activated state. The receptors include vascular cell adhesion molecule (VCAM), fibronectin, and mucosal addressin ( MAdCAM (e.g., MAdCAM-1). α4β7 integrin is Mucosal addressin cell adhesion molecule-1 (M cell adhesion molecule-1) is expressed on the endothelium of mesenteric lymph nodes and gastrointestinal mucosa. Through adhesive interactions with AdCAM-1, lymphocytes are involved in the recruitment and recruitment of lymphocytes to the GI mucosa and gut-associated lymphoid tissue. Mediates transport to the GALT.

[0056] As mentioned above, anti-α4β7 antibody, anti-MAdCAM antibody, soluble integrin subunit soluble MAdCAM (including fusion proteins such as Fc fusion proteins) A variety of polypeptides, including fusion proteins such as MAdCAM-α, have been identified that mediate MAdCAM-α expression. Any of these polypeptides can inhibit β4β7 integrin binding. The use of AdCAM-α4β7 integrin binding inhibition is referred to as "anti-α4β7 therapy." be.

[0057] Anti-α4β7 integrin antibody Anti-α4β7 antibodies for use in the methods provided by the present invention include certain In embodiments, an epitope on the α4 chain (e.g., humanized MAb21.6 (Bendig et al., U.S. Pat. No. 5,840,299), epitopes on the β7 chain (e.g., F IB504 or a humanized derivative (see, e.g., Fong et al., U.S. Pat. No. 7,522,633). No. 8,236), or a combination epitope formed by the association of the α4 and β7 chains. In one embodiment, the antibody is specific for the α4β7 integrin complex. For example, an antibody binds to a combination epitope on the α4β7 complex, but the chains are not linked together. It does not bind to epitopes on the α4 or β7 chains unless they are associated with each other. The association of β7 integrin with β-integrin, for example, is characterized by the presence of epitopes on both chains. or in the absence or presence of a suitable integrin partner. The epitope-binding site on one chain is inaccessible to antibody binding in the absence of cytochrome P450 activation. For example, by conformationally exposing the α4 or β7 integrin chains Thus, combination epitopes can be created. In another embodiment, the anti-α4β7 antibody binds to both the α4 and β7 integrin chains, thereby Such antibodies specific for the α4β7 integrin complex The body binds to α4β7 but cannot bind to α4β1, and / or, e.g. α E In another embodiment, the anti-α4β7 antibody is an Act-1 antibody. (Lazarovits, AIet al., J. Immunol., 133(4):1857-1862 (1984), Schweighoffer et al., J. Immunol., 151(2):7 17-729, 1993, Bednarczyk et al., J. Biol. Che m., 269(11):8348-8354, 1994). Murine Act-1 monoclonal The mouse ACT-1 hybridoma cell line producing the cloned antibody was Pharmaceuticals,Inc.,40Landsdowne Street ,Cambridge,MA 02139,USA on behalf of American Type Culture Collection,10801 University y Boulevard,Manassas,VA.20110-2209,USA , under the accession number PTA-3663, on August 22, 2001 under the Budapest Treaty. In another embodiment, the anti-α4β7 antibody is deposited under the provisions of U.S. Patent Application Publication No. 2010 / 023636. Human antibodies or α4β7 binding proteins using the CDRs provided in US Pat. No. 5,313,315. It is of high quality.

[0058] In one embodiment, the anti-α4β7 antibody binds to its ligand (e.g., a mucosal addressin, e.g., M AdCAM (e.g., MAdCAM-1), fibronectin and / or vascular adrenergic The primate MAdCAMs inhibit the binding of α4β7 to one or more of the vascular endothelial cell membrane proteins (VCAMs). No. 6,399,623, the entire teachings of which are incorporated herein by reference. In another embodiment, the anti-α4β7 antibody inhibits VCAM binding. MAdCAM (e.g., MAdCAM-1) and / or fibronectin It inhibits the binding of α4β7 to tyrosine.

[0059] Vedolizumab and related antibodies In certain embodiments, anti-α4β7 The antibody was vedolizumab (CAS Registry Number 943609-66-3, American In certain embodiments, the antibody is a HIV-1 related antibody. The anti-α4β7 antibody is a humanized version of the mouse Act-1 antibody discussed above. In general, humanized anti-α4β7 antibodies are derived from the three heavy chain complementarity determining regions (CDRs) of the mouse Act-1 antibody. (CDR, CDR1, SEQ ID NO: 4, CDR2, SEQ ID NO: 5, and CDR3, SEQ ID NO: 6) and a suitable human heavy chain framework region, The three light chain CDRs of this invention (CDR1, SEQ ID NO: 7, CDR2, SEQ ID NO: 8, and CDR3, The light chain will also contain a light chain containing SEQ ID NO:9) and a suitable human light chain framework region. The humanized Act-1 antibody is a consensus frame with or without amino acid substitutions. The polypeptide may contain any suitable human framework region, including, for example, a human ribozyme. For example, one or more of the framework amino acids may have a corresponding amino acid sequence in the mouse Act-1 antibody. The amino acid at position 144 of the human constant region may be replaced with another amino acid, such as the amino acid at position 144 of the human constant region. a human antibody kappa or lambda light chain, including allelic variants, if present; and / or γ (e.g., γ1, γ2, γ3, γ4), μ, α (e.g., α1, α2), It can be derived from a delta or epsilon heavy chain. The variant or portion thereof can be selected for effector function. For example, the mutated constant region (mutant) may have the ability to bind Fc receptors and / or bind complement. To minimize the force, it can be incorporated into a fusion protein (e.g., Winter et al.,GB 2,209,757B;Morrison et al.,WO 89 / 07142;Morgan et al.,WO94 / 29351,Dec.22 (See, e.g., 1994). A humanized version of the Act-1 antibody is disclosed in PCT Publication No. WO 2006 / 023361. Nos. 98 / 06248 and WO07 / 61679, each of which No. 6,399,633, the entire teachings of which are incorporated herein by reference.

