Methods of treating or preventing graft versus host disease

Abstract

To provide a method for treating or preventing GvHD in a human patient.SOLUTION: Provided is a method comprising administering to a patient suffering from GvHD or at risk for GvHD, a humanized antibody having binding specificity for human α4β7 integrin.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. Provisional Application No. 62 / 307,896, filed March 14, 2016, and and U.S. Provisional Application No. 62 / 420,825, filed November 11, 2016. The entirety of said application is incorporated herein by reference. [Background technology]

[0002] Allogeneic hematopoietic cell transplantation (allo-HSCT), such as hematopoietic stem cell transplantation, is a treatment for malignant hematologic disorders and It is an important therapy used in the treatment of hematologic and inherited blood disorders, but its use is limited to graft-versus-host disease. Limited by the serious complication of GvHD after allo-HSCT. D is a major cause of morbidity and mortality. The risk of GvHD varies and is influenced by patient factors, donor factors, factors, the degree of histocompatibility between donor and recipient, the conditioning regimen, and the type of tissue being treated. The GvHD prophylaxis regimen for patients undergoing allo-HSCT depends on the donor's hematopoiesis. Pretreatment allows cells to engraft and includes chemotherapy or radiation, and is given immediately before transplantation. The goal of the procedure is to help eradicate the patient's disease prior to infusion of hematopoietic stem cells (HSCs) and to improve immunity. The prognosis after transplantation is often life-threatening, with acute and Including chronic graft-versus-host disease. In patients receiving allogeneic hematopoietic stem cells after myeloablative conditioning. The risk of grade 2-4 acute GvHD is approximately 40%-50%. Reducing GvHD without autoimmune suppression improves overall outcome after allo-HSCT. It can be improved.

[0003] GvHD is a donor allogeneic response caused by histocompatibility antigens on host antigen-presenting cells (APCs). Intestinal flora and endotoxin inhibit APC activity. This process is thought to affect a critical stage in the development of gut-associated phosphorylation. Clinically, it occurs in the GALT through the use of T cell depletion methods and intestinal decolonization. GvHD reduction is possible, which is due to the effects of T cells and the gastrointestinal tract (GI) ) clearly demonstrates the respective roles of both the bacterial flora. Integrin α4β7 expression is associated with acute cutaneous GvHD and / or GvHD. Compared with patients without GvHD, patients with acute intestinal GvHD after transplantation had a higher incidence of naive and It has been shown that T cell migration to GALT and α4β7 and memory T cells are significantly more abundant. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) interactions are a key factor in acute GvHD. It has been studied using a mouse model.

[0004] The risk of GvHD varies and is influenced by patient factors, donor factors, and the relationship between the donor and recipient. It depends on the degree of histocompatibility, the conditioning regimen, and the method of GvHD prophylaxis. In patients who received hematopoietic stem cells from an unrelated donor after The risk of acute GvHD was approximately 40% to 50%. The adverse effects of immunosuppressive therapy for GvHD, including infections and the development of chronic GvHD, have been reported. The combined mortality rate due to GvHD and infections is higher than that of allo-H It is high in patients after SCT and is the second most common cause of death after the primary disease. The prognosis for patients who do not respond after initial HD treatment is poor.

[0005] GvHD prophylaxis is based on calcineurin inhibitors, methotrexate, and in vivo or have used various methods, such as ex vivo T cell depletion, to treat patients with allo-HSCT. However, even with GvHD prophylaxis, GvHD persists in all patients. It occurs in 30% to 50% of o-HSCT recipients (Gooley TA et al., N Engl J Med 2010;363(22):2091- 101; McDonald GB et al., Blood 2015;126( 1):113-20). Acute GvHD (grade II or higher) The first-line treatment for patients is a corticosteroid such as methylprednisolone. First-line treatments are effective in over 50% of patients, but sustained responses (up to 28 days) are rare. One-third achieved a complete response (CR) at 6 months after onset This has only been observed in patients with t Haematol 2015;2(1)e21-e9). Primary treatment with steroids In patients who do not respond to treatment, acute GvHD is primarily manifested by infection and / or multiple organ failure. associated with high rates of morbidity and mortality from ., Biol Blood Marrow Transplant 2009;15( 5):639-42; Xhaard A. et al., Biol Blood Marrow Transplant 2009;15(5):639-42). Despite this, there is no approved or accepted standard treatment for steroid-resistant GvHD. This leaves it with a largely untreatable disease with limited survival and limited response to major treatments. This indicates an unmet need.

[0006] Acute GvHD following allo-HSCT can affect the skin, liver, and, in its most severe and life-threatening form, In rare cases, the intestinal tract is involved. Generally, acute cutaneous GvHD is treated with currently available treatments, which are usually effective. It is not life-threatening, and the incidence of stage 3 or 4 liver GvHD is approximately 2%. (Gooley TA et al., N Engl J Med 2010; 363(22):2091-101). On the other hand, the development of stage 3 or 4 intestinal GvHD Although rates have decreased in recent years, most fatal GvHD cases involve the gastrointestinal (GI) tract. As such, many treatment courses remain unsuccessful (Gooley TA et al. , N Engl J Med 2010;363(22):2091-101). bottom Intestinal GvHD is characterized by secretory, protein-rich diarrhea (more than 1.5 liters per day in severe cases). It indicates abdominal pain due to gastrointestinal distension, inflammation of the small intestine and colon, mucosal ulcers, and bleeding. In a study of patients undergoing o-HSCT, 7.9% of patients had a 35-day post-transplant symptom onset. A median of 10 patients developed stage 3 or 4 intestinal GvHD (Casti lla-Llorente C et al., Bone Marrow Trans Plant 2014;49(7):966-71). Of these patients, 73% had Corticosteroid resistance before or within 14 days of the onset of stage 3 or 4 intestinal GvHD Significant risk factors for death were corticosteroid resistance and age over 18 years. These include increased serum bilirubin, and overt GI bleeding. There is an urgent unmet medical need for agents and methods for the treatment or prevention of It still exists. Summary of the Invention

[0007] The present invention provides a method for administering an antagonist of human α4β7 integrin to a subject in need thereof. The present invention relates to a method for treating or preventing graft-versus-host disease by administering

[0008] The present invention relates to α4β7 integrin antagonists, such as humanized anti-α4β7 antibodies (e.g., Prevention of graft-versus-host disease (GvHD) with anti-α4β7 antibodies such as vedolizumab In some embodiments, the patient has acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). He has myeloid leukemia (AML).

[0009] GvHD is a major cause of morbidity and mortality in patients undergoing allo-HSCT. The significant mortality caused by GvHD is a potential cure for the disease, e.g., malignancy. Limits the use of HSCT as a treatment option. Non-relapse mortality (due to GvHD, infection, etc.) Reducing steroids and steroid use may improve overall survival after allo-HSCT. Other systemic immunosuppressants (such as tacrolimus plus short-term methotrexate) are used to prevent GvHD. However, this standard of care is It may increase the risk of infection and is not completely effective. Immunosuppression for this purpose may also reduce the graft-versus-tumor (GvT) effect. As previously described, reducing GvHD without systemic immunosuppression is possible after allo-HSCT. The potential to improve overall outcomes in patients with this disease and to extend and / or save lives from this disease It has potential.

[0010] Hematopoietic stem cells expressing low levels of α4β7 integrin following allo-HSCT Naive T cells within the HSC inoculum are expressed in the host Peyer's patches (PPs) or mesenteric lymph nodes. They circulate to the MLN, where they come into contact with and activate gut microbial antibodies in the context of alloantigens. These activated effector T cells up-regulate α4β7 integrin. This then homed to the intestinal mucosa via the α4β7 / MADCAM-1 pathway, resulting in intestinal mucosal damage. Interactions between alloreactive effector T cells, gut microbiota, and intestinal mucosal tissues triggers the release of multiple inflammatory mediators, creating a positive feedback loop Disruption of the intestinal barrier leading to proliferation of alloreactive T cells, translocation of microorganisms and microbial stimuli, and The combination of this and a systemic cytokine storm leads to the diffuse systemic symptoms of GvHD.

[0011] Without wishing to be bound by any particular theory, in the prevention of GvHD, The present invention provides a method for the production of T cell-mediated secondary lymphoid tissues by inhibiting the α4β7 / MADCAM-1 pathway. This would block the first move to the government, e.g., PP or MLN. In some embodiments, the present invention inhibits and / or prevents the progression of acute GvHD. The present invention provides a method for reducing acute GVH on day 100 compared to the current standard of care (SOC). and a 50% reduction in cumulative incidence and severity of acute GVHD and a 25% reduction in one-year mortality. In other embodiments, the present invention provides improved six-month GVHD-free survival, improved one-year GVHD- and relapse-free survival, improved cumulative incidence and severity of acute GVHD at six months post-HSCT, improved cumulative incidence of chronic GVHD requiring immunosuppression at 12 months, or improved GRFS (GvHD- and relapse-free survival) compared to SOC. In some embodiments, administration of an α4β7 integrin antagonist, such as an anti-α4β7 antibody, results in a 5%, 10%, 15%, 20%, 25%, or 30% reduction in risk of mortality, e.g., a 40% reduction in risk of death from acute GVHD to, e.g., 35% or less.

[0012] In one aspect, the present invention provides a method for preventing graft-versus-host disease (GvHD), comprising: Human α4β7 inte- grated β-glucanase (GlcNAc) was administered to human patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). administering a humanized antibody having binding specificity for glycine; a. Humanized antibody at an initial dose of 75 mg, 300 mg, 450 mg, or 600 mg Intravenous infusion on the day before llo-HSCT, b. followed by a second dose of 75 mg, 300 mg, 450 mg, or 600 mg of the humanized antibody. Approximately 2 weeks after the initial administration, c. followed by a third dose of 75 mg, 300 mg, 450 mg, or 600 mg of the humanized antibody Approximately 6 weeks after the initial administration, This regimen is administered according to the following: Grade IIGvHD, Grade IGvHD, or Furthermore, humanized antibodies contain antigen-binding regions and The humanized antibody comprises at least a portion of an antibody of human origin, and has binding specificity for the α4β7 complex. and the antigen-binding region is SEQ ID NO: 7 (CDR1), SEQ ID NO: 8 (CDR2), and SEQ ID NO: Light chain CDR number 9 (CDR3) and sequence numbers 4 (CDR1) and 5 (CDR2), and the heavy chain CDR of SEQ ID NO: 6 (CDR3).

[0013] In another aspect, the present invention provides a method for reducing the incidence of acute graft-versus-host disease (GvHD). And, Human α4β7 infusion was administered to human patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). administering a humanized antibody having binding specificity for Tegrin; The humanized antibody is administered to a patient using the following dosing regimen: a. Humanized antibody at an initial dose of 75 mg, 300 mg, 450 mg, or 600 mg Intravenous infusion on the day before llo-HSCT, b. followed by a second dose of 300 mg of the humanized antibody administered intravenously approximately 2 weeks after the first dose; c. A third dose of 300 mg of humanized antibody is then administered intravenously approximately 6 weeks after the first dose. is administered according to A humanized antibody comprises an antigen-binding region of non-human origin and at least a portion of an antibody of human origin; The humanized antibody has binding specificity for the α4β7 complex, and the antigen-binding region is SEQ ID NO: 7 (C Light chain CDRs and sequence numbers of SEQ ID NO: 1 (CDR1), SEQ ID NO: 8 (CDR2), and SEQ ID NO: 9 (CDR3) Heavy chain CDRs of SEQ ID NO: 4 (CDR1), SEQ ID NO: 5 (CDR2), and SEQ ID NO: 6 (CDR3) The present invention relates to a method, comprising:

[0014] In another embodiment, the present invention provides a method for reducing the severity of acute graft-versus-host disease (GvHD). A method of Human α4β7 infusion was administered to human patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). administering a humanized antibody having binding specificity for Tegrin; The humanized antibody is administered to a patient using the following dosing regimen: a. Allo-H humanized antibody at an initial dose of 300 mg, 450 mg, or 600 mg Intravenous infusion on the day before SCT, b. followed by a second dose of 300 mg of the humanized antibody administered intravenously approximately 2 weeks after the first dose; c. A third dose of 300 mg of humanized antibody is then administered intravenously approximately 6 weeks after the first dose. and humanized antibodies are antibodies that contain an antigen-binding region of non-human origin and at least one antibody of human origin. The humanized antibody has binding specificity for the α4β7 complex and comprises at least a portion of the antigen-binding domain. The regions are SEQ ID NO: 7 (CDR1), SEQ ID NO: 8 (CDR2), and SEQ ID NO: 9 (CDR3). Light chain CDRs and SEQ ID NO: 4 (CDR1), SEQ ID NO: 5 (CDR2), and SEQ ID NO: 6 (CDR3). R3).

[0015] In some embodiments, the reduction in severity of acute graft-versus-host disease (GvHD) is achieved by modifying Grade I or Grade IIGv according to the revised Glucksberg criteria HD, or GvHD or GvHD of similar severity according to other scoring systems In some embodiments, the reduction in severity of acute GvHD results in a state in which the patient is not ill. At 100 days, compared with treatment with thotrexate and a calcineurin inhibitor alone, Cumulative incidence of acute GvHD in the In some embodiments, the severity of acute graft-versus-host disease is reduced by 50%. Reduction in the severity of GvHD (graft-versus-host disease) with methotrexate and calcineurin inhibitors alone The reduction in mortality within one year compared with treatment with

[0016] In some embodiments, the patient is monitored for biomarkers, clinical signs, and steroid use. risk of developing acute GvHD after measuring a criterion selected from the group consisting of: It is identified as being present.

[0017] In some embodiments, the humanized antibody remains viable for more than 15 days, more than 16 days after hematopoietic stem cell infusion. , more than 17 days, more than 20 days, or more than 21 days.

[0018] In some embodiments, the reduction in the occurrence of acute GvHD is due to the use of modified Glucks Grade I or Grade II G vHD according to the Berg criteria, or other scores The results of the analysis show similar severity of GvHD or no GvHD. In an embodiment, the reduction in the occurrence of acute GvHD is achieved by the combination of methotrexate and calcineurin inhibitors. Cumulative incidence and severity of acute GvHD at 100 days compared with treatment with anticoagulant alone A 50% reduction in the severity of GvHD grade II-IV or grade III-IV In another embodiment, the reduction in the occurrence of acute graft-versus-host disease (GvHD) is due to methotrexate. reduction in mortality within one year compared with treatment with rituximab and calcineurin inhibitors alone do.

