Alpha4beta7 integrin antibody compositions and methods of use

Abstract

Provided herein are variant [alpha] 4 [beta] 7 integrin antibodies and methods of use.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 504,966, filed May 30, 2023, U.S. Provisional Application No. 63 / 505,962, filed June 2, 2023, U.S. Provisional Application No. 63 / 559,922, filed November 16, 2023, U.S. Provisional Application No. 63 / 554,886, filed February 16, 2024, and U.S. Provisional Application No. 63 / 559,081, filed February 28, 2024, the entire contents of each of which are incorporated herein by reference. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on May 17, 2024, is named PRG-005WO_SL.xml and is 23.8 kilobytes in size. BACKGROUND

[0003] Integrins are cell adhesion transmembrane receptors that serve as extracellular matrix (ECM)-cytoskeleton linkers and transducers of biochemical and mechanical signals between cells and their environment. Due to their exposure on the cell surface and sensitivity to molecular inhibition, integrins such as a4b7 integrin have been investigated as pharmacological targets for treating various diseases including cancer and inflammatory diseases (e.g., inflammatory bowel disease). However, current integrin therapies are associated with serious side effects given the role of integrins in important biological processes and / or require multiple and frequent doses to maintain therapeutic efficacy. Thus, there is a need for improved a4b7 therapies. SUMMARY

[0004] In one aspect, the present disclosure provides a multi-dose regimen for use in treating a disease in a subject in need thereof, the multi-dose regimen comprising: (a) a first injectable liquid formulation comprising at least 500 mg total dose of an a4b7 binding antibody; and (b) a second injectable liquid formulation comprising at least 120 mg total dose of an a4b7 binding antibody, wherein the a4b7 binding antibody consists of: (i) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (ii) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0005] In certain embodiments, the first injectable liquid formulation comprises about 500 mg to about 1200 mg total dose of the a4b7 binding antibody, and the second injectable liquid formulation comprises about 120 mg to about 450 mg total dose of the a4b7 binding antibody.

[0006] In some embodiments, the first injectable liquid formulation comprises about 600 mg total dose of the a4b7 binding antibody, and the second injectable liquid formulation comprises about 300 mg total dose of the a4b7 binding antibody.

[0007] In some embodiments, the first injectable liquid formulation is for intravenous administration.

[0008] In certain embodiments, the first injectable liquid formulation is for subcutaneous administration. In some embodiments, the first injectable liquid formulation is suitable for administration as a single injection or multiple injections.

[0009] In certain embodiments, the second injectable liquid formulation is for subcutaneous administration. In some embodiments, the second injectable liquid formulation is suitable for administration as a single injection or multiple injections.

[0010] In some embodiments, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0011] In one aspect, the disclosure provides a dosing regimen for use in treating a disease in a subject in need thereof, the dosing regimen comprising: (a) a first formulation for administration to the subject comprising at least about 500 mg total dose of an a4b7 binding antibody; (b) a second formulation for subcutaneous administration to the subject after the first formulation comprising at least about 120 mg total dose of an a4b7 binding antibody, and thereafter at least eight weeks after administration of the second formulation as a maintenance dose, wherein the a4b7 binding antibody consists of: (i) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (ii) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0012] In some embodiments, the first formulation is for subcutaneous administration.

[0013] In some embodiments, the first formulation is for intravenous administration.

[0014] In certain embodiments, the first formulation comprises about 500 mg to about 1200 mg total dose of the a4b7 binding antibody. For example, in some embodiments, the first formulation comprises about 600 mg total dose of the a4b7 binding antibody.

[0015] In certain embodiments, the second formulation comprises about 120 mg to about 450 mg total dose of the a4b7 binding antibody. For example, in some embodiments, the second formulation comprises about 300 mg total dose of the a4b7 binding antibody.

[0016] In certain embodiments, the second formulation is administered at least two weeks after the first formulation, and thereafter as a maintenance dose at least eight weeks after administration of the second formulation.

[0017] In some embodiments, the first formulation is suitable for administration as a single injection or multiple injections. In some embodiments, the second formulation is suitable for administration as a single injection or multiple injections.

[0018] In certain embodiments, the first formulation and the second formulation are citrate-free.