[0060] In other specific embodiments, anti-α4β7 The humanized antibody may comprise a heavy chain variable region of vedolizumab (e.g., amino acids 20 to 14 of SEQ ID NO:1). 0) and the light chain variable region of vedolizumab or a variant sequence (e.g., the amino acid sequence of SEQ ID NO: 2). amino acids 20 to 131 or amino acids 1 to 112 of SEQ ID NO: 3). Depending on the circumstances, suitable human constant region(s) can be present. For example, humanized anti-α4β The seventh antibody has a heavy chain comprising amino acids 20 to 470 of SEQ ID NO:1 and amino acids 1 to 3 of SEQ ID NO:3. 219. In another example, the humanized anti-α4β7 antibody can comprise a light chain comprising SEQ ID NO: A heavy chain comprising amino acids 20 to 470 of SEQ ID NO:1 and a light chain comprising amino acids 20 to 238 of SEQ ID NO:2. A Vedolizide having two mouse residues switched to human residues. The humanized light chain of the mab is more human than the light chain of LDP-02 (compare SEQ ID NO: 2 with SEQ ID NO: 3) In addition, LDP-02 has a somewhat hydrophobic flexible alanine 114 and a hydrophilic site (A 115), which are slightly hydrophilic in vedolizumab. is replaced by a hydroxyl-containing threonine and a hydrophobic, potentially inward-facing valine residue. is.

[0061] Further substitutions into the antibody sequence can be made, for example, by abrupt substitutions to the heavy and light chain framework regions. Mutations, such as the substitution of isoleucine at residue 2 of the human GM607 CL kappa light chain variable region Mutation of the methionine at residue 4 of the human GM607 CL kappa light chain variable region to Mutation of alanine to valine at residue 24 of the human 21 / 28 CL heavy chain variable region. arginine to lysine mutation at residue 38 of the 21 / 28 CL heavy chain variable region Mutation of alanine to arginine at residue 40 of the CL heavy chain variable region; 21 / 28 A methionine to isoleucine mutation at residue 48 of the CL heavy chain variable region A sudden change from isoleucine to leucine at residue 69 of the CL heavy chain variable region; Mutations; 21 / 28 arginine to valine mutation at residue 71 of the CL heavy chain variable region; 21 / 28 Threonine to isoleucine mutation on residue 73 of the CL heavy chain variable region; or any combination thereof; and the CDRs of the mouse Act-1 antibody of the heavy chain CDRs (C DR1, SEQ ID NO: 4, CDR2, SEQ ID NO: 5, and CDR3, SEQ ID NO: 6) and the light chain CDR of mouse Act-1 antibody (CDR1, SEQ ID NO: 7, CDR2, SEQ ID NO:8, and CDR3, SEQ ID NO:9). .

[0062] In some embodiments, anti-α4β7 A humanized antibody may have at least about 95%, 96%, 97%, or 100% amino acids 20-140 of SEQ ID NO:1. %, 98%, or 99% sequence identity (e.g., 100% identical) and at least amino acids 20 to 131 of SEQ ID NO:2 or amino acids 1 to 112 of SEQ ID NO:3. have at least about 95%, 96%, 97%, 98%, or 99% sequence identity (e.g., In some cases, the antibody contains a light chain variable region (100% identical to any of these reference sequences). In embodiments, the anti-α4β7 humanized antibody may have one, two, three, four, five, six, seven, eight ... It may have 6, 7, 8, 9, 10 or more amino acid substitutions. In embodiments, any amino acid substitutions are conservative substitutions. In certain embodiments, the amino acid substitutions are non-conservative. In other embodiments, the substitutions can be in the CDRs, and in these embodiments Preferably, the substitutions are conservative. Amino acid sequence identity is determined using default parameters. The Lasergene system used (DNASTAR, Inc., Madison, W I) or by using a suitable sequence alignment algorithm such as BLASTp. In certain embodiments, the present invention provides a method for the preparation of a composition for use in the methods provided by the present invention. The anti-α4β7 antibody was vedolizumab (American Chemical Society CAS Registry Number 943609-66- 3).

[0063] Vedolizumab and related antibodies are administered intravenously, subcutaneously, or by infusion. The methods provided by the present invention may be administered by any suitable method, including by Formulations suitable for intravenous injection, which may be prepared in lyophilized form, are incorporated herein by reference. For example, the method is described in U.S. Patent Application Publication No. 20140377251, which is incorporated herein by reference. Liquid formulations suitable for subcutaneous injection are described in U.S. Patent Application Publication No. 201403, which is incorporated by reference. It is described in No. 41885.

[0064] In some embodiments, vedolizumab is administered at 50 mg, 100 mg, 108 mg, 16 5mg, 200mg, 216mg, 300mg, 450mg, 500mg, or more In some embodiments, vedolizumab is administered, for example subcutaneously, at a dose of 0 .05mg / kg, 0.10mg / kg, 0.15mg / kg, 0.2mg / kg, 0. Doses of 25 mg / kg, 0.3 mg / kg, 0.4 mg / kg, or 0.5 mg / kg 108mg, 200mg, 216mg, 450mg, 160mg, or 165mg Vedolizumab is administered once daily, once weekly, once monthly, or once weekly. In some embodiments, vedolizumab is administered at weeks 0, 2, and 3. The first and sixth doses are administered, and then every four weeks or every eight weeks thereafter. In these cases, vedolizumab is administered at least once and then administered for at least 1 month and at least 6 Vedolizumab is administered one or more times after 2 months or at least 1 year. In the form, 200, 300, or 450 mg of vedolizumab was administered at weeks 0, 2, and It may be administered by intravenous infusion at week 6, followed by four-week intervals or for eight weeks. In some embodiments, 200, 300, or 450 mg may be administered at intervals. Vedolizumab may be administered by intravenous infusion at weeks 0, 2, and 6; Then at 2-week, 3-week, or 4-week intervals, At most 216 mg of vedolizumab may be administered subcutaneously. 0, 450, or 600 mg vedolizumab intravenously at weeks 0, 2, and 4 Infusion may be administered, after which the final dose is about 75, 80, 85, 90, 95 or on the 100th day, e.g., between about 85 and about 90 days, between about 75 and about 90 days or between about 85 and about 100 days.