[0019] In another aspect, the present invention relates to a method for treating cancer or a non-malignant hematological disease, an immune disease, or an autoimmune disease. A method for treating a patient suffering from a disease, a. conditioning the immune system of hematopoietic stem cell transplant patients; b. administration of a humanized antibody having binding specificity for human α4β7 integrin; c. Waiting for at least 12 hours; d. administration of allogeneic hematopoietic stem cells; e. After waiting 13 days, a humanized antibody having binding specificity for human α4β7 integrin a second administration of f. After a waiting period of 4 weeks, a humanized antibody having binding specificity for human α4β7 integrin a third administration of A method comprising the steps of: In another aspect, the present invention provides a method of suppressing an immune response in a cancer patient, comprising: Human α4β7 infusion was administered to human patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). administering a humanized antibody having binding specificity for Tegrin; The humanized antibody is administered to a patient using the following dosing regimen: a. Humanized antibody at an initial dose of 75 mg, 300 mg, 450 mg, or 600 mg Intravenous infusion on the day before llo-HSCT, b. followed by a second dose of 300 mg of the humanized antibody administered intravenously approximately 2 weeks after the first dose; c. A third dose of 300 mg of humanized antibody is then administered intravenously approximately 6 weeks after the first dose. is administered according to Furthermore, humanized antibodies are antibodies that combine an antigen-binding region of non-human origin with at least a portion of an antibody of human origin. the humanized antibody has binding specificity for the α4β7 complex, and the antigen-binding region is 7 (CDR1), SEQ ID NO: 8 (CDR2), and SEQ ID NO: 9 (CDR3) Heavy chain of SEQ ID NO: 4 (CDR1), SEQ ID NO: 5 (CDR2), and SEQ ID NO: 6 (CDR3) The present invention relates to methods comprising: The humanized antibody may have a heavy chain variable region sequence of amino acids 20 to 140 of SEQ ID NO:1. The humanized antibody may have a light chain variable region sequence of amino acids 20-131 of SEQ ID NO:2. The humanized antibody has a heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 1 and an amino acid sequence of SEQ ID NO: 2. In some embodiments, the humanized antibody may have a light chain comprising amino acids 20 to 238. It is dolizumab.

[0020] In a further aspect, the present invention relates to a method of treating a transplant patient, wherein the transplant patient is Recipients of allogeneic hematopoietic cell infusions who are receiving anti-α4β7 antagonists In some embodiments, the α4β7 integrin antagonist is an anti-α4β7 In some embodiments, the anti-α4β7 antibody is a humanized antibody. In some embodiments, the anti-α4β7 antagonist is administered as a single dose for 10 to 28 days after infusion. , administered for 14 to 30 days, 15 to 32 days, or 15 to 35 days.

[0021] In an additional aspect, the present disclosure provides a method for treating graft-versus-host disease (GvHD) in humans. and a method for inducing binding to the human α4β7 integrin complex in a human in need thereof. In one embodiment, the method comprises administering an antibody having specificity for human α4β7 integrin. The antibody having binding specificity for the agonist complex is administered using the following regimen: a) a first antibody administration; a) administration of a second antibody about two weeks after the first administration; and c) administration of a third antibody about four weeks after the second administration. and optionally d) further antibody administrations, each administration being administered about 4 weeks after the most recent administration. , wherein each dose of a) through d) is 300 mg, or In some embodiments, each dose is 300 or 600 mg. Patients who received five doses of the antibody in a) to d) were further administered 300 mg of antibody at each dose. Repeat a) to d) with the given [Brief explanation of the drawings]

[0022] [Figure 1]Figure 1 is a schematic diagram outlining the study design from day -1 to day +50. Allo-HSCT will be performed on day 0. Vedolizumab will be administered the day before allo-HSCT (day -1) and on days +13 and +42 after allo-HSCT. [Figure 2] FIG. 2 shows how blocking α4β7 / MADCAM-1 interactions in GALT and MLN reduces the generation of alloreactive memory T cells and their subsequent entry into the intestine, thereby reducing the occurrence of GvHD. [Figure 3] Figure 3 is a graph showing simulated and observed PK data from three patients. The PK simulated data is represented by the area between the jagged lines (2.5 and 97.5 percentiles of the simulated data), the black dotted line without dots represents the median of the simulated data (points and lines are individual observations plotted using nominal times), and the horizontal dotted line represents the LLOQ of 0.2 mcg / mL. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention relates to a method for treating disease through the prevention of GvHD, the method comprising administering an anti-α4β α4β7 integrin antagonists, such as the α4β7 antibody, are administered to patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). This includes administering to patients undergoing allogeneic hematopoietic cell transplants such as SCT. In terms of form, the patient's disease is cancer, such as blood cancer (leukemia, lymphoma, In another embodiment, the patient's underlying disease is a myeloma or myelodysplastic syndrome. is a non-malignant hematological or immunological defect (bone marrow failure syndrome, hemoglobinopathies, or In one embodiment, the transplant patient is conditioned, e.g., In some embodiments, the patient undergoes a process to prepare the body to receive the transplant. The treatment is a myeloablative conditioning regimen ("bone-marrow conditioning") or is a treatment with a compound used in a myeloablative conditioning regimen. Less drug than the prescribed dose, e.g., 10%, 20%, 30%, 40%, 20-40%, 30- Drugs such as 50% or less than 50% are used as dose reduction conditioning (RIC). In some embodiments, the conditioning treatment is, for example, cyclophosphamide and / or busulfan. It can be chemically induced with flucloxin and / or fludarabine, or by total body irradiation, for example. Radiation-induced or chemical treatments such as cyclophosphamide and total body irradiation and radiation treatment.

[0024] In one embodiment, a patient, eg, a transplant patient, is administered allogeneic hematopoietic cells, eg, by transfusion. In some embodiments, the allogeneic hematopoietic cells are allogeneic hematopoietic stem cells, i.e., the patient is allogeneic. undergo hematopoietic stem cell transplantation (allo-HSCT). The blood cells are allogeneic white blood cells. In some embodiments, the allogeneic white blood cells are, e.g., In some embodiments, the allogeneic white blood cells include lymphocytes, such as T lymphocytes. In some embodiments, allogeneic leukocytes include lymphocytes expressing chimeric antigen receptors. In some embodiments, allogeneic white blood cells include natural killer cells. include cytotoxic T lymphocytes, e.g., T cells expressing CD8. In this study, allogeneic white blood cells were used in a study of at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 0%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% phosphorus In some embodiments, the allogeneic white blood cells are selected to consist of at least At least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 9 The cells are selected to consist of 6%, 97%, 98%, 99% or 100% T lymphocytes. In some embodiments, the allogeneic hematopoietic cells are administered to a subject in a manner that controls their behavior in the subject. , with one or more recombinant modifications known in the art.

[0025] In some embodiments, the α4β7 antagonist, such as an anti-α4β7 antibody, Prevents host-versus-host disease (GVHD). In some embodiments, an α4β7 antibody, such as an anti-α4β7 antibody, The 4β7 antagonist does not prevent prophylactic graft-versus-tumor activity. In some embodiments, the transplanted cells engraft with tolerance into the patient's tissue. The present invention provides a method for preventing transmigration by administering anti-α4β7 antibodies to patients undergoing allo-HSCT. In some embodiments, the present invention relates to a method for preventing graft-versus-host disease (GvHD). The antagonist is administered to the patient prior to receiving hematopoietic cells, such as allogeneic hematopoietic stem cells, and In another embodiment, the α4β 7 Antagonists are administered to patients shortly after receiving hematopoietic cell transplants, for example, up to 7 days after. In some embodiments, the anti-α4β7 antibody is administered to a mouse model, such as the Act-1 mouse model. It is a humanized antibody with epitope specificity to the monoclonal antibody. In some embodiments, the anti-α4β7 antibody is vedolizumab.

[0026] Hematopoietic cells, e.g., stem cells, are derived from the bone marrow or blood of a non-autologous donor (i.e., allogeneic) (e.g., In some embodiments, hematopoietic cells, e.g., peripheral blood or umbilical cord blood, may be derived from hematopoietic cells, e.g., For example, stem cells may be manipulated prior to infusion, e.g., by antibody selection or other mechanisms. These are cells enriched or depleted of specific cells, grown in vitro, They may be genetically modified or have undergone gene editing or gene therapy. Examples of hematopoietic cell compositions that have been enriched or depleted include those that have been subjected to negative selection, e.g., red blood cell selection. Separation of leukocytes from globules (e.g., dense solutions of sugars or polymers (e.g., FICOLL) Trademark) solution (Amersham Biosciences division of G E healthcare, Piscataway, NJ) or HISTOPAQUE (R)-1077 solution, Sigma-Aldrich Biotechnology y LP and Sigma-Aldrich Co., St. Louis, M Differential centrifugation via (O) and / or selection agents (e.g., direct separation methods (e.g., cell migration) column (R&D Systems, Minneapolis) Magnetic beads (e.g., Miltenyi Biotec, Aubur, MN) were placed in the (obtained from CA) or other beads) or fluorescent activity B cell markers such as CD19 or CD20, CD34, and CD 38, myeloid progenitor markers such as CD117, CD138, CD133, or ZAP70 - or binds to T cell markers such as CD2, CD3, CD4, CD5, or CD8 In one embodiment, the cells can be harvested by positive selection through binding of the cells to a reagent that binds to the cell surface. In this method, differential centrifugation separates the cell layer containing the white blood cells.

[0027] In some embodiments, the patient is suffering from a disease such as cancer or a non-malignant disease. In some embodiments, the patient has leukemia, e.g., acute lymphoblastic leukemia (ALL). ) or acute myeloid leukemia (AML). In some embodiments, the patient has: In some embodiments, the patient has a myelodysplastic or myeloproliferative disorder. have lymphoma, such as non-Hodgkin's lymphoma or Hodgkin's lymphoma. In this study, patients with non-malignant hematological disorders such as hemoglobinopathies (e.g., sickle cell disease) or thalassemia), bone marrow failure syndromes (e.g., aplastic anemia, Fanconi anemia, or Other bone marrow failure syndromes, immune disorders such as severe combined immunodeficiency syndrome (SCID), or diabetes In some embodiments, the patient has an autoimmune disease such as sclerosing cholangitis, cirrhosis, or hemochromatosis (e.g., in liver transplants), congestive heart disease, dilated coronary artery disease, or or severe coronary artery disease (e.g., in the case of a heart transplant), cystic fibrosis, chronic obstructive pulmonary disease, or may be due to pulmonary fibrosis (e.g., in cases of lung transplantation), or to diabetes, polycystic kidney disease, or systemic lupus erythematosus or focal segmental glomerulosclerosis (e.g., in kidney transplants) In some embodiments, the patient has a possible disorder, such as in the case of hematopoietic cell transplantation. For example, for the purpose of tolerance induction and for solid organ transplantation, such as liver, heart, lung or kidney transplantation. In another embodiment, the patient receives two transplants: a first allo-HSCT and a second allo-HSCT. receive a second two-transplant with allogeneic T cells via donor leukocyte infusion (DLI). In both transplantation procedures, there is a possibility of acute GvHD developing, and therefore, the administration of anti-α Administration of α4β7 integrin antagonists such as α4β7 antibodies is beneficial for both transplants. obtain.

[0028] Acute graft-versus-host disease (AGVHD) is a condition characterized by the proliferation of alloreactive immune cells, such as T cells, in the liver and skin (rash). It is characterized by damaging tissues such as the gastrointestinal tract and other mucous membranes. In some cases, autoreactive immune cells can cause acute graft-versus-host disease. The cells may become reactive with blood cell transfusion or may be signaled in the tissues of the patient, e.g., a transplant patient. The signal is recognized by alloreactive hematopoietic cells and can be activated upon recognition of the nucleus. or autoreactive immune cells that may be induced from conditioning regimens or tumor lysis syndrome, e.g. Prevention of GvHD involves the maintenance of hematopoietic cells, e.g., hematopoietic stem cells. This may be due to persistent α4β7 blockade initiated at the time of cell infusion. Prophylactic administration of vedolizumab to patients receiving It may prevent migration of alloreactive T cells to the mesenteric lymph nodes and GI mucosa, thereby preventing acute G Sustained α4β7 blockade further prevents GvHD during hematopoietic cell engraftment. For example, they block autoreactive immune cells and prevent the majority of acute myeloid leukemia. It persisted throughout the first 100 days after allo-HSCT, the period during which GvHD occurs. Provided at a dose sufficient to achieve receptor saturation. Grade III-IV or Index C- D acute GvHD is a risk factor for the development of chronic GvHD, and therefore, acute Gv Treatments that can prevent HD may reduce the risk of developing chronic GvHD. (Flowers M .ED et al. Blood 2011 Mar 17 117(11):3 214-19).

[0029] One aspect of the present invention is an α4β7 integrin antagonist for use in the prevention of GvHD. Unlike healthy subjects, Myeloablative or reduced-dose conditioning regimens following hematopoietic cell transplantation, such as Illo-HSCT Patients with α4β7 integrin expression exhibit a T cell population with fluctuations in α4β7 integrin expression during the post-transplant period. For example, the engraftment of HSCs is expected to significantly alter the expression of homing factors in the bone marrow of engrafted HSCs. and maturation of donor lymphocytes, as well as homing of donor lymphocytes to secondary lymphoid organs and other tissues. This involves immunization, which makes the patient highly susceptible to infection while engraftment occurs. Immunosuppressants (corticosteroids, Cyclosporine, methotrexate, mycophenolate mofetil, etc., and Alembic Antibody treatments such as tuzumab, antithymocyte globulin, or rituximab, and anti-TNF The administration of a therapeutic agent (e.g., a medicament) can improve engraftment and survival of the graft or disease (e.g., cancer or a non-malignant hematological disorder). Gut-selective treatments (such as anti-α4β7 antibodies) can affect the response of grafts to The generation and host of alloreactive gut-specific lymphocytes while potentially maintaining the GVT effect. This offers the potential to reduce gaming.

[0030] Another aspect of the present invention is the use of steroids for the treatment of GvHD, such as steroid-resistant acute intestinal GvHD. α4β7 integrin antagonists (e.g., vedolizumab) for Administering an integrin antagonist (e.g., vedolizumab) to a subject in need thereof The present invention relates to a method for treating GvHD, such as steroid-resistant acute intestinal GvHD, by

[0031] definition The term "pharmaceutical formulation" refers to a pharmaceutical formulation of an α4β7 antagonist, such as an anti-α4β7 antibody, in which the biological activity of the antibody is and in a dosage form that is effective and does not cause unacceptable toxicity to the patient to whom the formulation is administered. Refers to a preparation that does not contain certain additional ingredients.