[0019] In certain embodiments, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0020] In another aspect, the disclosure provides an injectable dosage form of an a4b7 binding antibody, the a4b7 binding antibody consisting of: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3, wherein the a4b7 binding antibody has a mean serum half-life in cynomolgus monkeys of greater than about 10 days.

[0021] In some embodiments, the mean serum half-life is about 17 days or more in cynomolgus monkeys.

[0022] In certain embodiments, the injectable dosage form is an injectable liquid formulation.

[0023] In certain embodiments, the a4b7 binding antibody is present at a concentration of at least 180 mg / mL.

[0024] In some embodiments, the injectable liquid formulation is citrate-free.

[0025] In one aspect, the present disclosure provides a method of treating a disease in a patient in need thereof, the method comprising: administering to a subject in need thereof (a) an effective amount of an induction dose of an α4β7 binding antibody, and (b) an effective amount of one or more maintenance doses of the α4β7 binding antibody, wherein the one or more maintenance doses are administered subcutaneously at least eight weeks apart, wherein the α4β7 binding antibody consists of: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0026] In certain embodiments, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0027] In certain embodiments, the effective amount of the induction dose of the α4β7 binding antibody is at least 600 mg, and the effective amount of each of the one or more maintenance doses of the α4β7 binding antibody is at least 300 mg.

[0028] In certain embodiments, the effective amount of the induction dose of the α4β7 binding antibody is about 600 mg, and the effective amount of each of the one or more maintenance doses of the α4β7 binding antibody is about 300 mg.

[0029] In some embodiments, the effective amount of the induction dose of the α4β7 binding antibody is administered subcutaneously.

[0030] In some embodiments, the effective amount of the induction dose of the α4β7 binding antibody is administered intravenously.

[0031] In some embodiments, the one or more maintenance doses are administered subcutaneously about 12 weeks apart.

[0032] In some embodiments, the one or more maintenance doses are administered subcutaneously about 26 weeks apart.

[0033] In some embodiments, the induction dose comprises a dose of α4β7 binding antibody that is about 2-fold or more of the dose of each of the one or more maintenance doses.

[0034] In one aspect, the present disclosure provides a method of achieving a Cmax of 35 µg / mL or greater of an α4β7 binding antibody in a subject six weeks after administering the α4β7 binding antibody to the subject in need thereof, the method comprising: administering to the subject in need thereof (a) an effective amount of an induction dose of the α4β7 binding antibody, and (b) an effective amount of one or more maintenance doses of the α4β7 binding antibody, wherein the one or more maintenance doses are administered subcutaneously at least eight weeks apart, wherein the α4β7 binding antibody consists of: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. 谷In some embodiments, the method further comprises subcutaneously administering at least about 300 mg of the a4b7 binding antibody to the subject in need thereof, and wherein the administering results in a mean serum concentration of the a4b7 binding antibody greater than 35 pg / mL for ten weeks after administration of at least about 300 mg of the a4b7 binding antibody.

[0035] In certain embodiments, intravenously administering about 600 mg to about 1200 mg of the a4b7 binding antibody.

[0036] In certain embodiments, subcutaneously administering about 600 mg to about 1200 mg of the a4b7 binding antibody.

[0037] In some embodiments, intravenously administering about 600 mg of the a4b7 binding antibody.

[0038] In some embodiments, subcutaneously administering about 600 mg of the a4b7 binding antibody.

[0039] In some embodiments, the method further comprises subcutaneously administering at least about 300 mg of the a4b7 binding antibody to the subject in need thereof, and wherein the administering results in a mean serum concentration of the a4b7 binding antibody greater than 35 pg / mL for ten weeks after administration of at least about 300 mg of the a4b7 binding antibody. 谷 is at least 6 pg / mL. In certain embodiments, the administering results in a serum C avgW0-W12 is at least 60 pg / mL.

[0040] In some embodiments, administering at least about 600 mg of the a4b7 binding antibody results in a serum C avgW30-W40 is at least 30 pg / mL.

[0041] In some embodiments, the method further comprises subcutaneously administering at least about 300 mg of the a4b7 binding antibody to the subject in need thereof, and wherein the administering results in a mean serum concentration of the a4b7 binding antibody greater than 35 pg / mL for ten weeks after administration of at least about 300 mg of the a4b7 binding antibody.