[0065] Treatment and prevention of gi-irAEs The present invention provides, inter alia, a method for preventing and / or preventing MAdCAM-α4β7 integrin binding. to treat a gi-irAE in a subject (or, e.g., In certain embodiments, the present invention provides a method for treating cancer by administering a therapeutically effective amount of Subjects treated by the methods provided herein include those receiving cancer immunotherapy (e.g., PD-1 antagonists). with CTLA4 antagonists or with both PD-1 and CTLA4 antagonists ) but is mediated by a polypeptide that inhibits MAdCAM-α4β7 integrin binding. When compared to a suitable control not treated with the drug, the subject exhibits one or more of the following: Improved compliance (e.g., lower incidence of treatment interruptions, dosage reductions, or discontinuation) (lower; higher treatment completion rate, longer treatment duration) e.g., at least 5, 10, 15, 20 , 25, 30, 35, 40, 45, 50% or more improved compliance; There is no significant decrease in efficacy of cancer immunotherapy (e.g., 30, 25, 20, 1 or in some embodiments, a decrease of 5, 10, or less than 5%; or in some embodiments, a decrease of 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% or more effective increased efficacy, such as increased efficacy; reduction in grade of gi-irAEs (e.g., at least or a mean grade reduction of 1, 2, 3, 4, or 5 grades; or no colitis or diarrhea 20, 30, 40, 50, 60, or 70% of subjects with specific grades of gi-irAEs, such as 70, 80, 90, or 100% or greater reduction in frequency of gi-irAEs Reduction in duration of (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40 , or a 50% shortened duration, e.g., 1, 2, 3, 4, 5, or 6 weeks; 3, 4, 5, or 6 months or longer), and incidence of gi-irAEs Delayed onset of symptoms (1, 2, 3, 4, 5, or 6 weeks; 1, 2, 3, 4, 5, or 6 months; or longer delay), corticosteroids (oral or systemic), antibiotics (oral or parenteral), noncorticosteroid immunosuppressants, colonoscopy, hospitalization, or Reduce or eliminate the use of these combinations (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, or 9 9% decrease); or any combination of the foregoing.

[0066] 27 receiving checkpoint inhibitors (CTLA-4 and / or PD-1) In a recent meta-analysis of 74 patients, the incidence of diarrhea ranged from 11% to 51%. The incidence of enterocolitis ranged from 1% to 16%. The relative risk (RR) for all grades of diarrhea was 1.64 (9.41). 5%CI: 1.19-2.26; p=0.002). 10.35 (95% CI: 5.78-18.53; p<0.00001). Another meta-analysis evaluating limumab-associated diarrhea (N=1571) found no significant difference in all grades. The overall incidence of diarrhea was 41.6% (95% CI: 33.6% to 50.0%). In this analysis, the overall incidence of grade ≥3 diarrhea was 8.4% (95% CI: 5. 5% to 12.7%). The RR for ipilimumab for all-grade diarrhea was 1.6 3 (95% CI: 1.37-1.97; p < 0.001), and grade ≥ 3 diarrhea. The relative risk for HIV infection was 2.19 (95% CI: 1.11-4.34; p = 0.025). The median time to onset of grade 2 / 3 colitis with limumab was 6.5 weeks. Recent advances in patients with melanoma treated with the combination of nivolumab and ipilimumab In phase III clinical trials, the incidence of diarrhea was 44%, with 9% being grade 3 / 4. Colitis was diagnosed in 12% of patients, with 8% being grade 3 / 4. The present invention provides a method for treating CTLA-4 inhibition, which is more frequently associated with CTLA-4 inhibition than D-1 inhibitors. The method may ameliorate these complications in whole or in part.

[0067] Received ipilimumab (monotherapy or combination therapy) of any grade Nearly half of patients with irAEs were treated with treatment interruption and immunomodulatory therapy (including infliximab). These results led to treatment interruption / discontinuation. Half of the irAEs were diarrhea / colitis. Current guidelines for the management of colitis / diarrhea Treatment should be interrupted if the condition is ≥ Grade 2 and if Grade 2 persists for > 5 days. If grade ≥ 3, begin prednisone or immediately if grade ≥ 3. Treatment is started when symptoms improve and steroids are gradually administered over a period of one month. All this can lead to problems in compliance with treatment. The main difficulty is in the current 1-2 mg / kg regimen when symptoms do not improve. Systemic steroids followed by infliximab were used empirically without clinical trial support. Corticosteroids shown to treat inflammatory bowel disease (IBD) Budesonide alone, a serotonin-releasing hormone (SLL) inhibitor, was used to prevent ipilimumab-induced colitis in a randomized clinical trial. However, the results were negative. The method is intended to address some or all of these complications without many of the complications of existing medical interventions. It can be improved in some areas.