[0032] The cell surface molecule, "α4β7 integrin" or "α4β7", is a fusion protein that binds to the α4 chain (CD49D It is a heterodimer of the β7 chain (ITGA4) and the β7 chain (ITGB7). Each chain is an alternative interleukin (ITG1). It can form heterodimers with the α4β1 or α E Forms β7. Human The α4 and β7 genes (GenBank (National Center for Biology) Technology Information, Bethesda, MD) RefSeq accession numbers NM_000885 and NM_000889, respectively, are B and T It is expressed by lymphocytes, especially memory CD4+ lymphocytes. Typically, α4β7 can exist in either a resting or activated state. The ligands for α4β7 are vascular cell adhesion molecule (VCAM), fibronectin, and and mucosal addressins (MAdCAMs (e.g., MAdCAM-1)).

[0033] An "α4β7 antagonist" is an agent that antagonizes or reduces the function of α4β7 integrin. Such antagonists are molecules that bind to or inhibit the α4β7 integrin and its integrin receptors. The α4β7 antagonist may antagonize the interaction with one or more ligands. 7 integrin heterodimers or complexes requiring both chains. α4β7 antagonists can bind to ligands such as MAdCAM. Antibodies such as anti-α4β7 integrin antibodies and "anti-α4β7 antibodies" that perform such binding functions are also known. In some embodiments, the α4β7 antagonist, such as an anti-α4β7 antibody, It has "binding specificity for the α4β7 complex" and binds to α4β7 but not to α4β1 or It does not bind to αEβ7.

[0034] The term "antibody" or "antibody(s)" is used broadly herein and specifically refers to a complete antibody. long antibodies, antibody peptide(s) or immunoglobulin(s), monoclonal antibodies , chimeric antibodies (including primatized antibodies), polyclonal antibodies, human antibodies, humanized antibodies, and antibodies from non-human species (including, for example, mouse, sheep, chicken, or goat) Human antibodies, monobodies and diabodies derived from transgenic human germline immunoglobulin sequences Recombinant antigen-binding forms of at least two full-length antibodies (e.g., each portion is a different antibody) Multispecific antibodies generated from a target antigen (containing the antigen-binding region of an antibody against a target antigen or epitope) (e.g., bispecific antibodies), and individual antigen-binding fragments of any of the foregoing, e.g., For example, antibodies, including dAbs, Fv, scFv, Fab, F(ab)'2, Fab' and the antibody from which it is derived.

[0035] The term "monoclonal antibody" as used herein refers to a substantially homogeneous population of antibodies. Antibodies obtained from a population (i.e., the individual antibodies comprising the population are identical and / or have the same epitope) The modifier "monoclonal" refers to a substantially homogeneous population of antibodies. characterize the antibody as if it were obtained from a specific It is not to be construed as requiring

[0036] An "antigen-binding fragment" of an antibody preferably comprises at least the heavy chain of an anti-α4β7 antibody. and / or the variable region of the light chain. For example, an antigen-binding fragment of vedolizumab may comprise: Amino acid residues 20 to 131 of the humanized light chain sequence of SEQ ID NO: 2 and the humanized heavy chain sequence of SEQ ID NO: 1 The antigen-binding fragment may comprise amino acid residues 20 to 140 of the amino acid sequence of the target polypeptide. Examples of fragments include Fab fragments, Fab' fragments, Fv fragments, sc fragments, and the like. Fv and F(ab')2 fragments. Antigen-binding fragments of antibodies include: It can be produced by enzymatic cleavage or by recombinant techniques, e.g., papain or pepsin cleavage to generate Fab or F(ab')2 fragments, respectively The antibody may also be used to identify a gene in which one or more stop codons are located at the natural stop site. Antibody genes can be produced in various truncated forms using a gene introduced upstream of the The F(ab') fragment was prepared to contain DNA sequences encoding the CH1 domain and hinge region of the heavy chain. A recombinant construct can be designed that encodes the heavy chain portions of the two fragments. In this case, the antigen-binding fragment binds to the α4β7 integrin and its ligands (e.g., mucosal addressin MAdCAM (e.g., MAdCAM-1), fibronectin) or inhibits binding to multiple

[0037] A "therapeutic monoclonal antibody" is an antibody used for the treatment of human subjects. The therapeutic monoclonal antibodies disclosed herein include anti-α4β7 antibodies. The "effector functions" are defined by the Fc region (native sequence Fc region or amino acid sequence Fc region) of such antibodies. This refers to the biological activity resulting from the sequence variant Fc region. C1q binding, complement-dependent cytotoxicity, Fc receptor binding; antibody-dependent cellular cytotoxicity (AD) CC), phagocytosis, and downregulation of cell surface receptors (e.g., B cell receptor (BCR)). To assess ADCC activity of a molecule of interest, the methods described in U.S. Pat. No. 5,500,362 may be used. or an in vitro ADCC assay such as that described in US Pat. No. 5,821,337. This can be done.

[0038] Full-length antibodies are classified into different "classes" depending on the amino acid sequence in the constant domain of their heavy chains. There are five major classes of full-length antibodies: IgA, IgD, Ig There are three types of antibodies: E, IgG, and IgM, some of which are classified as "subclasses" (isotypes). ), which can be further subdivided into, for example, IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are α, δ, ε, The subunit structures and three-dimensional configurations of different classes of antibodies are often referred to as γ, μ, and μ. It is well known. The "light chains" of antibodies from any vertebrate species are identified based on the amino acid sequence of their constant domains. There are two distinct types, called kappa (κ) and lambda (λ), It can be classified into one.

[0039] As used herein, the term "hypervariable region" refers to the amino acid residues of an antibody that are responsible for antigen-binding. The hypervariable regions are generally referred to as "complementarity determining regions" or "CDRs" (e.g., light chain variable domains). Residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) of the heavy chain Variable domains 31–35 (H1), 50–65 (H2), and 95–102 (H3); Ka bat et al., sequences of Proteins of Imm unological interest,5th Ed.Public Health Service, National Institutes of Health, Bethesda, Md. (1991)) and / or "super" variable loops" (e.g., residues 26-32 (L1) and 50-52 (L2) of the light chain variable domain) and 91-96 (L3) and 26-32 (H1), 53-55 ( H2) and 96~101(H3);Chothia and Lesk J.Mol.B 196:901-917 (1987)). "Functional Region" or "FR" residues are those other than the hypervariable region residues as herein defined. The hypervariable region or CDRs are those variable domain residues of one antibody chain. By transferring the antibody or antibody fragment from one to the other or to other proteins, the resulting (composite) antibody or Alternatively, antigen-binding specificity can be conferred to the binding protein.

[0040] "Humanized" forms of non-human (e.g., rodent) antibodies contain minimal sequences derived from the non-human antibody. Humanized antibodies are chimeric antibodies that contain only limited amounts of the recipient's The variable region residues are selected from mouse, rat, and rabbit antibodies with the desired specificity, affinity, and capacity. or replaced by residues from the hypervariable region (donor antibody) of a non-human species, such as a non-human primate In some cases, the human antibody is a human immunoglobulin (recipient antibody). Framework region (FR) residues are replaced by corresponding non-human residues. Additionally, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. For more details, see Jones et al.,Nature 321:522~525(1986);Riechma nn et al., Nature 332:323-329 (1988); and Pre Sta, Curr. Op. Struct. Biol. 2:593-596(1 See 992).

[0041] An "affinity matured" antibody may have one or more alterations in one or more hypervariable regions. and the affinity of the antibody for the antigen compared to the parent antibody without those modification(s). In one embodiment, the affinity matured antibody is a nanomolar antibody against the target antigen. Affinity matured antibodies can be produced by procedures known in the art and can have sub-picomolar or even picomolar affinities. Marks et al., Bio / Technology 10:779 -783 (1992) describes VH and VL domain shuffling. Random mutations of DR and / or framework residues were performed as described by Barbas et al. .,Proc Nat. Acad. Sci,USA91:3809~3813(19 94);Schier et al.,Gene169:147-155(1995); Yelton et al., J. Immunol. 155:1994-2004( 1995);Jackson et al., J. Immunol. 154(7): 3310-9(1995); and Hawkins et al., J. Mol. Bi ol. 226:889-896 (1992).

[0042] An "isolated" antibody is one that has been identified and separated and / or recovered from a component of its natural environment. In certain embodiments, the isolated antibody has (1) a specific activity as measured by the Lowry method. , purified to greater than 95% by weight of protein, or to 99% by weight or more, (2 ) Identify at least 15 amino acids of the N-terminal or internal amino acid sequence using a spin cup sequencer. (3) purified sufficiently to obtain a residue, and (4) stained with Coomassie blue or silver. Purified to homogeneity by SDS-PAGE under reducing or non-reducing conditions using a dye solution. Isolated antibodies are antibodies that are free from the presence of at least one component of the antibody's natural environment. , including antibodies in situ in recombinant cells. However, isolated antibodies are usually Both are produced by a single purification step.

[0043] "Cancer" or "tumor" refers to any malignant or tumour within a patient, including the primary tumour and any metastases. Cancer is intended to include any cancer of the blood system or of a solid tumor type. Hematological tumors may include, for example, myeloma (e.g., multiple myeloma), leukemia (e.g., Waldenstrom's disease), and the like. Ström syndrome, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, granulocyte leukemia, mononuclear leukemia, acute lymphoblastic leukemia, other leukemias), lymphomas (e.g., diffuse large intestine) malignant large cell lymphoma, follicular lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma Hematologic causes, including B-cell lymphomas such as Hodgkin's lymphoma, plasmacytoma, or reticulum cell sarcoma Tumors of origin and bone marrow disorders such as myelodysplastic syndrome, thrombocythemia, polycythemia vera, or myelofibrosis Solid tumors can occur in any organ, including the skin, lung, brain, breast, prostate, ovary, and kidney. It can occur in the intestines, kidneys, pancreas, liver, esophagus, stomach, intestines, bladder, uterus, cervix, testicles, adrenal glands, etc. As used herein, cancer cells, including tumor cells, are cells that are abnormally (enlarged) or abnormally (proliferated). Cells that divide at a rate that is similar to or faster than the rate at which they grow, and the control of their growth or survival is what causes cancer cells to develop or refers to cells that are different from cells of the same tissue that exist. Cancer cells are cells that are different from cells of the same tissue that exist. Sarcoma, myeloma, leukemia, lymphoma cells, and glioma, meningioma, medulloblastoma, Schwannoma, or tumors of the nervous system, including, but not limited to, epididymoma.

[0044] "Treatment" refers to therapeutic treatment. A subject in need of treatment may be a subject already suffering from the disease. Thus, as used herein, a patient (e.g., a human) to be treated includes those suffering from cancer or Diagnosed with a disease such as a non-malignant hematological disorder or suffering from a conditioning regimen Alternatively, the patient may not have GvHD but may be a transplant patient, For example, patients undergoing conditioning for allogeneic hematopoietic cell transplantation, allogeneic hematopoietic stem cell transplantation (allo-HSCT), Candidates or patients undergoing hematopoietic cell transplantation or recent (e.g., within the past 5 months) allo-H Additionally or alternatively, the patient may have undergone an allogeneic hematopoietic cell transplant, such as SCT. For example, after allo-HSCT, patients receive allogeneic T cells via donor leukocyte infusion (DLI). Alternatively, patients who have undergone allo-HSCT may be at increased risk of acute GvHD. or may be receiving corticosteroids for the treatment of GvHD. Treatment after SCT, for example after the onset of symptoms of GvHD, can alleviate symptoms and improve long-term survival. This may provide a longer survival time.

[0045] A disease, e.g., cancer or GvHD, is characterized by at least one symptom of the pathology (response / non-response, or as determined by known indicators in the art and described herein) is alleviated The term "inhibit" or "treat" refers to the reduction, termination, delay, minimization, or prevention of a condition. "Person" and "subject" are used interchangeably herein.

[0046] "Prevention" refers to treatment that results in the absence or reduction in the severity of an adverse event. In most cases, treatments are associated with a certain rate of adverse events or a certain rate of severe adverse events. events, but are instead given for prophylaxis and have a lower rate of adverse events (all i.e., reduced or decreased risk) or lower rates of serious adverse events (i.e., adverse a reduction or reduction in the risk that the event will be severe.

[0047] Allogeneic hematopoietic stem cell transplantation, including those who have undergone myeloablative or reduced-dose conditioning. In the context of hematopoietic stem cell transplant patients, the incidence of graft-versus-host disease is at least 25%. risk, 30%-60% risk, 35%-55% risk, 40%-50% risk or 45% to 65% risk and severity of all adverse events The mortality rate associated with this procedure can be as high as 30% to 50%. Prophylaxis of early-grade (e.g., grade III or IV or grade C or D) GVHD This may reduce the risk of adverse events or lead to treatment related to the mortality of transplant recipients due to GVHD. In some embodiments, the α4β7 antagonist may reduce the risk of developing glaucoma. Administration of, for example, an anti-α4β7 antibody prevents GVHD in the patient. Administration of an α4β7 antagonist, e.g., an anti-α4β7 antibody, can improve the intestinal response to GVHD in patients. In some embodiments, the α4β7 antagonist, e.g., anti-α Administration of 4β7 antibody prevents intestinal manifestations of GVHD in patients, but not skin or liver manifestations. In some embodiments, the α-antibody composition does not prevent one or more symptoms of GVHD in patients with α-antibody. Administration of α4β7 antagonists, e.g., anti-α4β7 antibodies, may facilitate the use of immunosuppressive therapy in patients. In some embodiments, the use of Administration of an α4β7 antagonist, such as an anti-α4β7 antibody, allows stem cells to engraft. In some embodiments, administration of an α4β7 antagonist to a patient undergoing allo-HSCT is Administration of anti-α4β7 antibodies, for example, induces stem cell engraftment and induces a graft-versus-tumor (GVT) effect. To cause something to occur.

[0048] The anti-α4β7 antibodies are substantially pure, and desirably substantially homogeneous (i.e., A "substantially pure" antibody is one that is free of contaminating proteins, etc. The antibody is at least about 90% by weight, at least about 95% by weight, or means a composition containing 97% by weight of the total protein. Based on the results, at least about 99% by weight of the protein is a specific antibody (e.g., anti-α4β7 antibody). It refers to a composition containing a certain protein.

[0049] Vedolizumab, an anti-α4β7 antibody, has binding specificity for the human α4β7 integrin The monoclonal antibody is already used in moderately to severely active ulcerative colitis (UC) and clonal Vedolizumab is indicated for the treatment of patients with GvHD. Vedolizumab has a novel gut-selective mechanism of action. By binding to the expressed α4β7, vedolizumab acts as an α4β7 antagonist and inhibits the intestinal Mucosal addressin cells expressed on endothelial cells by a subset of gaming memory T lymphocytes Blocks interaction with adhesion molecule-1 (MAdCAM-1).