[0042] In some embodiments, the method further comprises subcutaneously administering at least about 300 mg of the a4b7 binding antibody to the subject in need thereof four weeks after administration of the last dose of the a4b7 binding antibody.

[0043] In some embodiments, the method further comprises subcutaneously administering to the subject a maintenance dose of at least about 600 mg of the a4b7 binding antibody every twenty-six weeks after administration of the last dose of the a4b7 binding antibody.

[0044] In one aspect, this disclosure provides an α4β7 binding antibody comprising: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0045] In some embodiments, this disclosure provides an isolated nucleic acid encoding a heavy chain and / or a light chain of an α4β7-binding antibody, said antibody comprising: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the isolated nucleic acid encodes SEQ ID NO: 1. In some embodiments, the isolated nucleic acid encodes SEQ ID NO: 3.

[0046] In some embodiments, this disclosure provides a recombinant host cell comprising isolated nucleic acids encoding a heavy chain and / or a light chain of an α4β7-binding antibody, said antibody comprising: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the host cell comprises isolated nucleic acids encoding SEQ ID NO: 1. In some embodiments, the host cell comprises isolated nucleic acids encoding SEQ ID NO: 3.

[0047] In some embodiments, this disclosure provides an expression vector comprising isolated nucleic acids encoding a heavy chain and / or a light chain of an α4β7-binding antibody, said antibody comprising: (a) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (b) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the expression vector comprises isolated nucleic acids encoding SEQ ID NO: 1. In some embodiments, the expression vector comprises isolated nucleic acids encoding SEQ ID NO: 3.

[0048] In some embodiments, this disclosure provides a multiple dosing regimen, a dosing regimen, an injectable dosage form, and / or a method, each as provided herein, wherein the disease is a gastrointestinal inflammatory disease.

[0049] In some embodiments, this disclosure provides a multiple-dosing regimen, a dosing regimen, an injectable formulation, a method, and / or an antibody, each as provided herein, wherein the α4β7-binding antibody has a mean serum half-life greater than about 10 days in cynomolgus monkeys. In some embodiments, the mean serum half-life in cynomolgus monkeys is about 17 days or longer.

[0050] In some embodiments, this disclosure provides a multiple-dosing regimen, a dosing regimen, an injectable formulation, a method, and / or an antibody, each as provided herein, wherein the α4β7-binding antibody has one or more of the following properties: (a) a melting temperature (TmOnset) greater than about 55°C; (b) a melting temperature (TmOnset) greater than 56.2°C; (c) a G0F content of about 55.1% to about 60.4%; (d) a G1F content of about 16.6% to about 18.8%; (e) a Man5 content of about 7.3% to about 8.8%; (f) does not induce the T cell activation markers CD25 or CD69; (g) does not cause the release of cytokines, said cytokines being one or more of IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70, and TNF; (h) (i) Does not induce complement-dependent cytotoxicity (CDC) in primary human PBMCs and human β-lymphocytes expressing α4β7; (j) Does not induce antibody-dependent cytotoxicity (ADCC) in human NK cells; and (j) Does not affect the inhibitory activity of regulatory T cells expressing α4β7 integrin, wherein the inhibitory activity is measured by the presence of elevated CD71, CD25, Ki67, granzyme B, or OX40. Attached Figure Description

[0051] Figure 1A Cell binding of α4β7-binding antibodies was depicted. Cell binding (relative to MFI) of ascending concentrations of α4β7-binding antibody Ab001 (dashed line, hollow shape) or comparative antibody (solid line, solid shape) to PBMCs from three donors (donor 1 = circle; donor 2 = square; donor 3 = triangle) was determined. EC50 was calculated for each donor combination. 50 The values ​​are indicated in Table 2.

[0052] Figure 1B and Figure 1C The binding of α4β7-binding antibody Ab001 and comparative antibody to peripheral blood mononuclear cells expressing α4β7 was depicted. Figure 1B Ab001, labeled with (AlexaFluor-647), binds to cells expressing α4β7 isolated from PBMCs. Figure 1C The modification that prompted AF647-Ab001 to compete with unlabeled Ab001 demonstrates receptor occupancy. N = 3 donors.