[0068] Inhibitors of MAdCAM-α4β7 integrin binding inhibit its activity in the GI tract and intestinal lymph nodes. The use of gi-irAEs in the prevention of gi-irAEs is likely to be limited to lymphoid tissues, with the potential to: 1) inhibit T cell migration to tumors; 1) have no adverse effects on T cell subpopulations within the tumor microenvironment or the tumor microenvironment; and Patients with progressive metastatic melanoma receiving combination checkpoint inhibitor therapy with gi-irAE relief Clinical benefit with a favorable safety profile in patients with cancers such as laminoma For example, in some embodiments, the methods provided by the present invention Subjects treated with the method exhibit a reduction in diarrhea or colitis, or in some embodiments There was no grade 3 or 4 colitis (grade 3 colitis, grade 4 (or 3-5 days Grade 3) colitis or diarrhea that persists or worsens after treatment; Grade 1-2 If there is only diarrhea or any grade 2 symptoms, this symptom may be , and without the addition of prednisone or anti-TNF-α therapy, with systemic antidiarrheal therapy. or show a reduction in diarrhea or colitis, or in some embodiments In one embodiment, there are no grade 1 or 2 symptoms. In another embodiment, grade 4 diarrhea is observed. No or a reduction in grade 4 diarrhea was observed, more specifically, no or a reduction in grade 3 diarrhea or a reduction in grade 3 diarrhea was observed, and even more specifically, No grade 2 diarrhea or a reduction in grade 2 diarrhea is observed, or Even more specifically, no grade 1 diarrhea or no grade 1 diarrhea was observed. In yet other embodiments, no or no grade 4 colitis is observed. A reduction in grade 1 or 4 colitis was observed, more specifically, a reduction in grade 3 colitis was observed. No or grade 3 reduction in colitis was observed, and more specifically, no grade 2 colitis or a reduction in grade 2 colitis is observed, or Even more specifically, no grade 1 colitis is observed or grade 1 colitis is not observed. In yet another embodiment, a reduction in grade 4 colon inflammation is observed. No inflammation or diarrhea or reduction in grade 4 colitis or diarrhea More specifically, no grade 3 colitis or diarrhea was observed or A reduction in grade 3 colitis or diarrhea was observed, and more specifically, a reduction in grade 2 colitis or diarrhea was observed. No colitis or diarrhea or reduction in grade 2 colitis or diarrhea was observed or even more specifically, no grade 1 colitis or diarrhea is observed. or a reduction in grade 1 colitis or diarrhea is observed. The methods provided by the invention typically involve administering 0.5 to 2 mg / kg / day of prednisone equivalents. is indicated along with the suggested antibiotic prophylaxis for opportunistic infections (once grade 1 or or less is achieved, continue tapering steroids for 1 month), >5 days Reduce or eliminate the frequency of persistent or recurrent grade 2 symptoms, i.e. The methods provided by the invention may be used to reduce the need for corticosteroids and / or prophylactic antibiotics. In yet another embodiment, the methods provided herein further comprise: Discontinuation of treatment and administration of corticosterone at a dose of 1 to 2 mg / kg / day prednisone equivalent administration of steroids and / or prophylactic antibiotics for opportunistic infections and / or colonoscopy Reduce or resolve the frequency of grade 3 symptoms requiring intervention such as testing and / or hospitalization i.e., the methods provided by the present invention include administering corticosteroids and / or Reduce the need for prophylactic antibiotics, and / or colonoscopy, and / or hospitalization; or In yet another embodiment, the methods provided herein include discontinuing treatment and and administration of corticosteroids at a dose of 1 to 2 mg / kg / day prednisone equivalent, and and / or antibiotic prophylaxis for opportunistic infections, and / or colonoscopy, and / or Gray disease requiring interventions such as corticosteroid or non-corticosteroid immunosuppressants and / or hospitalization The method provided by the present invention reduces or eliminates the frequency of symptoms of class 4. luteosteroids, and / or prophylactic antibiotics, and / or colonoscopy, and / or or non-corticosteroid immunosuppressants, and / or reduce or eliminate the need for hospitalization. In certain embodiments, the methods provided herein include preventing the development of gi-irAEs. Delays the onset of, for example, colitis and / or diarrhea, typically occurring at peak times in weeks 5-10 The development of genomic DNA is delayed beyond the peak developmental stage (approximately 8 weeks of development), e.g., by the methods provided by the present invention. delays the onset of gi-irAEs by 2, 4, 5, 6, 8, 10 weeks or more, Specifically, for example, the possible occurrence of gi-irAEs and the frequency and severity of gi-irAEs. and / or severity, e.g., 1, 2, 3, 4, 5, or 6 weeks; or delay and abate for six months or longer.

[0069] In some embodiments of the invention, the following grading applies: Grade 1 (diarrhoea) For colitis, the mean score was <4 bowel movements per day compared to baseline. For colitis, the mean score was asymptomatic and clinically significant. clinical or diagnostic findings only); Grade 2 (diarrhoea was reduced by 100 mg / day compared to baseline) 4-6 bowel movements per hour, IV fluid requirement <24 hours, no interference with activities of daily living [ADLs] Grade 2 (for diarrhea, baseline level, abdominal pain, bloody stool); Grade 3 (for colitis, baseline level, abdominal pain, bloody stool); For rheumatoid arthritis, the following were required: ≥7 bowel movements per day, ≥24-hour IV fluid infusion, and activities of daily living (ADL). degree of obstruction, for colitis, severe abdominal pain, medical intervention is indicated, peritoneal signs) Grade 4 (for colitis, life-threatening, perforation). The grade of gi-irAEs such as colitis or diarrhea was determined according to the NCI CTCAE4.03 is determined by. EXAMPLES

[0070] Example 1 In patients with advanced melanoma, the efficacy and safety of standard-of-care immune checkpoint inhibitors was A Phase 1 study was conducted to evaluate the safety, tolerability, and pharmacodynamics of the combined vedolizumab treatment. A Phase B trial will be conducted. Approximately 52 subjects will be enrolled. Approximately 12 subjects will be enrolled in a dose-escalating treatment regimen. Treatment was assigned to each patient (expanded to a maximum of 46 patients). Between 2 and 15 sites were supported for inclusion.

[0071] Subjects were randomized to receive staging services for histologically confirmed unresectable disease according to the AJCC staging system. Patients with stage III or IV melanoma and an ECOG performance status of 0 to 1 Subjects must be adults, either male or female, with adequate bone marrow reserve and renal function. Patients with known or suspected active autoimmune disease have liver and kidney function. or corticosteroids (>10 mg prednisone or equivalent) or other systemic immunosuppressant therapy within 14 days of study drug administration Subjects were excluded who had received anti-PD-1, anti-PDL-1, anti-PDL-2, or anti-CTLA 4 Subjects previously treated with the antibody will also be excluded.

[0072] Vedolizumab was administered IV at doses of 200 or 450 mg at weeks 1, 3, 5, and 13. Nivolumab will be administered at the standard dose of 3 mg / kg Q2W (every 2 weeks). The standard of care for nivolumab in combination with ipilimumab is as follows: Both nivolumab (1 mg / kg) and ipilimumab (3 mg / kg) were administered as follows: IV, Q3W (once every 3 weeks) for 4 doses, followed by nivolumab (3 mg / kg g) will be administered IV Q2W until disease progression or unacceptable toxicity. The duration of the study is a maximum of 50 weeks, and the evaluation period is 12 months. Figure 1 shows the dosing schedule. Provides a graphical depiction of the rule.

[0073] The primary endpoint for this study was treatment-emergent adverse events (TEAEs, e.g., The study was conducted to assess the incidence and severity of adverse events (including severe TEAEs) including colitis or diarrhea. Secondary endpoints in this study included investigator-assessed objective response rate (ORR). Response measures, duration of response (DOR), and response outcome measures using RECIST v1.1 Investigator-assessed progression-free survival (PFS) and overall survival (OS) were Serial tumor biopsies will also be collected and analyzed using, but not limited to, immunohistochemistry and gene expression profiling. Changes in immune cell infiltration or other putative biomarkers using methods that include filtering Quantification of IL-1 expression will be completed after monotherapy and combination therapy.

[0074] Example 2 In patients with advanced melanoma, the efficacy and safety of standard-of-care immune checkpoint inhibitors was To evaluate the safety, tolerability, and pharmacodynamics of the concomitant vedolizumab treatment, The Phase 1b study will enroll up to approximately 52 subjects. Approximately 12 subjects will be Subjects were assigned to dose escalation treatment (expanded to a maximum of 46 subjects). 2 to 15 sites were enrolled. wear.