[0050] Presence of anti-drug antibodies, sex, body size, concomitant use of immunosuppressants, type of disease, albumin Several factors, including the concentration of erythropoietin, and the degree of systemic inflammation, may contribute to accelerated antibody clearance. Furthermore, there is a consistent relationship between efficacy and exposure, as opposed to drug dose. This has been observed for many of these drugs, e.g., higher trough drug concentrations correlate with more potent efficacy. Differences in drug clearance are important for this observation. For example, cancer patients may receive immunosuppressive treatment for tumors or treatment for infections. Therefore, understanding the clearance determinants of therapeutic antibodies in transplant patients is crucial for drug development. This may lead to optimization of the drug regimen.

[0051] Previous studies have administered doses ranging from 0.2 to 10 mg / kg (intravenously) to healthy volunteers. The pharmacokinetics and pharmacodynamics of vedolizumab (α4β7 receptor) after a single dose were compared. The peak concentration was reached (saturation), safety, and tolerability were investigated (unpublished data). After administration, serum concentrations of vedolizumab increase approximately biexponentially to approximately 1-10 ng / mL. After this point, the concentration decreased nonlinearly. The pharmacokinetics and pharmacodynamics of 0.5 and 2 mg / kg IV infusions in patients with CD were It has been investigated after injection and infusion of 2, 6, and 10 mg / kg in patients with UC. The pharmacokinetics of izumab are generally consistent after IV infusion in the dose range of 2 to 10 mg / kg in patients with UC. After repeated dosing, the initial dose of vedolizumab was followed by rapid and nearly complete α4β7 receptor saturation was achieved.

[0052] The efficacy and safety of vedolizumab induction and maintenance therapy in patients with CD were evaluated in GEMINI 2 (ClinicalTrials.gov number, NCT00783692) and G EMINI3 (ClinicalTrials.gov number, NCT01224171 ) study demonstrated the effects of vedolizumab on induction and maintenance therapy in CD patients. Response (efficacy) relationships have been shown elsewhere.

[0053] The present invention relates to treatment of GvHD or allogeneic hematopoietic cell transplant patients, for example, undergoing allo-HSCT. By preventing GvHD-related adverse events in a subject (e.g., a human patient), The present invention relates to methods of treating human patients, including adults (e.g., 18 years of age or older), young adults, and adults with The pharmaceutical composition comprising the anti-α4β7 antibody may be administered to a human or a child. for treating or preventing transplant patients, cancer patients, and patients with non-malignant hematological diseases, such as It can be used to prevent GvHD in subjects with

[0054] The severity of acute GvHD was assessed according to the modified Glucksberg criteria (Table 2) and the blood and bone marrow transplant clinical trial. Bone Marrow Transplant Trial Network (BMT CTN) Modified International Bone Marrow Transplant Registry (IBMTR) The clinical stage and grade of GvHD were determined according to the GvHD index in Table 3. They are classified as follows. [Table 1] [Table 2] [Table 3-1] [Table 3-2]

[0055] Allogeneic hematopoietic cells (e.g., allo-HSCs) can be derived from α4β7 antibodies, such as anti-α4β7 antibodies. After antagonist administration, there were no GvHD, only skin GvHD, only liver GvHD, and only skin and liver GvHD. and liver GvHD only, skin or liver GvHD only without intestinal GvHD, grade IV No GvHD, Grade III and No IVGvHD, Stage 1 or Stage 2 Intestinal GvHD only and stage 2-3 skin and / or liver GvHD only, Grade I ~IIGvHD only, or no GvHD or cutaneous GvHD only, GvHD of index A only, GvHD only with index A or B, no GvHD with index C or D, or GVT The cells can be engrafted by any of the above methods.

[0056] Preventing the development of acute GvHD is important in preventing the development of GALT, mesenteric lymph nodes, and / or GI mucosa. This results in a reduction or blockage of alloreactive T cell migration to the membrane. Prevention of vHD is recommended approximately 50 days after allogeneic hematopoietic cell transplantation (e.g., allo-HSCT). 75th day, about 90th day, about 100th day, about 110th day, about 120th day, about 150th day, If the patient shows no signs of acute GvHD at or about day 180, the procedure can be considered a success. In some embodiments, patients who have undergone allogeneic hematopoietic cell transplantation (e.g., allo-HSCT) Patients receiving immunosuppressive therapy should not receive further immunosuppressive therapy, e.g., after conditioning or during the initial transplant period. After (e.g., immediately before and / or after), e.g., 0-1 week, 0-2 weeks after allogeneic hematopoietic cell transplantation and receiving no further immunosuppressive therapy for 0-3 weeks or 0-4 weeks. The patient is treated with a regimen.

[0057] Remission is defined by conventional World Health Organization (WHO) criteria as follows: blasts <5% cytosis, blood count recovery, and no evidence of extramedullary disease. Acute and / or chronic GvHD remission lasted approximately 4, 5, 6, 9, or 12 months after allo-HSCT. It can continue.

[0058] GvHD recurrence or progression-free survival (GRFS) was measured in patients with grade 3-4 acute GvHD, all Chronic GvHD requiring immunosuppressive drugs, recurrence or progression of the disease, or any other cause Death is defined as a death resulting from a stroke.

[0059] Engraftment is the process by which transplanted hematopoietic cells colonize the patient or adapt to the patient's tissue environment, e.g., by multiplying. Signals of maturation or the initiation of proliferation, differentiation, and implementation of functional properties derived from blood lineage cells. The process of allo-HSCT engraftment is a process in which the cells are programmed to grow by the immune system. is measured by quantifying blood components such as neutrophils and platelets. , which varies depending on the source of hematopoietic stem cells, for example, umbilical cord blood stem cells are longer than peripheral blood stem cells. Neutrophil engraftment (absolute neutrophil count recovery [ANC]) was defined as an ANC of 500 / mm for 3 consecutive days. 3 >2000 / mm in 1 day 3 The first day of the three-day period is defined as neutrophil production. It is considered to be the day of arrival.

[0060] The mean α4β7 expression level on lymphocytes in peripheral blood was significantly higher in patients with allogeneic hematopoietic cell transplantation (e.g., myeloblastoma). In the allogeneic HSCT population, the administration of anti-α4β7 antibodies (e.g., vedolizumab) This can be measured by a pre- and post-MADCAM-1-Fc binding inhibition assay.

[0061] including, but not limited to, interleukin 6 (IL-6), interleukin 17 (IL-17), and blood or serum biomarkers, including tumor suppressor 2 (ST2), and / or These include, but are not limited to, CD8+, CD38+, and CD8+ bright effector memory T cells. Changes in cellular biomarkers, including CD4+ T cells and CD4+ memory T cells, are associated with the development of acute GvHD. One or more of these may be predictors of disease or severity after allo-HSCT. Detecting an increase in these markers may indicate the onset of acute GvHD. Detection can include immunodetection of the biomarker, e.g., detecting blood cells expressing the biomarker. Antibody binding to cells and measurement of the amount of antibody binding (e.g., by flow cytometry) is the measurement of antibody binding to soluble biomarkers in serum and the amount of antibody binding (e.g., E This can be achieved by using a control or a test obtained early in or before transplantation. The amount of biomarker in the sample or in a certain standard (e.g., biomarker in a non-transplant population) Comparison with the biomarker level (e.g., biomarker abundance) provides an indication of whether the biomarker level has changed (e.g., increased). In some embodiments, allogeneic hematopoietic cell transplantation (e.g., allo-HS) may be provided. Administration of α4β7 antagonists such as anti-α4β7 antibodies to patients undergoing CT is or preventing a change or increase in more than one of these biomarkers.

[0062] Patients tested positive for antibodies targeting α4β7 antagonists, such as anti-α4β7 antibodies. For example, at baseline, 20 days after allo-HSCT, and 100 days after allo-HSCT. At various time points, patients were tested to confirm whether they were positive for anti-vedolizumab antibodies. obtain.

[0063] Patients can be tested for the development of GvHD, which requires systemic immunosuppression.

[0064] α4β7 antagonists, such as anti-α4β7 antibodies, inhibit the binding of α4β7 integrin to its ligand. In terms of treatment, an effective amount is administered in an amount effective to inhibit binding of the desired preventive effects (e.g., alloreactive T cells to GALT, mesenteric lymph nodes, and / or GI mucosa) reduce or eliminate migration, and reduce the incidence or severity of GvHD) An effective amount of an anti-α4β7 antibody, e.g., a saturating (e.g., α4β7 inhibitor) is sufficient to induce α4β7 proliferation. The titer is sufficiently effective to maintain the neutralization of tegrin and sustain the α4 β7 blockade. α4β7 antagonists, such as anti-α4β7 antibodies, can The dose can be determined by methods known in the art. The dosage may depend, for example, on the age, sensitivity, tolerance and overall health of the individual. Examples include topical routes such as intranasal or inhaled or transdermal administration, via feeding tubes or suppositories. and non-injectable routes such as intravenous, intramuscular, subcutaneous, intraarterial, intraperitoneal, or intravitreal administration. Oral administration is an example. A suitable dose for the antibody is about 0.05 mg / kg body weight per treatment. 0.1 mg to about 10.0 mg, for example, about 2 mg / kg to about 7 mg / kg, about 3 mg / kg It can be about 6 mg / kg, or about 3.5 to about 5 mg / kg. In this case, the administered dose is about 0.3 mg / kg, about 0.5 mg / kg, about 1 mg / kg, Approx. 2mg / kg, approx. 3mg / kg, approx. 4mg / kg, approx. 5mg / kg, approx. 6mg / kg, The dose is about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg. In some embodiments, vedolizumab is administered at doses of 50 mg, 75 mg, 100 mg, 300 mg, or 400 mg. The dose is administered in doses of 450 mg, 500 mg, or 600 mg. In this condition, vedolizumab is available in 108 mg, 90-120 mg, 216 mg, and 160 mg doses. , 165 mg, 155-180 mg, 170 mg or 180 mg doses. In some embodiments, vedolizumab is administered in a dose of 180 to 250 mg, 300 to 350 mg, or g, or administered in doses of 300-500 mg.

[0065] In the case of α4β7 antagonists such as anti-α4β7 antibodies stored as lyophilized solids, In this case, the antibody is reconstituted in a solution such as water for injection prior to administration. In this case, the final dosage form of the anti-α4β7 antibody (e.g., after dilution of the reconstituted antibody (e.g., saline) , Ringer's solution or 5% dextrose solution infusion system)) is approximately 0.5 mg / The final dosage form can be from about 0.3 mg / ml to about 3.0 mg / ml. mg / ml, about 1.0mg / ml to about 1.4mg / ml, about 1.0mg / ml to about 1.3 mg / ml, about 1.0 mg / ml to about 1.2 mg / ml, about 1.0 to about 1.1 mg / ml , about 1.1mg / ml~about 1.4mg / ml, about 1.1mg / ml~about 1.3mg / ml , about 1.1mg / ml~about 1.2mg / ml, about 1.2mg / ml~about 1.4mg / ml , about 1.2 mg / ml to about 1.3 mg / ml, or about 1.3 mg / ml to about 1.4 mg The final dosage form may be at a concentration of about 0.6 mg / ml, 0.8 mg / ml, 1.0 mg / ml, mg / ml, 1.1mg / ml, approx. 1.2mg / ml, approx. 1.3mg / ml, approx. 1.4m g / ml, about 1.5mg / ml, about 1.6mg / ml, about 1.8mg / ml or about 2. In one embodiment, the total dose is 75 mg. In this embodiment, the total dose is 150 mg, 225 mg, 375 mg, or 525 mg. In another embodiment, the total dose is 300 mg. In one embodiment, the total dose is In one embodiment, the total dose is 450 mg. In another embodiment, the total dose is 600 mg. Anti-α4β7 antibody The dose is administered in 250 ml of saline, Ringer's solution, or 5% dextrose. It can be diluted into a solution.

[0066] The dose is administered to the patient over about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, or about 40 minutes. can be administered.

[0067] The dosing regimen is intended to prevent GvHD or to treat severe grades of GvHD in patients with GvHD. Risk of ulcerative colitis and low index level such as Grade III or IV, Index C or Index D In some embodiments, the dosing regimen can be optimized to provide a reduction in The agonist does not alter the CD4 to CD8 ratio in the cerebrospinal fluid of treated patients. Anti-α4β7 antagonists do not impair immune surveillance of the nervous system, such as the brain or spinal cord.

[0068] In one embodiment, the dosing regimen is administered on the day before allogeneic stem cell transplant (allo-HSCT). Initial administration, subsequent administration approximately 2 weeks after the initial administration, and approximately 6 weeks after the initial administration In one embodiment, the initial administration of the anti-α4β7 antibody comprises a second subsequent administration after the initial administration of the anti-α4β7 antibody. This anti-α4β7 antibody dosing regimen is recommended for patients with Crohn's disease. or the induction dose and schedule of vedolizumab approved for the treatment of ulcerative colitis However, it is not recommended to treat patients with a conditioning regimen followed by transplantation such as allo-HSCT. Subjects undergoing allogeneic hematopoietic cell transplantation, such as It is expected that the expression level of these genes will change significantly in the T cell population. , if you have an infection or GVHD or other adverse events from the transplant process. For example, the clearance of anti-α4β7 antibodies may be affected by the drugs used for pretreatment. If kidneys are damaged by the virus, treatment with dialysis increases clearance of antibodies from the bloodstream. Alternatively, anti-α4β7 antibodies could be used during initial treatment after myeloablative therapy. There may be other physiological conditions that may result in unexpectedly high clearance of .

[0069] In some embodiments, the anti-α4β7 antibody is administered after allogeneic hematopoietic cell transplantation (e.g., allogeneic hematopoietic cell transplantation). In some embodiments, the antibody is administered prior to α4β7 administration, such as an anti-α4β7 antibody. β7 antagonists are used in patients before and after allogeneic hematopoietic cell transplantation (e.g., allo-HSCT). In some embodiments, an α4β7 antagonist, such as an anti-α4β7 antibody, is administered to a subject. The study was conducted after allogeneic hematopoietic cell transplantation (e.g., allo-HSCT). (e.g., allo-HSCT) 1 day, 1-2 days, 1-3 days, 2-3 days, or 2 Administered to patients within 4, 2, 3, 4, 5, 6, or 7 days In some embodiments, the anti-α4β7 antibody is administered 1 to 10 times after allo-HSCT. 0 days, 5-80 days, 5-30 days, 10-28 days, 10-50 days, 14-30 days For patients for 15-32 days, 18-25 days, 15-35 days, or more than 100 days For example, anti-α4β7 antibodies (e.g., vedolizumab) are administered intravenously to allogeneic As an initial dose on the day before hematopoietic cell transplantation (e.g., allo-HSCT) and 2 days after the initial dose and again six weeks later.