[0053] Figure 2A and Figure 2BThe α4β7-binding antibody Ab001 (i.e., an α4β7-binding antibody comprising a heavy chain consisting of the sequence according to SEQ ID NO: 1 and a light chain consisting of the sequence according to SEQ ID NO: 3) was described as blocking the adhesion of MAdCAM-1 and VCAM-1. Figure 2A The percentage of total adhesion inhibition mediated by integrin-mediated MAdCAM-1 adhesion was depicted. The percentage of inhibition was calculated after treatment with increasing concentrations of α4β7-binding antibody or a comparative antibody. The IC50 of the α4β7-binding antibody was also described. 50 The value was 86 pM, and the IC50 of the antibody was compared with that of the drug. 50 It is 83 pM. Figure 2B The percentage of total adhesion inhibition was depicted for integrin-mediated VCAM-1 adhesion (a potential off-target interaction). The percentage of inhibition was calculated after treatment with increasing concentrations of α4β7-binding antibody, comparative antibody, or positive control antibody. The positive control antibody inhibited VCAM-1 adhesion, but neither the α4β7-binding antibody nor the comparative antibody achieved the stated inhibition.

[0054] Figure 3 The half-life of the α4β7-binding antibody Ab001 in non-human primates (NHPs) was plotted. The α4β7-binding antibody or the comparative antibody was administered intravenously to NHPs, and monitoring continued until day 21 post-injection. The normalized concentrations of the α4β7-binding antibody or the comparative antibody were calculated at each time point and used to determine the β-elimination half-life. Data from external studies of the comparative antibody (dashed lines) were also plotted to demonstrate comparable results.

[0055] Figure 4 This study depicted the simulated maintenance of trough concentrations at 6 weeks post-IV induction, which was associated with higher remission rates in ulcerative colitis. During the clinical trial at 6 weeks post-induction, C was used in patients treated with comparative antibody therapy. 谷 The percentages of patients with values ​​≤ 17, 17–25, 25–35, and ≥ 35 µg / mL are plotted in a stacked bar chart. Also shown are C-values ​​from a simulated trial of 1000 patients treated with comparative antibodies at doses of 300 mg, 350 mg, and 400 mg and the α4β7-binding antibody described herein (e.g., Ab001). 谷 The percentage of patients with the value.

[0056] Figure 5 Quarterly maintenance dosing of α4β7-binding antibodies to maintain clinically relevant AUC levels was described. Relative AUC was calculated using a simulated trial of 1000 patients for the α4β7-binding antibodies described herein (e.g., Ab001) with a half-life of 35 or 50 days. ss , 1年The values ​​were calculated and compared with clinical trial data of comparable antibodies administered intravenously (IV) and subcutaneously (SC). The relative AUC of quarterly dosing frequencies ranging from 2 weeks (Q2W) to 16 weeks (Q16W) was calculated. ss , 1年 value.

[0057] Figure 6 Depicting the clinically relevant C from maintenance dosing during maintenance administration 谷 Data from patients with values. In a simulated trial of 1000 patients, C was calculated for patients treated with the comparative antibody administered intravenously (IV; 300 mg dose) and subcutaneously (SC; 108 mg or 320 mg dose), and for patients receiving a 300 mg subcutaneous α4β7-binding antibody (e.g., Ab001) with a half-life of 43, 53, or 56 days. 谷 Percentage of patients ≥ 6 µg / ml. C0 plotted for dosing frequency across the Q2W to Q20W range. 谷 Percentage of patients with ≥ 6 µg / ml.

[0058] Figure 7A and Figure 7B Simulations depicting serum concentrations of the α4β7-binding antibody (e.g., Ab001) and the comparative antibody described herein. Figure 7A Induction and maintenance dosing regimens based on administration at W0 and W2 during induction, using the subcutaneous (SC) administration route, are described. Figure 7B Serum concentrations were depicted based on the antibody half-life, with Q8W IV administration of a comparative antibody and Q12W SC administration of the α4β7-binding antibody (e.g., Ab001) described herein.

[0059] Figure 7C (Left) is a graph showing the clinical remission rate (%) at week 6 of ulcerative colitis; Figure 7C (Right) depicts the induced simulation of serum concentrations of the α4β7-binding antibody (e.g., Ab001) and the comparative antibody described herein.