[0075] Subjects were randomized to receive staging services for histologically confirmed unresectable disease according to the AJCC staging system. Patients with stage III or IV melanoma and an ECOG performance status of 0 to 1 Subjects must be adults, either male or female, with adequate bone marrow reserve and renal function. Patients with known or suspected active autoimmune disease have liver and kidney function. or corticosteroids (>10 mg prednisone or equivalent) or other systemic treatment with immunosuppressants within 14 days of administration of study drug Subjects were excluded who had received anti-PD-1, anti-PDL-1, anti-PDL-2, or anti-CTLA 4 Subjects previously treated with the antibody will also be excluded.

[0076] Vedolizumab was administered IV at doses of 200 or 450 mg at weeks 1, 3, 5, and 13. Both nivolumab (1 mg / kg) and ipilimumab (1 mg / kg) were administered. IV, Q3W (once every 3 weeks) for 4 doses, followed by nivolumab (3 mg / kg kg or 240 kg fixed dose) until disease progression or unacceptable toxicity. The drug is administered IV Q2W starting at the beginning of week 13 and on day 85. Treatment duration is up to 50 weeks. The evaluation period is 12 months. Figure 2 provides a graphical depiction of this dosing schedule. do.

[0077] The primary endpoint for this study was treatment-emergent adverse events (TEAEs, e.g., The study was conducted to assess the incidence and severity of adverse events (including severe TEAEs) including colitis or diarrhea. Secondary endpoints in this study included investigator-assessed objective response rate (ORR). Response measures, duration of response (DOR), and response outcome measures using RECIST v1.1 The investigator-assessed progression-free survival (PFS) and overall survival (OS) were assessed by the patient. The changes in microbiota composition and fecal calprotectin in fecal samples after treatment were compared with those before and after treatment. Changes in serum levels of C-reactive protein before and after treatment are measured.

[0078] All numerical ranges describing any parameter in this application, e.g., "about," " With respect to "at least," "less than," and "greater than," this statement also applies to the enumerated values. It is to be understood that the term "a" necessarily encompasses any range bounded by "a" or "b." The statement "at least 1, 2, 3, 4, or 5" also means, inter alia, 1-2, 1-3, 1 Also describe ranges such as ~4, 1~5, 2~3, 2~4, 2~5, 3~4, 3~5, and 4~5. do.

[0079] All patents, applications, or non-patent literature cited herein, including reference sequence information, are incorporated herein by reference in their entirety. References to these for all purposes and for the suggestions contained therein. It should be understood that they are incorporated herein by reference in their entirety. In the event of any inconsistency between the incorporated document and this application, this application shall control. Genome loci, genomic sequences, functional annotations, allelic variants, and reference mRNAs (e.g., exon boundaries or response elements) and protein sequence (e.g., conserved domain structure), H omologene, GeneID or other accession number, including OMIM (typically References National Center for Bioscience Information (see National College of Biological Sciences (NCBI) accession numbers) All information related to the disclosed reference gene sequences, as well as chemical references (e.g., Pu bChem compound, PubChem substance, or PubChem Bioassay entries, including annotations, e.g. structures and assays (a) are incorporated herein by reference in their entireties.

[0080] The headings used in this application are for convenience only and shall not affect the interpretation of this application. It is not.

[0081] Preferred features of each of the aspects provided by the present invention may be combined with any of the other aspects of the present invention. mutatis mutandis and is defined by, but not limited to, the independent claims. Individual features of specific embodiments and aspects of the present invention, including examples that are illustrated and actually implemented, are described below. Combinations and permutations of elements, including, for example, numerical ranges and exemplary embodiments, are also encompassed. For example, the specific experimental parameters illustrated in the working examples may deviate from the invention. can be adapted for use in the claimed invention without any modification. For example, The disclosed materials include various individual and collective combinations of these compounds and Even if specific reference to each of the permutations may not be expressly disclosed, are specifically contemplated and described herein. Thus, the classes of elements A, B, and C are disclosed, as well as examples of combinations of classes D, E, and F with element AD. If they are listed separately, then each is considered an individual item. Thus, in this example, the combination AE, AF, B- Each of D, BE, BF, CD, CE, and CF is specifically contemplated, and A, B, and C; D, E, and F; and combinations AD and AD disclosed in the examples. Likewise, any subset or combination of these should be considered as specific. Thus, for example, subgroups of AE, BF, and CE are Specifically envisaged are A, B, and C; D, E, and F; and the examples of combinations AD. The concept should be considered as disclosed from the disclosure. It applies to all aspects of this application including elements of steps of methods of making or using. The foregoing aspects of the invention, as will be appreciated by those skilled in the art following the teachings herein, Any combination or permutation of the invention may be used as long as it is novel and inventive compared to the prior art. It is possible to claim that an element is described in one or more references known to those skilled in the art. To the extent that they are, these are in particular negative conditions of a feature or combination of features. may be excluded from the claimed invention by reason of a claim or disclaimer.

[0082] Unofficial sequence listing >Sequence number 1 >Heavy chain of humanized anti-α4β7Ig; the sequence in italics is the leader sequence; the sequence underlined is a CDR. [Table 1] >Sequence number 2 The light chain of humanized anti-α4β7Ig; the italicized sequence is the leader sequence; the underlined sequence is The sequences in bold, underlined and italics are the CDRs and are the end of the variable region. [Table 2] >Sequence number 3 Mature humanized light chain of LDP-02; underlined sequences are CDRs, bold underlined The italicized sequence is the end of the variable region. [Table 3] [Table 4]