[0070] In certain embodiments, the present invention provides a method for treating allogeneic hematopoietic cell transplantation (e.g., allogeneic hematopoietic stem cell transplant patients). The present invention provides a method for preventing GvHD in a patient using vedolizumab. 7An initial dose of 300 mg of the antibody (vedolizumab) was administered to the blood of people with leukemia. The first step is administering vedolizumab to cancer patients, and the second step is performing allo-HSCT one day after the initial administration of vedolizumab. followed by a 300 mg dose of vedolizumab 2 weeks after the initial dose. followed by a second 300 mg dose of vedolizumab 6 weeks after the initial dose Alternatively, in some embodiments, an anti-α4β7 antibody (beta- The dose of rituximab should be lower than 300 mg (e.g., 75 mg or 150 mg) or higher. (e.g., 450 mg or 600 mg).

[0071] The present invention provides a method for treating GVHD in patients undergoing allogeneic hematopoietic cell transplantation (e.g., allo-HSCT). The present invention provides an anti-α4β7 antibody for use in preventing the early onset of anti-α4β7 antibody. Doses were administered the day before allo-HSCT, 2 weeks after the initial dose, and 6 weeks after the initial dose. Its use in prophylaxis may further include administering tacrolimus and / or methotrexate. In some embodiments, the anti-α4β7 antibody may include administration of vedolizumab. is.

[0072] The present disclosure provides an effective amount of an antagonist of human α4β7 integrin, such as an anti-α4β7 antibody. (e.g., vedolizumab) to treat GvHD in a subject in need thereof. The present invention also relates to a method for treating acute GvHD and steroid-resistant acute GvHD. Examples of steroid-resistant acute GvHD include, for example, B , C or D severity index (using the BMTCTN-modified IBMTR index), 0 to 3 ECOC performance status and / or ≥ 60 mL / min / 1.73 m 2 of Creatinine clearance (based on Cockcroft-Gault estimates) associated with enteropathy Steroid-resistant patients with corticosteroid-resistant acute GvHD are corticosteroids such as corticosteroids, such as steroids, hydrocortisone, prednisone, or methylprednisolone worsening or no improvement or increase in symptoms on the 5th to 7th day of treatment with iodine The method or treatment may be administered to patients with evidence of bone marrow engraftment. It is particularly useful for treating GvHD in patients undergoing allo-HSCT, including those with It is beneficial to

[0073] Human α4β7 infusion is being investigated for the treatment of GvHD (including steroid-resistant acute GvHD). Antibodies with binding specificity to tegrin (e.g., vedolizumab) have been shown to inhibit the activity of tegrin in one or more doses of approximately 3 00mg, 350mg, 400mg, 450mg, 500mg, 550mg or 600 The patient may be administered a dose of 100 mg of antibody, for example, a dose of 300 mg or 600 mg. Each dose administered is the same amount of antibody, e.g., repeated administration of 300 mg of antibody (vedolizumab) or repeated administration of 600 mg of antibody (vedolizumab).

[0074] The antibody having binding specificity for human α4β7 integrin is administered according to the administration regimen. One regimen can include: a) a first antibody administration; b) a second antibody administration; a) a second antibody administration about two weeks later; and c) a third antibody administration about four weeks after the second administration. Optionally, if each additional dose is administered about 4 weeks after the most recent dose, In some embodiments, each antibody can be administered according to a dosing regimen. A dose may contain about 300 mg of antibody (e.g., vedolizumab), or each dose may contain about 600 mg. g antibodies (e.g., vedolizumab).

[0075] The antibody having binding specificity for human α4β7 integrin is available for use in patients in need thereof. When administered intravenously, for example, by intravenous infusion, This can take from about 30 minutes to about 60 minutes.

[0076] Pharmaceutical compositions comprising anti-α4β7 antibodies may be used in transplant patients, cancer patients, and other patients as described herein. , for treating patients with non-malignant hematological diseases or for preventing GvHD in subjects suffering therefrom. The pharmaceutical composition comprising the anti-α4β7 antibody can be used for the prevention of It can be used to treat GvHD (including steroid-resistant acute GvHD) as described. An α4β7 antagonist such as an anti-α4β7 antibody can also be used to inhibit α4β7 integration. It is administered in an amount effective to inhibit phosphorus from binding to its ligand.

[0077] The methods described herein involve administering to a patient an effective amount of an anti-α4β7 antibody. If the anti-α4β7 antibody is in a solid formulation, such as a dry formulation, the administration process involves converting the formulation into a liquid. In one embodiment, the dry formulation can be, for example, as described above. It may be reconstituted with a liquid for use in injections, such as intravenous, intramuscular, or subcutaneous injections. In another embodiment, the solid or dry formulation can be, for example, a patch, a cream, an air freshener, or the like. They can also be administered topically in the form of a steroid or suppository.

[0078] α4β7 antagonists, which are anti-α4β7 antibodies, target the α4 chain (e.g., humanized MAb21). 6 (Bendig et al., U.S. Pat. No. 5,840,299), β7 chain (e.g., FIB504), or a humanized derivative (e.g., Fong et al., The epitope on the α4 chain and the β7 chain is AMG-181, or U Another antibody described in S2010 / 0254975 is an anti-α4β7 antibody. Thus, the antibody binds to a combined epitope on the α4β7 complex, but the chains do not associate with each other. If the α4 integrin and β7 chains are not present, they will not bind to epitopes on the α4 or β7 chains. The association of integrins allows for the formation of combined epitopes, e.g., both chains carrying epitopes of each other. by juxtaposing residues present on the appropriate integrin partner. In the presence or absence of integrin activation, epitopes inaccessible to antibody binding The binding site of the tope is located on one of the chains (e.g., the α4 integrin chain or the β7 integrin chain). In another embodiment, the anti-α4β The α4β7 antibody binds to both the α4 and β7 integrin chains, and therefore Anti-α4β7 antibodies can bind to α4β7, but does not bind to α4β1 and / or e.g., α E It also does not bind to β7. The anti-α4β7 antibody binds to the same or substantially the same epitope as the Act-1 antibody. (Lazarovits, AI et al., J. Immunol., 133(4):1857-1862(1984), Schweighoffer et al. al., J. Immunol., 151(2):717-729,1993;B Ednarczyk et al., J. Biol. Chem., 269(11): 8348-8354, 1994). Mouse Act-1 monoclonal antibody-producing mouse The ACT-1 hybridoma cell line was obtained from Millennium Pharmaceuticals. cals, Inc.,40 Landsdowne Street, Cambrid ge, Mass. 02139, USA, on behalf of the provisions of the Budapest Treaty Below, August 22, 2001 American Type Culture Collec tion, 10801 University Boulevard, Manass as, Va. 20110~2209, USA with acceptance number PTA-3663 In another embodiment, the anti-α4β7 antibody is a human antibody or a U.S. Pat. Proteins that bind to α4β7 using the CDRs provided in Patent Publication No. 2010 / 0254975 It's plagiarism.

[0079] In one embodiment, the α4β7 antagonist is an anti-MAdCAM antibody (e.g., U.S. Patent No. 5,629,492). No. 8,277,808, PF-00547659, or WO2005 / 067620 (See antibodies described in U.S. Pat. No. 7,803,904) or and engineered forms of the ligand, such as MAdCAM-Fc chimeras.

[0080] In one embodiment, the anti-α4β7 antibody is an antibody that binds α4β7 to one or more of its ligands (MAs). dCAM (e.g., MAdCAM-1), fibronectin, and / or vascular addressing It inhibits binding to mucosal addressins such as vascular endothelial cell membrane (VCAM). , PCT Publication No. WO 96 / 24673, the entire teachings of which are incorporated herein by reference. In another embodiment, the anti-α4β7 antibody inhibits VCAM binding without inhibiting VCAM binding. , α4β7 to MAdCAM (e.g., MAdCAM-1) and / or fibronectin inhibits the binding of

[0081] In one embodiment, the anti-α4β7 antibody for use in treatment is a humanized version of the murine Act-1 antibody. Suitable methods for preparing humanized antibodies are known in the art. Generally, humanized anti-α4β7 antibodies have the complementarity of the three heavy chains of the mouse Act-1 antibody. CDR1, SEQ ID NO: 4; CDR2, SEQ ID NO: 5; and CDR3, SEQ ID NO: and a heavy chain comprising a suitable human heavy chain framework region. The three light chain CDRs of the mouse Act-1 antibody (CDR1, SEQ ID NO: 7, CDR2, SEQ ID NO: and a light chain comprising CDR1, CDR2, SEQ ID NO: 8 and CDR3, SEQ ID NO: 9) and a suitable human light chain framework region. Humanized Act-1 antibodies can be produced by the same method as described above, with or without amino acid substitutions. The nucleotide sequence may comprise any suitable human framework region, including a nucleotide sequence of the ... For example, one or more framework amino acids may be present in, for example, a mouse Act-1 antibody. It can be substituted for another amino acid, such as an amino acid at the corresponding position in the body. The common region or a portion thereof, if present, comprises the kappa region of a human antibody, including allelic variants. or lambda light chains, and / or gamma (e.g., gamma 1, gamma 2, gamma 3, gamma 4), mu, alpha (e.g., alpha 1 , α2), δ or ε heavy chains. , variants or portions thereof can be selected to tailor effector function. For example, mutated constant regions (variants) can enhance Fc receptor binding and / or complementation. It can be incorporated into fusion proteins to minimize its ability to anchor in the body (e.g. See, for example, Winter et al., UK Patent No. 2,209,757B, Morris on et. al.,WO89 / 07142;Morgan et. al.,WO9 4 / 29351, December 22, 1994). The humanized version of the Act-1 antibody is , as described and taught in PCT Publication Nos. WO98 / 06248 and WO07 / 61679 The entire contents of which are incorporated herein by reference. Treatment Using Anti-α4β7 Integrin Antibodies The method is described in Publication Nos. US2005 / 0095238, US2005 / 009523 8, WO2012151248 and WO2012 / 151247 .

[0082] In one embodiment, the anti-α4β7 antibody is vedolizumab. 002, also known as ENTYVIO™ or KYNTELES™, is a It is a humanized antibody (IgG1mAb) that targets the lymphocyte integrin α4β7. β47 integrin is a mucosal address expressed on endothelial cells of mesenteric lymph nodes and GI mucosa. through adhesive interactions with mAdCAM-1 (MAdCAM-1), the GI mucosa, intestinal Mediates lymphocyte migration to vascular-associated lymphoid tissue (GALT) and mesenteric lymph nodes. Izumab binds to the α4β7 integrin and antagonizes its adhesion to MAdCAM-1, Therefore, migration of naive T cells to GALT and mesenteric lymph nodes, and expression of intestinal homins Impairs migration of leukocytes into the GI mucosa.

[0083] In another embodiment, the humanized anti-α4β7 antibody for use in treatment has the amino acid sequence of SEQ ID NO: 1. a heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 2, and amino acids 20 to 131 of SEQ ID NO: 2, or the sequence The light chain variable region comprises amino acids 1-112 of sequence number 3. If desired, a suitable human constant region may be used. For example, a humanized anti-α4β7 antibody may have an amino acid sequence similar to that of SEQ ID NO: 1. The heavy chain may comprise amino acids 20 to 470 of SEQ ID NO: 3 and a light chain may comprise amino acids 1 to 219 of SEQ ID NO: 3. In another embodiment, the humanized anti-α4β7 antibody is a humanized anti-α4β7 antibody comprising amino acids 20-31 of SEQ ID NO:1. 470 and a light chain comprising amino acids 20 to 238 of SEQ ID NO: 2. Vedolizumab is available from the Chemical Abstract Service (CAS, USA). It is listed under the Chemical Society registration number 943609-66-3.

[0084] Substitutions into the humanized anti-α4β7 antibody sequence include, for example, substitutions to the heavy and light chain framework regions. For example, a mutation from isoleucine to valine at residue 2 of SEQ ID NO: 10 can be used. Mutation, methionine to valine at residue 4 of SEQ ID NO: 10, residue of SEQ ID NO: 11 Alanine to glycine mutation at 24, arginine to glycine at residue 38 of SEQ ID NO:11 a mutation to lysine, a mutation from alanine to arginine at residue 40 of SEQ ID NO: 11, A methionine to isoleucine mutation at residue 48 of SEQ ID NO:11, residue 69 of SEQ ID NO:11 an isoleucine to leucine mutation at residue 71 of SEQ ID NO:11; an arginine to leucine mutation at residue 72 of SEQ ID NO:11; a threonine to isoleucine mutation at residue 73 of SEQ ID NO:11; or any combination thereof, and the CDRs of mouse Act-1 antibody (CDR heavy chain CDRs having CDR1, SEQ ID NO:4, CDR2, SEQ ID NO:5 and CDR3, SEQ ID NO:6 and the light chain CDRs of mouse Act-1 antibody (CDR1, SEQ ID NO: 7, CDR2, SEQ ID NO: 8). The light chain CDRs may be swapped with CDR3 (SEQ ID NO: 8 and CDR3, SEQ ID NO: 9).

[0085] α4β7 antagonists, such as anti-α4β7 antibodies, alone or in combination with other drugs, can be used to treat an individual's The α4β7 antagonist, such as an anti-α4β7 antibody, can be administered to a subject (e.g., a human) in combination with an additional drug In one embodiment, the α4β7 Two or more α4β7 antagonists inhibit the binding of the integrin to its ligands. In such embodiments, the agent (e.g., anti-MAdCAM (e.g., anti-MAdC AM-1) or a monoclonal antibody such as an anti-VCAM-1 monoclonal antibody) is administered. In other embodiments, the additional agent may be administered via a pathway different from the α4β7 pathway in leukocytes. Such agents inhibit the binding of endothelial ligands in the ducts, e.g., chemokines (CC Chemokine (TECK) expressed in the thymus of CCR9-expressing lymphocytes or CCL25), or the agent inhibits the binding of LFA-1 to intercellular adhesion molecules (IC For example, anti-TECK or anti-CCR9 antibodies or or disclosed in PCT Publication Nos. WO03 / 099773 or WO04 / 046092 small molecule CCR9 inhibitors, such as inhibitors of ICAM-1 or ICAM expression An oligonucleotide or the like that prevents the inflammatory bowel disease is administered in addition to the formulation of the present invention. In some embodiments, one or more additional active ingredients typically administered for prophylactic treatment of GvHD are components (e.g. methotrexate or calcineurin inhibitors, e.g. tacrolimus or cyclosporine) is used in the methods of the present invention in combination with an α4β7 antagonist such as an anti-α4β7 antibody. In one embodiment, the dose of the co-administered drug may be adjusted to the dose of an anti-α4β7 antibody. The effects of α4β7 antagonists such as α4β7 agonists may be reduced over time during treatment.