[0060] Figure 7D This is a graph showing the prediction of human half-life through NHP allometric growth extension.

[0061] Figure 7E The maintenance simulation of serum concentrations of the α4β7 binding antibody (e.g., Ab001, 300 mg Q12W) and the comparative antibody (108 mg Q2W) described herein was depicted when administered subcutaneously (300 mg Q12W for Ab001 and 108 mg Q2W for the comparative antibody).

[0062] Figure 7F Simulated serum concentrations of the α4β7-binding antibody described herein (e.g., Ab001, SC administration, 4–6 injections per year for maintenance) and the comparative antibody (IV / SC administration, 26 injections per year for maintenance) are depicted.

[0063] Figures 8A-8C This is a graph showing a human PK simulation (simulated using a dose of 75 mg / kg NHP-SC (n = 6, M / F)). Figure 8A This is a graph showing the simulated human curve of the α4β7 binding antibody (e.g., Ab001) described herein at 600 mg. Figure 8B This is a graph showing the simulated human curve of the α4β7 binding antibody (e.g., Ab001) described herein at 600 mg Q26W. Figure 8C This is a graph showing the simulated human curves of the α4β7 binding antibody (e.g., Ab001) described herein at 400 mg, 200 mg, and Q12W.

[0064] Figure 9 This is a graph showing the serum concentration-time curves after single subcutaneous and intravenous administration of the α4β7-binding antibody Ab001 in male and female monkeys. Male and female monkeys were administered single subcutaneous doses of Ab001 of 30 mg / kg, 75 mg / kg, or 150 mg / kg, or a single intravenous dose of Ab001 of 150 mg / kg.

[0065] Figures 10A-10C This shows that based on NHP t 1 / 2 A graph showing the data from a human PK-induced simulation study of the α4β7-binding antibody Ab001 relative to a comparative antibody. Figure 10A This is a graph showing the induced simulation of serum Ab001 concentration in humans at a subcutaneous dose of 600 mg in week 0 and 300 mg in week 2. Figure 10B This is a graph showing the induced simulation of serum Ab001 concentration in humans at a subcutaneous dose of 600 mg in week 0 and at subcutaneous doses of 300 mg in weeks 2 and 6. Figure 10C This is a graph showing the induction simulation of serum concentrations of the comparative antibody in humans at an intravenous dose of 300 mg in weeks 0, 2, and 6.

[0066] Figures 11A-11D This shows that based on NHP t 1 / 2 A graph showing the human PK maintenance simulation study of the α4β7-binding antibody Ab001 relative to the comparative antibody. Figure 11A This is a graph showing the maintenance simulation of serum Ab001 concentration in humans at a subcutaneous dose of 600 mg every 26 weeks. Figure 11BThis is a graph showing the maintenance simulation of serum Ab001 concentration in humans at a subcutaneous dose of 300 mg every 12 weeks. Figure 11C This is a graph showing the maintenance simulation of serum concentrations of the comparative antibody in humans at an intravenous dose of 300 mg every 8 weeks. Figure 11D This is a graph showing the maintenance simulation of serum concentrations of the comparative antibody in humans at a subcutaneous dose of 108 mg every 2 weeks.

[0067] Figure 12 This is a graph showing human pharmacokinetic curves of the α4β7-binding antibodies (such as Ab001) described herein at 600 mg and 300 mg in a single escalation dose study.

[0068] Figure 13 This is a graph showing human pharmacokinetic curves of the α4β7 binding antibody (such as Ab001) described herein at 600 mg and 300 mg in multiple escalation dose studies. Detailed Implementation

[0069] To facilitate understanding of this disclosure, several terms and phrases are defined below.