[0083] The present invention includes the following embodiments. [1] Gastrointestinal immune-related adverse events (gi-irA) in mammalian subjects undergoing cancer immunotherapy E) A method of treatment comprising administering a therapeutically effective amount of a compound that inhibits MAdCAM-α4β7 integrin binding. The method comprises administering to the subject a polypeptide that inhibits the proliferation of the subject. [2] The cancer immunotherapy is directed to 4-1BB, B7H3, B7H4, CCR2, CD27, CD4 0, CD40L, CD244, CSF1R, CTLA4, CXCR4, GITR, IDO , KIR2DL1, KIR2DL3, NKG2A, NKG2D, OX40, TIM3,R Select from AF kinase, PD-1, PDL-1, VISTA, or a combination of these The method according to [1] above, comprising treatment with a modulator of one or more targets. [3] The treatment includes a modulator of a target that is a T cell co-receptor, more specifically, the T The cellular co-receptor is an inhibitory receptor, more specifically, said inhibitory receptor is CTLA4 , PD-1, or CTLA4 and PD-1, Law. [4] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is Anti-α4β integrin, such as anti-α4β7 integrin, which competes with vedolizumab for binding to integrin 7 integrin antibody, more specifically, the antibody is an antibody that specifically binds to the epitope of vedolizumab. More specifically, the antibody has a complementarity determining region (CDR) of vedolizumab. More specifically, the antibody is vedolizumab. Any method as described above. [5] The antibody comprising the complementarity determining region (CDR) of vedolizumab has a heavy chain sequence of SEQ ID NO:1. The method according to [4] above, comprising a light chain variable region and a light chain variable region of SEQ ID NO: 2 or SEQ ID NO: 3. Law. [6] The anti-α4β7 integrin antibody is administered at a dose of about 1.25 to 8.0 mg / kg, for example, about 1. 25~4.25mg / kg, 1.75~3.75mg / kg, 2.25~3.25mg / In some embodiments, the anti-α 4β7 integrin antibody, about 5.0 to 8.0 mg / kg, 5.5 to 7.5 mg / kg, Administered at a dose of 6.0-7.0 mg / kg or 6.43 mg / kg, as above [4] The method according to [7] The subject is undergoing treatment with an anti-PD-1 antibody, and the anti-PD-1 antibody is 1, and more specifically, the antibody binds to an epitope of nivolumab. More specifically, the antibody has a complementarity determining region (CDR) of nivolumab. More specifically, the antibody is nivolumab. Any method as described above. [8] The anti-PD-1 antibody treatment is administered at a dose of about 0.5 to 6.0 mg / kg, for example, 0.5 to 2.0mg / kg, 0.5~1.5mg / kg, 0.75~1.25mg / kg, 1.0 mg / kg; 1.5~6.0mg / kg, 2.0~5.0mg / kg, 2.0~4.0m g / kg, 2.5-3.5 mg / kg, or 3.0 mg / kg. The method described in [7]. [9] The subject is undergoing treatment with an anti-CTLA4 antibody, the anti-CTLA4 antibody being and more specifically, the antibody competes with ipilimumab for binding to TLA4. More specifically, the antibody has an epitope specificity of the complementarity determining region of ipilimumab. More specifically, the antibody is ipilimumab. The method according to any one of claims 1 to 8.

[10] The anti-CTLA4 antibody is about 1.5 to 10.0 mg / kg, 2.0 to 5.0 mg / kg , 2.0-4.0mg / kg, 2.5-3.5mg / kg, or 3.0mg / kg The method according to [9] above, wherein the amount of

[11] The method according to any one of the above [1] to

[10] , wherein the subject is a human, such as an adult human. Law.

[12] The subject has melanoma (including unresectable or metastatic melanoma), non-small cell lung cancer ( (both squamous and non-squamous), renal cell carcinoma, head and neck cancer, bladder cancer, small cell lung cancer, bladder Cancer, colorectal cancer (including metastatic cancer), Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and prostate cancer (including metastatic hormone refractory prostate cancer), The method according to any one of [1] to

[11] .

[13] Any of the above-mentioned [1] to [9], wherein the subject has melanoma, lung cancer, or lymphoma. The method according to any one of the preceding claims.

[14] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an anti-α4β7 Integrin antibodies, at about 10 μg / ml or more, e.g., about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 5 The method according to any one of the above-mentioned [1] to

[0013] , wherein the compound is administered to achieve a serum concentration of 0 μg / ml or more.

[15] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an anti-α4β7 Integrin antibodies, two or more times, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 doses; for example, the doses may be the same or, for example, 2 The initial dose was 0.00 mg, followed by escalating doses of 450 mg. The method according to any one of the above [1] to

[14] .

[16] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an anti-α4β7 Integrin antibodies, approximately 108, 150, 165, 200, 216, 250, 300 , 350, 400, 450, 500, 550, 600, 650, 700, 750 mg, The present invention relates to any one of the above [1] to

[15] , which is administered to a human subject in a unit dose of 1 or more. The method described.

[17] Each dose of the polypeptide that inhibits MAdCAM-α4β7 integrin binding is The method according to

[16] above, wherein the dosage is 50 mg.

[18] Each dose of the polypeptide that inhibits MAdCAM-α4β7 integrin binding is The method according to

[16] above, wherein the dosage is 0.00 mg.

[19] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is The method according to any one of the above [1] to

[18] , wherein the method is administered at least once before immunotherapy. .

[20] At least one of the polypeptides inhibits MAdCAM-α4β7 integrin binding. After one dose, A PD-1 antagonist, an anti-PD-1 antibody, is administered every 2 weeks at a dose of, for example, about 3 mg / kg. given or Anti-CTLA4 antibody is administered every 3 weeks, for example at a dose of about 3 mg / kg, and the PD-1 antagonist is administered to the patient at a dose of, for example, about 1 mg / kg; or Anti-CTLA4 antibody is administered every 3 weeks, for example at a dose of about 3 mg / kg, and A PD-1 antagonist is administered to the patient at a dose of, for example, about 1 mg / kg, and the anti-CTLA4 antibody is administered to the patient at a dose of, for example, about 1 mg / kg. After the fourth dose, no further anti-CTLA4 antibody was administered and the PD-1 antagonist was administered for 2 weeks. For example, the drug is administered at a dose of about 3 mg / kg every 20 minutes. The method described. [twenty one] The polypeptide that inhibits MAdCAM-α4β7 integrin binding comprises at least The vaccine is administered four times, the second dose being administered about two weeks after the first dose, and the third dose being administered about two weeks after the first dose. a fourth dose is administered about 12 weeks after said first dose; The method according to any one of the above-mentioned [1] to

[20] , wherein the patient is administered [twenty two] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is a gi-ir The method according to any one of the above [1] to

[21] , which is administered prophylactically before the onset of symptoms of AE. How to. [twenty three] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is a gi-ir The method according to any one of the above-mentioned [1] to

[21] , wherein the method is administered according to the symptoms of AE. [twenty four] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is Antagonists, combination of CTLA4 antagonists and PD1 antagonists, and CTLA4 antagonists and OX40 agonists combination with CTLA4 antagonist, combination with KIR antagonist, combination with CTLA4 antagonist and CD27 agonist Combination therapy with CTLA4 antagonists, combination therapy with IDO antagonists, and combination therapy with CTLA4 antagonists and epithelial proliferation For cancer immunotherapy selected from the group consisting of combination with epidermal growth factor receptor (EGFR) antagonists The method according to

[22] above, wherein the compound is administered prophylactically or therapeutically to the subject. [twenty five]

[24] The above-mentioned CTLA4 antagonist is ipilimumab or tremilimumab. The method described.