[0086] In some embodiments, the co-administered drug is a calcineurin inhibitor such as tacrolimus. In some embodiments, calcineurin inhibitor treatment inhibits allogeneic hematopoietic cell proliferation. It is initiated before cell transplant (e.g., allo-HSCT) and continued for at least 100 days after. In one embodiment, tacrolimus treatment is administered after allogeneic hematopoietic cell transplantation (e.g., allo- Tacrolimus treatment can be initiated during conditioning for hemoglobin-associated cytotoxic T cell transplant (HSCT). Tacrolimus treatment is initiated at approximately 1 ng / dL, Approximately 2ng / dL, approximately 3ng / dL, approximately 4ng / dL, approximately 5ng / dL, approximately 6ng / dL, Approximately 7ng / dL, approximately 8ng / dL, approximately 9ng / dL, approximately 10ng / dL, or approximately 5-1 Tacrolimus treatment is recommended for patients with allogeneic hematopoietic cell transplantation (e.g., If no signs of GvHD are observed after allo-HSCT, Tacrolimus treatment can be maintained at therapeutic levels for about 1 month, about 3 months, or about 100 days. It stops by about 5, 6, or 7 months after allogeneic hematopoietic cell transplantation (e.g., allo-HSCT). It can be stopped.

[0087] In some embodiments, the co-administered drug is methotrexate. In some cases, methotrexate is used in patients after allogeneic hematopoietic cell transplantation (e.g., allo-HSCT). to approximately 2, 4, 6, 8, 10, or 12 mg / m 2 IV (e.g., 1, 3, 6, and 11) The amount of methotrexate administered to patients may be varied based on toxicity. Or may be retained.

[0088] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present invention. Xu's citation is incorporated herein by reference. [Example]

[0089] Example 1 Phase 1b open-label dose-ranging study in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) Standard graft-versus-host disease (GvHD) prophylaxis (tacrolimus plus short-term methotrexate) in adult patients with To evaluate the safety, tolerability, and clinical activity of adding vedolizumab to Rexartan Vedolizumab dose selection was based on cohort and pharmacokinetic (PK) A rule-based dose-finding study design was followed as per the guidance. Acceptable PK Once a tolerable dose is identified, cohorts at that dose level will be screened to evaluate the tolerability and efficacy of vedolizumab. This could be expanded to further assess gender.

[0090] Eligibility begins on day -1 (referring to the day of the first IV infusion of vedolizumab) and continues for up to 28 days. This is determined through a screening period where all eligibility criteria are met and written information is provided. Patients who provide informed consent will be enrolled in this study. Administered on day -1 before allo-HSCT, then on day +13 and after allo-HSCT Administered on days +42 and +43. Patients undergoing unrelated myeloablative transplantation for the treatment of hematologic malignancies Patients aged 60 years or younger are eligible for enrollment. A recommended Phase 2 dose has been identified. After the initial dose, cohorts at that dose level will be randomized to receive the FDA-approved ... Myeloablative conditioning or Expand to include additional patients (75 or younger) receiving reduced-dose conditioning (RIC). It is possible.

[0091] Patients who have previously undergone allogeneic transplantation or cord blood transplantation, ex vivoT Any in vivo T cell depleting antibody, or If patients plan to undergo RIC (only in the dose-finding portion of the study), Excluded from: Active cerebro / meningeal disease, active cytomegalovirus (CMV) colitis or signs and symptoms of progressive multifocal leukoencephalitis (PML) or a history of PML Additionally, patients with non-malignant hematological disorders (e.g., aplastic anemia, sickle cell disease) are excluded. Patients with erythroid anemia (e.g., thalassemia, Fanconi anemia) were excluded from both parts of the study. Be removed.

[0092] For PK endpoints, evaluable patients received vedolizumab and had at least one PK K samples were taken.

[0093] Patients who remain in remission are monitored for safety and development of acute and chronic GvHD. For one year after HSCT or until patient death or withdrawal of consent or sponsor's request. All patients will be followed until the end of the study. Overall survival (OS) will be assessed by the time of death. , withdrawal of consent, termination of the study by the sponsor, or after the last patient has enrolled in this study. Patients will be followed for up to one year. Patients will attend the +100 day visit (±7 days) and At this point, post-treatment follow-up observation will begin.

[0094] Dose escalation began with the lower dose cohort receiving 75 mg IV vedolizumab on day -1. HSC infusions were initiated on days +13 and +42 after allo-HSCT. (within 12 hours of completing IV vedolizumab infusion on day -1). The first patient in the study underwent allo-HSCT on day -1 for dose-limiting toxicity (DLT). Patients were monitored until day +28 (DLT observation period) after the start of the first IV infusion of vedolizumab. This will include assessment of neutrophil recovery by day +28. The first patient in the first cohort If 75 mg IV vedolizumab was tolerated and engraftment occurred, patients were transferred to the first cohort. Two more patients will be enrolled. If none of the first three patients experience a DLT, If this occurred, the next cohort would receive vedolizumab 300 mg IV on day -1 and allo-HS The first patient in this cohort will receive 300 mg of fluticasone on days +13 and +42 after CT. If IV vedolizumab is tolerated and engraftment occurs, two additional patients will be admitted to the second cohort. Patients will be enrolled. The first 3 patients will be treated without experiencing DLT at 300 mg. If tolerated, a decision on whether to increase the IV vedolizumab dose in subsequent cohorts will be made based on P If one of the first three patients experiences a DLT, Three additional patients were enrolled at the same dose level and had a DLT from Day -1 to + Patients will be monitored until Day 28. If none of the additional patients experience a DLT, the next cohort will be The decision to increase the IV vedolizumab dose in this setting will be guided by PK results. If two or more patients experience a DLT in either the 3- or 6-patient cohort, If so, the IV vedolizumab dose will be reduced for the next 3 patients in the cohort. Patients will be monitored for DLTs in a manner similar to that in which patients in previous cohorts were monitored.

[0095] Tolerability in patients undergoing unrelated myeloablative transplantation for the treatment of hematologic malignancies After identification of a tolerable dose level with feasible PK, a cohort at that dose level will undergo myeloablative Patients who have received comprehensive or reduced-dose conditioning (RIC) and have hematological malignancies or myeloproliferative neoplasms Approximately 100 patients have undergone either related or unrelated allo-HSCT for the treatment of their tumor. This group of patients will receive vedolizumab IV. This allowed for further evaluation of tolerability and clinical activity.

[0096] Vital signs, physical and neurological examinations, adverse event (AE) assessment, and laboratory tests Obtain clinical values (chemistry, hematology, and urinalysis) to assess the safety and tolerability of vedolizumab IV To exclude patients with progressive multifocal leukoencephalitis (PML), Risk Assess sessment and Minimization for PML(RAMP) The questionnaire was administered at screening and on day -1 of Vedriz, the day before allo-HSCT. The study was performed before IV mab administration and on days +13 and +42 after allo-HSCT.

[0097] Serial blood samples for vedolizumab PK evaluation will be obtained at pre-specified time points Vedolizumab PK was analyzed at each dose level for each of the first three patients. The concentration-time profile of vedolizumab influences the level of targeted saturation of α4β7. If α4β7 is saturated, clearance by vedolizumab will be The clearance is linear, and if α4β7 is not saturated, the clearance becomes nonlinear indicating rapid elimination. If vedolizumab clearance is nonlinear at the 300 mg dose, all patients Subsequent doses of approximately 150 mg were administered until linear PK clearance was achieved. Increase in dosage increments (up to a maximum of 600 mg).

[0098] Vedolizumab and anti-vedolizumab antibodies and serum biomarkers (including, but not limited to, interferon Interleukin 6 [IL-6], interleukin 17 [IL-17], and tumor suppressor factors Serial blood samples for determination of serum concentrations of 2 [ST2] were obtained at pre-determined time points. Additionally, blood samples are subjected to flow cytometry for cellular immunophenotyping. and various cell biomarkers (CD8+, CD38+, CD8+ The level of CD4+ memory T cells is determined by the level of CD4+ effector memory T cells, and CD4+ memory T cells. The cell population was counted and the MACAM-1-FC binding inhibition assay was performed at pre-defined times. Do it in points.

[0099] Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI) as of June 14, 2010. CTCAE), version 4.03.

[0100] Example 2 Treatment of Graft-versus-Host Disease Open-label Phase 2a study in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) Tolerability and efficacy of intravenously administered vedolizumab for the treatment of graft-versus-host disease in patients with rhesus malabsorption. The study was conducted to evaluate the efficacy and safety of intravenously administered vedolizumab for this indication. The study will also be used to identify recommended doses and regimens for . The study will involve approximately 38 participants. Patients were enrolled and administered either 300 mg or 600 mg of vedolizumab IV on days 1 and 15. Patients were randomized 1:1 to two treatment groups to receive treatment on days 1, 43, 71, and 99. It will be made into a system.

[0101] A. Explanation of the investigational drug The vedolizumab drug product is a sterile, lyophilized solid formulation provided in a single vial, with each vial containing Each formulation contains a nominal dose of 300 mg of vedolizumab antibody. Contains 60 mg / mL of active vedolizumab antibody, 50 mM histidine / histidine HCl , 125 mM arginine HCl, 100 mg / mL sucrose, and pH 6.3 Contains 0.6 mg / mL polysorbate 80. Each vial contains 4.8 mL of sterile water for injection. For a 300 mg dose, 5.0 mL is withdrawn from each vial and 0. Diluted in 9% sodium chloride to a volume of approximately 250 mL. For a 600 mg dose, 5 0.0 mL was removed from each of the two vials and diluted with 0.9% sodium chloride to approximately 2 The infusion was diluted to a volume of 50 mL. All participants received the infusion at the same time each day throughout the study. If a participant has intolerable vedolizumab-related toxicity, treatment will be discontinued. Stop.

[0102] B. Test Overview The study will treat patients with acute intestinal GvHD that is refractory to first-line steroid therapy. The study was designed to evaluate the safety, tolerability, and clinical activity of vedolizumab for the treatment of Clinical GvHD scoring is used to assess response to treatment (Mart in PJ et al., Biol Blood Marrow Transpla nt 2009;15(7):777-84.) Adrenal cortex for the treatment of acute GvHD. Patients with acute intestinal GvHD who have not received systemic therapy other than steroids (those who have not received prophylaxis) (can be enrolled in this study)

[0103] Eligibility continued for up to 28 days prior to Day 1 (referring to the day of the first IV infusion of vedolizumab). Patients who meet all eligibility criteria will be screened for this Approximately 38 evaluable patients will be enrolled in the study.

[0104] Patients received either 300 mg or 600 mg vedolizumab IV on days 1 and 15. Patients were randomized 1:1 to two treatment groups to receive treatment on days 1, 43, 71, and 99. Approximately 10 patients will be enrolled at each dose level, and their 28-day evaluation, safety, and After obtaining available data from the efficacy, tolerability, efficacy, and PK results, the patient will be enrolled in both The following patients were evaluated at the dolizumab dose levels (300 mg and 600 mg) in this study: Bayesian statistical methods are used to facilitate the determination of appropriate doses for Cohorts at selected dose levels will be randomly selected to further evaluate the tolerability and efficacy of tafamidis. The study will be expanded by adding 18 evaluable patients. Both dose levels will be determined based on cumulative results. It can be expanded based on the Patients who responded to and tolerated all five planned doses of vedolizumab and treatment Patients who showed recurrence of intestinal GvHD symptoms after discontinuation of the drug (i.e., after the fifth dose) were included in the extended phase. They can participate in a randomized controlled trial in which they receive 300 mg of vedolizumab IV twice every two weeks. Subsequent doses may be administered every four weeks for up to one year after the first dose of study drug.

[0105] Vital signs, physical and neurological examinations, AE assessments, and laboratory values (chemical, Hematological and urinalysis will be obtained to assess the safety and tolerability of IV vedolizumab. The clinical signs were measured during the screening period and on days 1, 7, 15, 22, and 30 of the study. Days 28, 36, 43, 71, 99, 4 months later, and 5 months later At the first follow-up, at the 6-month follow-up, at the 9-month follow-up, and at the 12-month follow-up Physical and neurological examinations will be obtained throughout the entire consultation and also at any extension visits. Laboratory values will be obtained throughout the screening period, and symptoms prompting a physical examination will be reported on Day 1 of the study. , 7th day, 15th day, 22nd day, 28th day, 36th day, 43rd day, 71st day, 99th day, Obtained at the 12-month follow-up visit and again at any extension visit. Endoscopy will be performed to assess the clinical response to vedolizumab treatment.

[0106] Serial blood samples for vedolizumab PK evaluation were collected on days 1, 2, and 3 of the study. Day 1, 5th, 7th, 9th, 11th, 15th, 16th, 18th, 20th, 2 Day 2, 24, 28, 32, 36, 40, 43, 71 and Serial blood samples will be obtained on day 99. Anti-vedolizumab antibodies and serum biomarkers will be assessed. Carbohydrate (including but not limited to IL-6, IL-17, and ST2) (McDonald GB e t al., Blood 2015;126(1):113-20; Ponce D M et al., Biol Blood Marrow Transplant 2 015;21(11)1985-93.] and / or correlate with the severity of acute GvHD. , cellular biomarkers (including but not limited to CD8+, CD38+, and CD8+ bright effector memory T cells, and CD4+ memory T cells) (Khandelwal P et al., Biol Blood Marrow Transplant 2 015;21(7):1215-22.) serum concentration determination. Other potential biomarkers for GvHD (Levine JE et al., L ancet Haematol 2015;2(1):e21-e9.) is citrulline (Vokurka S et al., Med Sci Monit 2013;19 :81-5.), serum intestinal fatty acid binding protein (Van den Abbeele P . et al., ISME J 2013;7(5):949-61.), and overall Surrogate markers for endogenous intestinal disease (e.g., REG3a (Levine JE et al. l., Biol Blood Marrow Transplant 2012;18 (1 Suppl):S116-24.) and urinary indoxyl sulfate (Weber D. et al., Blood 2015;126(14):1723-8. Fecal samples were collected for microbiology on days 36, 43, 71, and 99 of the study. The samples are collected for analysis.

[0107] Changes in health-related quality of life were assessed using the EQ-5D and FACT-BMT. It will be assessed using a questionnaire. Healthcare resource utilization measures will be collected throughout the study. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI) as of June 14, 2010. CTCAE), version 4.03 (Common Termino logy Criteria for Adverse Events(CTCAE). National Cancer Institute, National Ins. titutes of Health, US Department of He alth and Human Services Series v4.03. Ju ne 14, 2010. Publication No. 09-5410.).