[0070] As used herein, unless otherwise specified, the term "antibody" should be understood to mean a complete antibody (e.g., a complete monoclonal antibody) or a fragment thereof, such as an Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody) or an antigen-binding fragment of an antibody (e.g., an antigen-binding fragment of a monoclonal antibody), including modified, engineered, or chemically conjugated complete antibodies, antigen-binding fragments, or Fc fragments. Typically, an antibody is a multimeric protein containing four polypeptide chains. Two of these polypeptide chains are referred to as immunoglobulin heavy chains (H chains), and two are referred to as immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are linked by interchain disulfide bonds. The immunoglobulin heavy chain is linked by interchain disulfide bonds. The light chain consists of a variable region (VL) and a constant region (CL). The heavy chain consists of a variable region (VH) and at least three constant regions (CH1, CH2, and CH3). The variable region determines the binding specificity of the antibody. Each variable region contains three hypervariable regions called complementarity-determining regions (CDRs), flanked by four relatively conserved regions called framework regions (FRs). The extent of FRs and CDRs has been defined (Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs, designated CDR1, CDR2, and CDR3, contribute to antibody binding specificity. Naturally occurring antibodies have been used as starting materials for engineered antibodies, such as chimeric and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab', (Fab')2, Fv, single-chain antibodies (e.g., scFv), microantibodies, and biantibodies. Examples of modified or engineered antibodies include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). Examples of chemically conjugated antibodies are antibodies conjugated to a toxin moiety.

[0071] The terms "variable domain" and "variable region" are used interchangeably and refer to the portion of an antibody or immunoglobulin domain that exhibits variability in its sequence and participates in determining the specificity and binding affinity of a particular antibody. This variability is not uniformly distributed throughout the entire variable domain of an antibody; it is concentrated in subdomains of each variable region within both the heavy and light chain variable regions. These subdomains are called "hypervariable regions" or "complementarity-determining regions" (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domain are called "framework" regions (FRMs or FRs) and provide a scaffold for the six CDRs in three-dimensional space to form the antigen-binding surface.

[0072] As used herein, the term "Fc polypeptide" for a dimer Fc refers to one of two polypeptides that form the Fc domain of the dimer, namely a polypeptide containing the C-terminal constant region of the immunoglobulin heavy chain, which is capable of stable self-association. For example, the Fc polypeptide of a dimer IgG Fc contains the IgG CH2 and IgG CH3 constant domain sequences. Fc can belong to the IgA, IgD, IgE, IgG, and IgM classes. These classes are also designated as α, δ, ε, γ, and μ, respectively. Several of these classes can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0073] The terms “Fc receptor” and “FcR” are used to describe receptors that bind to the Fc region of an antibody. For example, an FcR can be a naturally occurring human FcR. Typically, an FcR is an FcR that binds to IgG antibodies (γ receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (“activating receptors”) and FcγRIIB (“inhibitory receptors”), which have similar amino acid sequences, differing primarily in their cytoplasmic domains. Other isotypes of immunoglobulins can also be bound by certain FcRs (see, for example, Janeway et al., *ImmunoBiology: the immune system in health and disease*, (Elsevier Science Ltd., NY) (4th ed., 1999)). The activating receptor FcγRIIA contains an activating motif (ITAM) based on the tyrosine residue of the immunoreceptor in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an inhibitory motif (ITIM) based on the tyrosine residue of the immunoreceptor in its cytoplasmic domain (reviewed in Daëron, Annu. Rev. Immunol. [Annals of Immunology] 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. [Annals of Immunology] 9:457-92 (1991); Capel et al., Immunomethods [Immunomethods] 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. [Journal of Laboratory and Clinical Medicine] 126:330-41 (1995). The term “FcR” in this article encompasses other FcRs, including those to be identified in the future. The term also includes neonatal receptor FcRn, which is responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0074] The terms “recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably herein and, in some embodiments, refer to any mammalian subject requiring diagnosis, treatment, or therapy, particularly a human. For therapeutic purposes, “mammal” means any animal classified as a mammal, including humans, livestock, and farm animals, as well as laboratory animals, zoo animals, racing animals, or pet animals, such as dogs, horses, cats, cattle, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human. These terms do not require medical personnel supervision.

[0075] As used herein, the term "effective amount" means an amount of compound (e.g., the compound disclosed herein) sufficient to achieve a beneficial or desired result. An effective amount may be administered in one or more applications, doses, or administrations, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treatment" includes any effect that improves or alleviates symptoms of a disease, ailment, or condition, such as relief, reduction, regulation, reduction, or elimination.

[0076] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent and an inert or active carrier, which makes the composition particularly suitable for in vivo or in vitro diagnostic or therapeutic uses.