[26] The method according to

[24] above, wherein the OX40 agonist is a MEDI6469 antibody.

[27] The method according to the above-mentioned

[0024] , wherein the IDO antagonist is INCB024360 (epacadostat).

[28] The above-mentioned

[24] , wherein the EGFR antagonist is erlotinib or gefitinib. How to.

[29] The cancer subject of the cancer immunotherapy is melanoma, non-small cell lung cancer, head and neck cancer, colorectal cancer, The method according to

[24] above, wherein the cancer is selected from the group consisting of cancer and lymphoma.

[30] The polypeptide that inhibits MAdCAM-α4β7 integrin binding is a TIM3 antagonist. Antibody, PD-1 antagonist, combination of PD-1 antagonist and KIR antagonist, PD-1 antagonist and CD 27 agonist, and combination of PD-1 antagonist and 4-1BB agonist. The method described in the above

[0023] , which is administered according to the symptoms of gi-irAE for selected cancer immunotherapy.

[31] The PD-1 antagonist is nivolumab or pembrolizumab. Method of posting.

[32] The method according to

[24] or

[30] above, wherein the KIR antagonist is lirilumab.

[33] The method according to the above-mentioned

[24] or

[30] , wherein the CD27 agonist is varlilumab. Law.

[34] The method described in the above

[0030] , wherein the 4-1BB agonist is PF-05082566 or utomirumab.

[35] The cancer subject of the cancer immunotherapy is head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and rhabdomyosarcoma. The method according to

[24] above, wherein the tumor is selected from the group consisting of glioblastoma and glioblastoma.

[36] Cancer immunotherapy is being performed, but the patient is not receiving treatment with a polypeptide that inhibits MAdCAM-α4β7 integrin binding. The subject exhibits improved comparator activity compared to a suitable control not treated with the polypeptide. lower incidence of drug interactions (e.g., treatment interruptions, discontinuations, and dosage reductions; higher treatment completion the rate of progression of the disease, longer treatment duration, no significant decrease in efficacy of the cancer immunotherapy, Increased efficacy of immunotherapy, reduction in grade of gi-irAEs, and duration of gi-irAEs shortening of treatment duration, delaying onset of gi-irAEs, and Reduced use of steroid immunosuppressants, colonoscopies, hospitalizations, or a combination of these or resolved; or a combination of any one or more of the above [1] to

[35] 2. The method according to claim 1 ,

Claims

1. Gastrointestinal immune-related adverse events (gi-irA) in mammalian subjects undergoing cancer immunotherapy E) A method of treatment comprising administering a therapeutically effective amount of a compound that inhibits MAdCAM-α4β7 integrin binding. The method comprises administering to the subject a polypeptide that inhibits the proliferation of the subject.

2. The cancer immunotherapy comprises 4-1BB, B7H3, B7H4, CCR2, CD27, CD4 0, CD40L, CD244, CSF1R, CTLA4, CXCR4, GITR, IDO , KIR2DL1, KIR2DL3, NKG2A, NKG2D, OX40, TIM3,R Selected from AF kinase, PD-1, PDL-1, VISTA, or a combination thereof The method of claim 1, further comprising treatment with a modulator of one or more targets that are targeted by the method.

3. The treatment includes a modulator of a target that is a T cell co-receptor, more specifically, the T The cellular co-receptor is an inhibitory receptor, more specifically, said inhibitory receptor is CTLA4 , PD-1, or CTLA4 and PD-1.

4. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an α4β7 integrin. anti-α4β7 integrin, which competes with vedolizumab for binding to integrin 7 integrin antibody, more specifically, said antibody is an antibody that specifically binds to the epitope of vedolizumab. More specifically, the antibody has a complementarity determining region (CDR) of vedolizumab. and even more particularly, said antibody is vedolizumab.

13. The method according to claim 1.

5. The antibody comprising the complementarity determining region (CDR) of vedolizumab has a heavy chain fragment of SEQ ID NO:

1.

5. The method of claim 4, comprising a light chain variable region of SEQ ID NO: 2 or SEQ ID NO:

3. 。

6. The anti-α4β7 integrin antibody is administered at a dose of about 1.25 to 8.0 mg / kg, for example, about 1. 25-4.25mg / kg, 1.75-3.75mg / kg, 2.25-3.25mg / kg, or 2.86 mg / kg; in some embodiments, the anti-α 4β7 integrin antibody, about 5.0 to 8.0 mg / kg, 5.5 to 7.5 mg / kg, 5. The method according to claim 4, wherein the compound is administered at a dose of 6.0 to 7.0 mg / kg, or 6.43 mg / kg. The method described.

7. The subject is undergoing treatment with an anti-PD-1 antibody, and the anti-PD-1 antibody is 1, and more specifically, the antibody binds to an epitope of nivolumab. and more specifically, the antibody has a complementarity determining region (CDR) of nivolumab. and even more particularly, wherein the antibody is nivolumab.

13. The method according to claim 1.

8. The anti-PD-1 antibody treatment is administered at a dose of about 0.5 to 6.0 mg / kg, e.g., 0.5 to 2.0mg / kg, 0.5-1.5mg / kg, 0.75-1.25mg / kg, 1.0 mg / kg; 1.5 to 6.0 mg / kg, 2.0 to 5.0 mg / kg, 2.0 to 4.0 m g / kg, 2.5-3.5 mg / kg, or 3.0 mg / kg. Item 7. The method according to item 7.

9. The subject is undergoing treatment with an anti-CTLA4 antibody, the anti-CTLA4 antibody being and more specifically, the antibody competes with ipilimumab for binding to TLA4. More specifically, the antibody has an epitope specificity of the complementarity determining region of ipilimumab. and more particularly, said antibody is ipilimumab. The method according to any one of claims 1 to 5.