[0108] C. Duration of treatment Patients will receive up to five IV vedolizumab infusions (days 1, 15, 43, 71, and (a single dose on each of the first 99 days) will be administered after review and agreement by the medical monitor. Patients who responded to and tolerated all five planned doses of vedolizumab, and Patients who showed recurrence of intestinal GvHD symptoms after discontinuation of treatment (i.e., after the fifth dose) were 300 mg vedolizumab IV twice every 2 weeks, followed by every 4 weeks as the first dose of study drug Doses other than 300 mg and / or doses other than every 4 weeks may be administered for up to 1 year after starting treatment. The frequency of treatment may be selected based on the cumulative safety, efficacy, and PK results. If, in the opinion of the investigator, the patient would benefit from the treatment, the investigator and may receive the drug for more than one year with the sponsor's consent.

[0109] D. Evaluation Period Patients may receive vedolizumab if they do not experience a recurrence from a malignant tumor. If patients have unacceptable vedolizumab-related toxicity, treatment will be discontinued. Overall survival (OS) was assessed every 3 months until death, withdrawal of consent, or termination of the study by the sponsor. Patients will be followed for up to one year after the end of treatment or the last patient enrolled in the study. Patients were required to participate in the LTFU safety study for 6 months after the last dose of study drug. can be.

[0110] E. Inclusion and Exclusion Criteria The main criteria for inclusion were adult patients aged 18 years or older who had undergone a single allo-HSCT. and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry with bowel disease complications of severity B, C, or D according to the IBMTR index Adult patients aged 18 years or older with primary steroid-resistant acute GvHD will be enrolled. Patients were randomly assigned to receive bone marrow engraftment and to receive a performance score of 0 to 3 based on Eastern Cooperative Oncology Group performance status. and ≥ 60 mL / min / 1.73 m 2 Based on the Cockcroft-Gault estimate Must have evidence of creatinine clearance estimate.

[0111] Patients with chronic GvHD, relapse of malignant tumor after allo-HSCT, or acute Systemic medications other than corticosteroids for the treatment of chronic GvHD (other than GvHD prophylaxis) Patients receiving active CNS disease or active cytomegalovirus are excluded from this study. Patients with PML or signs and symptoms of PML or any history of PML were also excluded. Additionally, patients with severe hepatic veno-occlusive disease / sinusoidal obstruction syndrome are excluded. Patients who meet the following criteria may enroll in this study: 1. Male or female patients aged 18 years or older. 2. Recipients of one allo-HSCT but have not received more than one allo-HSCT Those who have not been there. 3. Patients with primary steroid-resistant GvHD. Steroid-resistant disease is treated with 2 mg / kg of methylprednisolone or equivalent at 5-7 days of treatment or no improvement, or 2 mg / kg methylprednisolone or equivalent It is defined as the lack of a complete response after 14 days of first-line treatment with other systemic therapies for GvHD. Patients who develop intestinal GvHD despite receiving the drug should be monitored for the entire duration of the disease, even if the intestinal GvHD persists. Please note that even if you do not show up throughout the exam, you can still take the exam 5-7 days later. As long as the patient meets the definition of steroid resistance above, they will be treated with increased steroid doses. A change in the dosage (e.g., an increase in methylprednisolone of 1 mg / kg to 2 mg / kg) was received before enrollment. Patients with chronic kidney disease can also take the test. Eastern Cooperative Oncology Group (ECOG) performance status of 3 to 4.0 (See Table 4) [Table 4] 5. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry The patients were those with bowel disease complications with a severity index of B, C, or D using the IBMTR index. Acute GvHD (see Tables 1 and 3). Here, complications from acute GvHD in other organs are also considered. Note that this is also allowed. 6. ≥ 0.5 × 10 for 3 consecutive days 9 Evidence of bone marrow engraftment defined by absolute neutrophil count of 0.05 / L . 7. For patients with serum creatinine concentrations above the institutional limit, ≥ 60 mL / min / l .73m 2 Creatinine clearance based on Cockcroft-Gault estimates. 8. Sufficient cognitive ability to reliably complete the RAMP questionnaire at baseline. 9. Have been menopausal or surgically sterilized for at least 1 year prior to the screening visit If you are undergoing gestational diabetes or have childbearing potential, you must sign an informed consent form. It was considered a highly effective method of contraception from the time of administration through 18 weeks after the last dose of study drug. Agree to simultaneously implement one additional effective (barrier) method or this is the subject Women who agree to practice total abstinence when it is consistent with a desirable and normal lifestyle Patients. (Periodic abstinence methods [e.g., calendar, ovulation, symptomatic temperature, and postovulation methods], extravaginal Ejaculation, spermicide alone, and lactational amenorrhea are unacceptable methods of contraception. (Do not use with condoms.) Male patients, even if surgically sterilized (i.e., post-vasectomy status): All trials Use effective barrier contraception throughout the study treatment period and for 18 weeks after the last dose of study drug. agree to this, or if this is in line with the subject's preferred and usual lifestyle, A person who agrees to practice complete abstinence. (Periodic abstinence methods [e.g., calendar, ovulation, symptomatic temperature] and postovulatory methods], extravaginal ejaculation, spermicide only, and lactational amenorrhea are unacceptable contraceptive methods (Female and male condoms should not be used together.) 10. Consent may be withdrawn by the patient at any time without prejudice to future medical care. shall be provided prior to the performance of any test-related procedure outside of the standard of medical care, with the understanding that Requires voluntary written consent. 11. Appropriate blood collection procedures are in place for the blood samples required for the study, including PK and biomarker sampling. Patients with planned central venous access devices are allowed. Patients who meet any of the following exclusion criteria will not be enrolled in this study: 1. Chronic GvHD (including acute-chronic overlap syndrome) at screening Existence. 2. Disease recurrence after allo-HSCT. 3. Hyperacute GvH, defined as hematopoietic stem cell infusion within the first 15 days of GvHD onset Patients with D. 4. Receiving systemic medications other than corticosteroids for the treatment of acute GvHD. vHD prophylactic medications (eg, calcineurin inhibitors) may be continued. 5. Acute steroid-resistant GvHD for ≥28 days after first-line treatment. 6. Patients who have a positive PML subjective checklist should be considered for possible PML prior to enrollment. The patient must be evaluated by a physician (see Section 10.7). If not, it is excluded. 7. Evidence of encephalopathy on screening. 8. Evidence of severe hepatic veno-occlusive disease / sinusoidal obstruction syndrome. 9. Less than 3 weeks of lifespan 10. History of any major neurological disorder, including multiple sclerosis or neurodegenerative disease, within the past 3 years Patients with a history of stroke or brain tumor within the past year will also be excluded. 11. Patients with active cytomegalovirus (CMV) colitis (Section 8.5 See 3). 12. Demonstrated by a positive test for HBV surface antigen and / or HCV RNA Patients with chronic hepatitis B (HBV) or hepatitis C (HCV) infection. 13. Any identified congenital or acquired immune deficiency (e.g., various general immune deficiencies, human immunodeficiency virus [HIV] infection, organ transplant). 14. Clostridium difficiency in stool samples during screening Positive le toxin test or evidence of other enteric pathogens (e.g., adenovirus). 15. Evidence of uncontrollable active systemic infection. 16. In the opinion of the investigator or medical monitor, treatment according to this protocol Any serious medical or psychiatric condition that could potentially prevent completion of the study. 17. Any activity that, in the opinion of the investigator or medical monitor, may confound or confound the results of the study. Any unstable or uncontrolled cardiovascular disease, pulmonary disorder, or Harm, liver damage, kidney damage, GI disorders, genitourinary disorders, blood disorders, blood clotting disorders, immunological disorders , endocrine / metabolic disorders, neurological disorders, or other medical disorders. 18. History of hypersensitivity or allergy to vedolizumab or any of its components. 19. If female, have been pregnant before, during, or within 18 weeks of participating in this study Pregnant or breastfeeding or intending to become pregnant, or donating eggs during this period Patients who are intended to. 20. Men may not donate sperm during this study or for 18 weeks thereafter. Patients who are intended to

[0112] F. Study Endpoints Primary and secondary endpoints of the study.

[0113] Primary endpoints and metrics 1. Subject's overall response (partial response (PR) + very good partial response (VG)) on day 28 The rate of patients with a CR (progressive response) and a complete response (CR) was 100%. A complete response (CR) was defined as the resolution of all signs and symptoms of acute graft-versus-host disease (GvHD). It is justified.

[0114] Very good partial response (VGPR) was defined as resolution of signs and symptoms of GvHD. 1) Skin: No rash or residual erythematous rash without blisters covering less than 25% of the body area (minimal) (Excluding slight residual erythema and hyperpigmentation) 2) Liver: Total blood glucose level <2mg / dL at the time of enrollment Serum bilirubin concentration or <25% of baseline. 3) Intestinal: a) Tolerating food or enteral nutrition Participants who tolerated the condition, b) had mostly solid stools, c) had no obvious gastrointestinal bleeding or stomach cramps, d ) Nausea or vomiting rarely occurs.

[0115] A partial response (PR) is defined as the absence of progression in any organ and one or more organs with a G Defined as an improvement in vHD stage. 2. Experienced a serious adverse event (SAE) through 28 days after the first IV vedolizumab administration Number and percentage of patients. An adverse event (AE) is any untoward medical event in a clinical trial participant who receives a drug. It is defined as an occurrence, but it does not necessarily have to be causally related to this treatment. E is for any adverse medical occurrence, serious risk, contraindication, side effect or caution at any dose. , leading to death, life-threatening, requiring hospitalization or prolongation of current hospitalization, persistent have a congenital anomaly / birth defect or have a medical condition that results in a serious or serious disability / incapacity Of these, those that are potentially related to pharmaceutical products are defined as being of biological importance. Possible events are defined as adverse drug reactions.

[0116] Secondary endpoints Percentage of subjects who died without recurrence of primary malignancy at 6 months after allo-HSCT. Percentage of subjects with CR at day 28.

[0117] The proportion of subjects with an overall intestinal response at day 28. The overall intestinal response was determined by the proportion of subjects with an acute intestinal Gv Symptoms of acute intestinal GvHD are defined as the resolution of all signs and symptoms of GvHD. Symptoms of acute intestinal GvHD range from 1 being the most severe to 1 being the most severe. The International Bone Marrow Transplant Registry (IB) graded the disease on a scale of 1 to 4. Glucksberg for MTR and Blood and Marrow Transplant Clinical Trials Network (BMCT) T CTN) is measured using a modified standard.

[0118] OS at 6 and 12 months. OS is the period from the date of enrollment to the date of death from any cause. It is defined as follows.

[0119] Patients who were alive without recurrence of GvHD or primary malignancy at 6 and 12 months Elephant proportions.

[0120] From the first dose of vedolizumab IV through 18 weeks after the last dose of vedolizumab IV Number and percentage of patients who experienced investigational emergent adverse events (TEAEs). TEAEs are those that are associated with the study drug. It is defined as an adverse event that occurs after receiving From the first dose of vedolizumab IV through 18 weeks after the last dose of vedolizumab IV, S Number and percentage of patients who experienced AEs.

[0121] Mean pre-dose vedolizumab serum concentration (trough concentration) on day 99. The serotonin-releasing hormone (SHR) administered through both 6 and 12 months from the start of the first IV infusion of vedolizumab was Total dose of steroid (mg / kg / day of methylprednisolone or equivalent).

[0122] Clinical trial endpoints Proportion of subjects with CR at days 15, 43, 71, and 99 and 6 months If.

[0123] Complete bowel response at 15, 43, 71, and 99 days and 6 months Percentage of subjects.

[0124] Proportion of subjects free of active GvHD recurrence or death at 6 and 12 months.

[0125] Proportion of subjects with endoscopic response (free choice).

[0126] The proportion of patients who developed chronic GvHD requiring systemic immunosuppression.

[0127] Presence of anti-vedolizumab antibodies (assessments were taken at baseline and at the end of the exposure period) (Performed on specimens).

[0128] Patients who tested positive for anti-vedolizumab antibodies at baseline, day 20, and 6 months Percentage of people.

[0129] Serum biomarkers (including but not limited to interleukin [IL]-6, IL-17, and tumor suppressor 2 [ST2]) and / or cells that may correlate with the severity of acute GvHD. Biomarkers (including but not limited to CD8+, CD38+, and CD8+ bright effect Changes in CD4+ memory T cells and CD4+ memory T cells can be tested for GvHD. Other biomarkers for urinary tract infection include citrulline, serum intestinal fatty acid binding protein, and total cholesterol. These include surrogate markers for endogenous intestinal disease (e.g., REG3a and urinary indoxyl sulfate). nothing.

[0130] Changes in the fecal microbiome.

[0131] Length of hospital stay, type of hospitalization (intensive care, general ward, emergency care), outpatient visits, outpatient / visits prescriptions administered between visits, medical tests between visits, and surgical procedures during the study period. Healthcare resource utilization scale. European Quality of Life 5-Dimensional ( EQ-5D) score (Stark RG et al., Infamm BowelD is 2010;16(1):42-51).

[0132] Functional Assessment of Cancer Therapy -Bone Marrow Transplant Scale (FACT-BMT) Score (Parikh A et al., Inflamm Bowel Dis 2 Change from baseline in (012;18(8)1470-9).

[0133] Example 3 Monte Carlo Simulation of Vedolizumab Serum Concentrations in a Clinical Trial A kinetic model was performed. Simulations included inter-individual effects in addition to the effects of body weight and albumin. The covariates included the variance and residual variance of the covariates. All other covariates were set to their standard values. 000 adult patients were simulated in this study. Albumin and weight were normally distributed. The simulated administration regimen was administered via 30-minute IV infusion. Days -1, +13, and +42 (i.e., days 0 and 14 relative to the first dose) and 43 days) and vedolizumab 75 mg.

[0134] Data observed from three patients enrolled in a Phase 1b open-label dose-ranging study (Example 1) The data was overlaid on the simulation data (see Figure 3). The "clarity" is due to residual variation. Figure 3 shows the measured and simulated vedolizumab The time course of serum concentrations is shown in the figure. In this figure, the vedolizumab concentration in one patient was The blood glucose level did not reach 10 μg / ml except immediately after the first dose. maintained vedolizumab levels above 10 μg / ml for several days, but not after the first dose. A third patient maintained vedolizumab levels above 10 μg / ml for several days after the first dose. did.

[0135] Sequence disclosure [Table 5-1] [Table 5-2]

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Claims

1. A method for treating graft-versus-host disease (GvHD) in a human, comprising administering to a subject in need thereof and administering to a human the antibody having binding specificity for the human α4β7 integrin complex. wherein the antibody is administered in the following regimen: a) a first antibody administration; b) about 2 weeks after the first administration; c) a second antibody administration about 4 weeks after said second administration; and optionally d) additional antibody doses, each additional dose being administered about 4 weeks after the most recent dose, followed by and each dose of a) to d) is 300 mg, or each dose of a) to d) is The method, wherein the amount is 600 mg.