[0077] As used herein, the term "pharmaceuticalally acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solutions, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0078] As used herein, the term “a / species (a and an)” means “one / species or more / species” and includes the plural unless the context does not apply.

[0079] As used herein, unless the context clearly indicates otherwise, all numerical values ​​or ranges of values ​​include integers within or covering such ranges, as well as fractions of values ​​or integers within or covering such ranges. Thus, for example, references to a range of 90%–100% include 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., and 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so on. In another example, the range of 1-5,000 times includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, as well as 1.1, 1.2, 1.3, 1.4, 1.5 times, 2.1, 2.2, 2.3, 2.4, 2.5 times, and so on.

[0080] As used herein, “about” a number means a range that includes the number and extends from 10% below the number to 10% above the number. “about” a range means 10% below the lower limit of the range and extending to 10% above the upper limit of the range.

[0081] "Identity percentage (%)" refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same positions in an alignment. For example, "Amino acid sequence identical to SEQ ID NO: YX%" means that the amino acid sequence is identical to SEQ ID NO: Y, and specifically, X% of the residues in the amino acid sequence are identical to the residues in the sequence disclosed in SEQ ID NO: Y. Typically, such calculations are performed using computer programs. Exemplary programs for comparing and aligning sequence pairs include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and nick BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0082] Throughout this specification, where compositions are described as having, comprising, or containing specific components, or processes and methods are described as having, comprising, or including specific steps, it is contemplated that additional compositions of this disclosure are substantially composed of or consisting of the described components, and methods of this disclosure are substantially composed of or consisting of the described processing steps.

[0083] Generally, unless otherwise specified, specified percentages of compositions are by weight. Furthermore, if a variable is not defined, its previous definition shall prevail. α4β7 integrin binding antibody

[0084] This article provides α4β7 binding antibodies (e.g., α4β7 binding proteins, long-acting α4β7 binding antibodies, long-acting α4β7 binding molecules, or long-acting α4β7 targeting molecules). The α4β7 binding antibodies provided herein exhibit binding specificity against the target antigen, human α4β7 integrin. The α4β7 binding antibodies described herein may have improved lifetime and / or specificity. The α4β7 binding antibodies described herein may be specific for α4β7 but not for related integrins (including α4β1 and αEβ7).

[0085] In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having 100% sequence identity with the amino acid sequence according to SEQ ID NO: 1. In a specific embodiment, the α4β7-binding antibody comprises or is composed of a heavy chain containing an amino acid sequence having 100% sequence identity with the amino acid sequence according to SEQ ID NO: 1, including the absence of a C-terminal lysine residue.

[0086] In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having 100% sequence identity with the amino acid sequence according to SEQ ID NO: 3.

[0087] In some embodiments, the α4β7 binding antibody comprises a heavy chain and a light chain, wherein the heavy chain contains at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) of the amino acid sequence identical to the heavy chain of the same α4β7 binding antibody disclosed in Table 1, and the light chain contains at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) of the light chain of the same α4β7 binding antibody disclosed in Table 1. In a specific embodiment of such a heavy chain, a C-terminal lysine residue is absent.

[0088] In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7 binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 3.In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain comprising an amino acid sequence according to SEQ ID NO: 3. In a specific embodiment of such a heavy chain, a C-terminal lysine residue is absent.

[0089] In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7 binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 3.

[0090] In some embodiments, the antigen-binding site comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the heavy and light chain sequences of the antibody disclosed in Table 1A, which are determined according to Kabat (see Kabat et al., (1991) Sequences of Proteins of Immunological Interest, NIH Publication No. 91-3242, Bethesda), Chothia (see, for example, Chothia C and Lesk A M, (1987), J Mol Biol 196: 901-917), MacCallum (see MacCallum RM et al., (1996) J Mol Biol 262: 732-745), IMGT (see Lefranc, (1999) The Immunologist, 7, 132-136), or any other CDR determination method known in the art. Table 1A. Sequences of α4β7-binding antibodies

[0091] In some embodiments, the antigen binding sites include HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 disclosed in Table 1B. Table 1B.

[0092] In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 4. In some embodiments, the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence having 100% sequence identity with the amino acid sequence according to SEQ ID NO: 4.