10. The anti-CTLA4 antibody is about 1.5 to 10.0 mg / kg, 2.0 to 5.0 mg / kg , 2.0-4.0 mg / kg, 2.5-3.5 mg / kg, or 3.0 mg / kg 10. The method of claim 9, wherein the amount

11. 2. The method of any one of the preceding claims, wherein the subject is a human, such as an adult human.

12. The subject has melanoma (including unresectable or metastatic melanoma), non-small cell lung cancer ( (both squamous and non-squamous), renal cell carcinoma, head and neck cancer, bladder cancer, small cell lung cancer, bladder Cancer, colorectal cancer (including metastatic cancer), Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and prostate cancer (including metastatic hormone refractory prostate cancer).

13. A method according to any one of the preceding claims.

13. 10. The method of claim 1, wherein the subject has melanoma, lung cancer, or lymphoma. The method according to

14. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an anti-α4β7 Integrin antibodies, about 10 μg / ml or more, e.g., about 11, 12, １３、１４、１５、１６、１７、１８、１９、２０、２５、３０、３５、４０、４５、５ Any of the preceding claims is administered to achieve a serum concentration of 0 μg / ml or more. The method according to any one of claims 1 to 5.

15. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an anti-α4β7 Integrin antibodies, two or more times, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 doses; for example, the doses may be the same or, for example, 2 The initial dose was 100 mg, followed by escalating doses of 450 mg.

4. The method according to any one of the preceding claims,

16. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is an anti-α4β7 Integrin antibodies, about 108, 150, 165, 200, 216, 250, 300 , 350, 400, 450, 500, 550, 600, 650, 700, 750 mg, 2. The method according to claim 1, wherein the composition is administered to a human subject in one or more unit doses. method.

17. Each dose of the polypeptide that inhibits MAdCAM-α4β7 integrin binding is 17. The method of claim 16, wherein the dosage is 50 mg.

18. Each dose of the polypeptide that inhibits MAdCAM-α4β7 integrin binding is 17. The method of claim 16, wherein the dosage is 100 mg.

19. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is 2. The method according to any one of the preceding claims, administered at least once prior to immunotherapy.

20. At least one of the polypeptides inhibits MAdCAM-α4β7 integrin binding. After one dose, A PD-1 antagonist, an anti-PD-1 antibody, is administered every two weeks, for example at a dose of about 3 mg / kg. given or The anti-CTLA4 antibody is administered at a dose of, for example, about 3 mg / kg every three weeks, and the PD-1 antagonist is administered, for example at a dose of about 1 mg / kg, or The anti-CTLA4 antibody is administered at a dose of, for example, about 3 mg / kg every three weeks, and A PD-1 antagonist is administered to the patient at a dose of, for example, about 1 mg / kg, and the anti-CTLA4 antibody After the fourth dose, no further anti-CTLA4 antibody was administered and the PD-1 antagonist was administered for 2 weeks.

2. The method according to claim 1, wherein the medicament is administered every 20 minutes at a dose of, for example, about 3 mg / kg. method.

21. The polypeptide that inhibits MAdCAM-α4β7 integrin binding comprises at least The vaccine is administered four times, the second dose being administered about two weeks after the first dose, and the third dose being administered about two weeks after the first dose. a fourth dose is administered about 12 weeks after said first dose; 2. The method of any one of the preceding claims, wherein the subject is administered

22. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is 2. The method according to any one of the preceding claims, which is administered prophylactically, prior to the onset of symptoms of an AE. 。

23. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is The method of any one of claims 1 to 21, administered in response to symptoms of an AE.

24. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is Antagonist, combination of CTLA4 antagonist and PD1 antagonist, CTLA4 antagonist and OX40 agonist combination with CTLA4 antagonist and KIR antagonist; combination with CTLA4 antagonist and CD27 agonist Combination of CTLA4 antagonist and IDO antagonist, and combination of CTLA4 antagonist and epithelial proliferation and combination with an EGFR antagonist. The method of claim 22, wherein the antibody is administered prophylactically or therapeutically to

25. 25. The method of claim 24, wherein the CTLA4 antagonist is ipilimumab or tremilimumab. Method of posting.

26. 25. The method of claim 24, wherein the OX40 agonist is a MEDI6469 antibody.

27. 24. The IDO antagonist is INCB024360 (epacadostat). The method according to

28. 25. The method of claim 24, wherein the EGFR antagonist is erlotinib or gefitinib. method.

29. The cancer subject of the cancer immunotherapy is melanoma, non-small cell lung cancer, head and neck cancer, colorectal cancer, 25. The method of claim 24, wherein the cancer is selected from the group consisting of cancer and lymphoma.

30. The polypeptide that inhibits MAdCAM-α4β7 integrin binding is a TIM3 antagonist. Antibody, PD-1 antagonist, combination of PD-1 antagonist and KIR antagonist, PD-1 antagonist and CD 27 agonist and combination of a PD-1 antagonist and a 4-1BB agonist.

2. The method of claim 1, wherein the therapeutic agent is administered in response to symptoms of gi-irAE for the purpose of selected cancer immunotherapy.

3. The method according to claim 3.

31. The method of claim 30, wherein the PD-1 antagonist is nivolumab or pembrolizumab. How to.

32. 31. The method of claim 24 or 30, wherein the KIR antagonist is lirilumab.

33. 31. The method of claim 24 or 30, wherein the CD27 agonist is varlilumab.

34. The 4-1BB agonist is PF-05082566 or utomirumab.

30. The method according to claim 30.

35. The cancer subject of the cancer immunotherapy is head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and rhabdomyosarcoma.

25. The method of claim 24, wherein the tumor is selected from the group consisting of glioblastoma.

36. Patients undergoing cancer immunotherapy are receiving MAdCAM-α4β7 integrin binding inhibitors. The subject exhibits improved comparator activity compared to a suitable control not treated with the polypeptide. patient outcomes (e.g., lower incidence of treatment interruptions, discontinuations, and reductions in dosage; higher treatment completion (c) a significant decrease in efficacy of said cancer immunotherapy; Increased efficacy of immunotherapy, reduction in grade of gi-irAE, and duration of gi-irAE shortening of the time to presentation, delay in onset of gi-irAE, corticosteroids, antibiotics, non-corticosteroids Reduced use of steroid immunosuppressants, colonoscopies, hospitalizations, or a combination of these or any combination thereof.

13. The method according to claim 1.

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