2. 2. The method of claim 1, wherein the GvHD is acute GvHD.

3. 3. The method of claim 2, wherein the acute GvHD is steroid-resistant acute GvHD.

4. The human has an intestinal disease severity index of B, C or D using the BMT CTN modified IBMTR index.

4. The method according to claim 1, wherein the patient has steroid-resistant acute GvHD accompanied by disease complications. The method described in paragraph .

5. The method according to any one of claims 1 to 4, wherein the human in need thereof is an allogeneic undergoing hematopoietic stem cell transplantation.

6. 6. The method of claim 5, wherein the human in need thereof has had a bone marrow transplant. method.

7. 7. The method of any one of claims 1 to 6, wherein the human in need thereof is Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 , the method.

8. The method according to any one of claims 1 to 7, wherein the human in need thereof is Based on the Croft-Gault estimate: ≥ 60 mL / min / 1.73 m 2 Creatinine The method of claim 1, wherein the first and second electrodes have an offset.

9. The method of any one of claims 1 to 8, wherein the antibody is administered intravenously.

10. 10. The method of claim 9, wherein the antibody is administered by infusion.

11. 11. The method of claim 10, wherein the antibody is infused over a period of about 30 to about 60 minutes.

12. The antibody comprises the CDRs: Light chain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO: 8 and CDR3 SEQ ID NO: 9 and Heavy chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6 The method according to any one of claims 1 to 11, comprising:

13. 1, wherein the antibody has a heavy chain variable region sequence of amino acids 20 to 140 of SEQ ID NO:

1.

13. The method according to any one of claims 1 to 12.

14. 1, wherein the antibody has a light chain variable region sequence of amino acids 20 to 131 of SEQ ID NO:

2.

13. The method according to any one of claims 1 to 12.

15. the antibody having a heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 1 and a heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 2 The method of claims 1 to 12, having a light chain comprising 0 to 238.

16. The method of any one of claims 1 to 15, wherein the antibody is a humanized antibody.

17. 17. The method of claim 16, wherein the antibody is vedolizumab.

18. 1. A method for reducing the severity of acute graft-versus-host disease (GvHD), comprising: Those who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are at risk of developing acute GvHD A human patient is administered a humanized antibody having binding specificity for human α4β7 integrin. Status given Includes The humanized antibody is administered to the patient using the following dosing regimen: a. administering the humanized antibody at an initial dose of 300 mg, 450 mg, or 600 mg al lo-HSCT followed by intravenous infusion; b. followed by a second dose of 300 mg of the humanized antibody approximately two weeks after the initial dose. Intravenous infusion; c. followed by a third dose of 300 mg of the humanized antibody approximately 6 weeks after the initial dose. Intravenous infusion; is administered according to The humanized antibody comprises an antigen-binding region of non-human origin and at least a portion of an antibody of human origin. the humanized antibody has binding specificity for the α4β7 complex, and the antigen-binding domain The regions are the following CDRs: Light chain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO: 8 and CDR3 SEQ ID NO: 9 and Heavy chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6 Including, This method reduces the occurrence of GvHD.

19. The reduction in severity of acute graft-versus-host disease (GvHD) is achieved by the use of a modified Glucksberg clone. Grade I or II GvHD or other scoring according to criteria 10. The method of claim 1, wherein the system results in GvHD or no GvHD of similar severity.

8. The method according to claim 8.

20. the reduction in severity of acute GvHD is greater than or equal to methotrexate and a calcineurin inhibitor alone Grade II-IV or Grade III at 100 days compared with treatment with - a 50% reduction in the cumulative incidence and severity of acute GVHD in patients with IV How to do it.

21. The reduction in severity of acute graft-versus-host disease (GvHD) is achieved by administering methotrexate and calcitonin.

18. A reduction in mortality within one year compared to treatment with a neurin inhibitor alone. The method described below.

22. The patient is selected from the group consisting of biomarkers, clinical signs, and unresponsiveness to steroid use.

18. The method of claim 17, wherein the subject is identified as being at risk for suffering from acute GvHD after measurement of a criterion selected from the group consisting of: The method described below.

23. 19. The method of claim 18, wherein the humanized antibody is administered more than 15 days after hematopoietic stem cell infusion. How to do it.

24. 1. A method of suppressing an immune response in a cancer patient, comprising: Human α4β7 insulin was administered to human patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). administering a humanized antibody having binding specificity for Tegrin; The humanized antibody is administered to the patient using the following dosing regimen: a. administering the humanized antibody at an initial dose of 300 mg, 450 mg, or 600 mg al lo - intravenous infusion on the day before HSCT; b. followed by a second dose of 300 mg of the humanized antibody approximately two weeks after the initial dose. Intravenous infusion; c. followed by a third dose of 300 mg of the humanized antibody approximately 6 weeks after the initial dose. Intravenous infusion; is administered according to Furthermore, the humanized antibody may comprise at least one antigen-binding region of a non-human origin and one of a human origin. the humanized antibody has binding specificity for the α4β7 complex, The original binding region contains the following CDRs: Light chain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO: 8 and CDR3 SEQ ID NO: 9 and Heavy chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6 The method comprising:

25. A method of treating a transplant patient, wherein the transplant patient is a recipient of an infusion of allogeneic hematopoietic cells. and administering an anti-α4β7 antagonist.

26. said transplant patient before a conditioning regimen selected from myeloablative conditioning or reduced-dose conditioning; 26. The method of claim 25, wherein the recipient is a human.

27. 27. The method of claim 25 or 26, wherein the anti-α4β7 antagonist is administered prior to the infusion. The method described.

28. the anti-α4β7 antagonist is administered in at least one dose in multiple doses prior to the infusion; 27. The method of claim 25 or 26,

29. the anti-α4β7 antagonist is administered at the first dose in multiple doses on the same day of the infusion; 27. The method of claim 25 or 26,

30. The anti-α4β7 antagonist is administered at the first dose in a repeat dose the next day after the infusion.

27. The method of claim 25 or 26, wherein the

31. wherein the anti-α4β7 antagonist is administered in a single dose for 10 to 28 days after the infusion.

27. The method according to claim 25 or 26.

32. 27. The method of claim 27, wherein a dose of an anti-α4β7 antagonist is administered between the pretreatment and the infusion.

29. The method according to claim 28.

33. 33. The method of any one of claims 25 to 32, wherein the transplant patient is suffering from cancer.

34. 34. The method of claim 33, wherein the cancer is a blood cancer.

35. 3. The method of claim 2, wherein the blood cancer is leukemia, lymphoma, myeloma, or myeloproliferative neoplasm.

4. The method according to claim 4.

36. The leukemia is acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). The method of claim 35.

37. 33. The method according to any one of claims 25 to 32, wherein the transplant patient suffers from a non-malignant hematological or immunological disorder. The method according to any one of claims 1 to 5.

38. The non-malignant hematological or immunological disorders include hemoglobinopathies, bone marrow failure syndromes, and immunological disorders.

38. The method of claim 37, wherein the disease is selected from the group consisting of:

39. The anti-α4β7 antagonist has binding specificity for the α4β7 integrin complex. The method according to any one of claims 25 to 38, wherein the antibody is an anti-α4β7 antibody having the formula:

40. the anti-α4β7 antibody is a humanized antibody, and the antigen-binding region of the humanized antibody is CDRs of: Light chain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO: 8 and CDR3 SEQ ID NO: 9 and Heavy chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6 40. The method of claim 39, comprising:

41. 41. The method of claim 40, wherein the humanized antibody is reconstituted from a lyophilized formulation.

42. 41. The method of claim 39 or 40, wherein the humanized antibody is administered intravenously.

43. the humanized antibody has a heavy chain variable region sequence of amino acids 20 to 140 of SEQ ID NO:

1.

43. The method according to any one of claims 40 to 42.

44. the humanized antibody has a light chain variable region sequence of amino acids 20 to 131 of SEQ ID NO:

2.

44. The method according to any one of claims 40 to 43.

45. The humanized antibody has a heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 1 and an amino acid sequence comprising amino acids 20 to 470 of SEQ ID NO: 2 45. The method of claim 43 or 44, wherein the antibody has a light chain comprising amino acids 20 to 238.

46. The method of any one of claims 40 to 45, wherein the humanized antibody is vedolizumab. 。

47. Furthermore, tacrolimus, tacrolimus and methotrexate, or methotrexate 47. The method of claim 25, further comprising treating the transplant patient using method.

48. Furthermore, the engraftment of the allo-HSCs can be detected by measuring the number of neutrophils. The method of any one of claims 25 to 47, comprising:

49. Furthermore, interleukin 6 (IL-6), interleukin 17 (IL-17), tumor tumorigenesis suppressor factor 2 (ST2), CD8+ cells, CD38+ cells, CD8+bright and CD4+ memory T cells. and measuring the amount of said biomarker before or one week after said infusion. the biomarkers measured within 20-100 days after the infusion 49. The method of claim 48, wherein:

50. The patient has an adverse event that does not involve stage 3 or stage 4 intestinal GvHD.

50. The method of any one of claims 25 to 49.

51. The method according to any one of claims 25 to 50, wherein the allogeneic hematopoietic cells are allogeneic hematopoietic stem cells. method.

52. 51. The method of any one of claims 25 to 50, wherein the allogeneic hematopoietic cells are allogeneic white blood cells. How to do it.

53. 53. The method of claim 52, wherein the allogeneic white blood cells are T lymphocytes.

54. 1. A method for preventing graft-versus-host disease (GvHD), comprising: Human α4β7 insulin was administered to human patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). administering a humanized antibody having binding specificity for Tegrin; The humanized antibody is administered to the patient using the following dosing regimen: a. An initial dose of 75 mg, 300 mg, 450 mg, or 600 mg of the humanized antibody Administered intravenously the day before allo-HSCT; b. followed by 75 mg, 300 mg, 450 mg, or 600 mg of the humanized antibody a second dose administered intravenously about two weeks after the initial dose; c. followed by 75 mg, 300 mg, 450 mg, or 600 mg of the humanized antibody. a third dose administered intravenously about 6 weeks after the initial dose; is administered according to Furthermore, the humanized antibody may comprise at least one antigen-binding region of a non-human origin and one of a human origin. the humanized antibody has binding specificity for the α4β7 complex and The combined region contains the following CDRs: Light chain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO: 8 and CDR3 SEQ ID NO: 9 and Heavy chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6 The method comprising:

55. The administration regimen is effective in treating Grade II GvHD, Grade I GvHD, or no GvHD.

55. The method of claim 54, wherein the condition is

56. 55. The method of claim 54, wherein the prevention results in sustained α4β7 blockade during hematopoietic stem cell infusion. How to do it.

57. 56. The method of claim 54 or 55, wherein tacrolimus is co-administered to the human patient.

58. 58. The method of claim 54, wherein methotrexate is co-administered to the human patient. The method described.

59. 59. The method of claim 54, wherein the humanized antibody is administered to the patient over a period of about 30 minutes. The method according to any one of claims 1 to 5.

60. 60. The method of any one of claims 54 to 59, wherein the humanized antibody is reconstituted from a lyophilized formulation. The method described.

61. 61. The method of claim 60, further comprising reconstituting the humanized antibody to comprise a stable liquid formulation. How to post.

62. the humanized antibody has a heavy chain variable region sequence of amino acids 20 to 140 of SEQ ID NO:

1.

62. The method of any one of claims 54 to 61.

63. the humanized antibody has a light chain variable region sequence of amino acids 20 to 131 of SEQ ID NO:

2.

63. The method of any one of claims 54 to 62.

64. The humanized antibody has a heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 1 and an amino acid sequence comprising amino acids 20 to 470 of SEQ ID NO: 2 64. The method of claim 62 or 63, wherein the antibody has a light chain comprising amino acids 20 to 238.

65. The method of any one of claims 54 to 64, wherein the humanized antibody is vedolizumab. 。

66. Treating patients with cancer or non-malignant hematologic, immune, or autoimmune diseases 1. A method for producing a medicament for use in a medical device, comprising: a. conditioning the immune system of the hematopoietic stem cell transplant patient; b. Administration of a humanized antibody having binding specificity for human α4β7 integrin Top and c. Waiting for at least 12 hours; d. administering allogeneic hematopoietic stem cells; e. After waiting for 13 days, humanized α4β7 integrin-binding specificity antibody was obtained. a second administration step of the antibody; f. After a waiting period of 4 weeks, humanized α4β7 integrin-binding specificity antibody was obtained. a third administration step of the antibody; The method comprising:

67. 67. The method of claim 66, further comprising administering tacrolimus to the patient.

68. 68. The method of claim 66 or 67, further comprising administering methotrexate to said patient. The method described.

69. 67. The method of claim 66, wherein said conditioning of the immune system is a myeloablative conditioning or a reduced-dose conditioning.

69. The method of any one of claims 1 to 68.

70. The patient has an adverse event that does not involve stage 3 or stage 4 intestinal GvHD.

70. The method according to any one of claims 66 to 69.

71. The patient has an adverse event not involving Grade III or Grade IV GvHD.

70. The method according to any one of claims 66 to 69.

72. 70. The method of any one of claims 66 to 69, wherein the patient has leukemia or lymphoma. method.

73. 70. The method according to any one of claims 66 to 69, wherein the allogeneic hematopoietic stem cells are from peripheral blood. The method described.

74. 70. Any of claims 66 to 69, wherein the allogeneic hematopoietic stem cells engraft without further immunosuppressive treatment. The method according to any one of claims 1 to 5.

75. The humanized antibody comprises an antigen-binding region of non-human origin and at least a portion of an antibody of human origin. the humanized antibody has binding specificity for the α4β7 complex, and the antigen-binding domain The regions are the following CDRs: Light chain: CDR1 SEQ ID NO:7 CDR2 SEQ ID NO: 8 and CDR3 SEQ ID NO: 9 and Heavy chain: CDR1 SEQ ID NO: 4 CDR2 SEQ ID NO: 5 and CDR3 SEQ ID NO: 6 70. The method of any one of claims 66 to 69, comprising:

76. 76. The method of claim 75, wherein the humanized antibody is reconstituted from a lyophilized formulation.

77. the humanized antibody has a heavy chain variable region sequence of amino acids 20 to 140 of SEQ ID NO:

1.

76. The method of claim 75.

78. the humanized antibody has a light chain variable region sequence of amino acids 20 to 131 of SEQ ID NO:

2.

76. The method of claim 75.

79. The humanized antibody has a heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 1 and an amino acid sequence comprising amino acids 20 to 470 of SEQ ID NO: 2 79. The method of any one of claims 75 to 78, wherein the antibody has a light chain comprising amino acids 20 to 238.

80. The method of any one of claims 75 to 78, wherein the humanized antibody is vedolizumab. 。

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