[0093] In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises a light chain containing an amino acid sequence having 100% sequence identity with the amino acid sequence according to SEQ ID NO: 5.

[0094] In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 5. In some embodiments, the α4β7-binding antibody comprises: a heavy chain comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 5.In some embodiments, the α4β7 binding antibody comprises: a heavy chain comprising the amino acid sequence according to SEQ ID NO: 4; and a light chain comprising the amino acid sequence according to SEQ ID NO: 5.

[0095] In some embodiments, the α4β7 binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence consisting of SEQ ID NO: 3.

[0096] In some embodiments, the α4β7-binding antibody Ab001 comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence consisting of SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody Ab001 comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence consisting of SEQ ID NO: 3.

[0097] The α4β7 binding antibody disclosed herein may possess the following properties:

[0098] The α4β7 binding antibody disclosed herein can exhibit the following N-glycan performance analysis (determined using enzymatically released N-glycans, labeled and monitored by hydrophilic interaction liquid chromatography (HILIC) coupled to a fluorescence detector (FLD):

[0099] In some embodiments, the α4β7 binding antibody comprises one or more of the following properties: (a) The mean serum half-life in cynomolgus monkeys is greater than about 10 days. (b) The mean serum half-life in cynomolgus monkeys is about 17 days or longer. (c) The chain-breaking temperature TmOnset is greater than approximately 55°C. (d) The chain-breaking temperature TmOnset is greater than 56.2°C. (e) Does not induce T cell activation markers CD25 or CD69. (f) Does not result in the release of cytokines at least 6 hours after administration, said cytokines including one or more of IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70, and TNF. (g) Does not induce complement-dependent cytotoxicity (CDC) in primary human PBMCs and human β-lymphocytes expressing α4β7. (h) Does not induce antibody-dependent cytotoxicity (ADCC) in human NK cells, and (i) Does not affect the inhibitory activity of regulatory T cells expressing α4β7 integrin, wherein the inhibitory activity is measured by the presence of elevated CD71, CD25, Ki67, granzyme B or OX40. Fc modification

[0100] This article provides α4β7-binding antibodies containing the modified Fc region. Unless otherwise specified herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0101] In some embodiments, the α4β7 binding antibody comprises a modified Fc, wherein the modified Fc comprises one or more modifications. In some embodiments, the one or more modifications promote selective binding to the Fc-γ receptor.

[0102] In some embodiments, one or more modifications in the modified Fc are selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more modifications in the modified Fc are selected from the group consisting of: S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0103] In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of: L234A / L235A; V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S; C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; L234A / L235A / P329G.

[0104] In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of: M428L / N434S (LS); M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV); T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (S PLE); L234A / L235A (LA); M428L / N434A; L234A / G237A (LAGA); L234A / L235A / G237A; L234A / L235A / P329G; D265A / YTE; LALA / YTE; LAGA / YTE; LALAGA / YTE ;LALAPG / YTE;N297A / LS;D265A / LS;LALA / LS;LALAGA / LS;LALAPG / LS;N297A / DHS;D265A / DHS;LALA / DHS;LAGA / DHS;LALAGA / DHS;LALAPG / DHS;SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; 4A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265 A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW; LALAGA / DW; LALAPG / DW; N297A / YD; / YD; LALAGA / YD; LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVV, LALAGA / QVV; LALAPG / QVV; DDRVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV;LAGA / DDRVV; LALAGA / DDRVV; and LALAPG / DDRVV. In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of: M428L / N434S (LS) and M252Y / S254T / T256E (YTE). In some embodiments, the modified Fc comprises M428L / N434S (LS) modification. In some embodiments, the modified Fc comprises M252Y / S254T / T256E (YTE) modification.

[0105] In some embodiments, the Fc of the α4β7 binding antibody described herein lacks a C-terminal lysine residue (e.g., Ab001), and the lack of this residue is expected to reduce pI. In some embodiments, compositions containing α4β7 binding antibodies (where the Fc lacks a C-terminal lysine residue) (e.g., Ab001) have a more uniform charge distribution compared to compositions containing α4β7 binding antibodies (where the Fc contains a C-terminal lysine residue). While the lack of a C-terminal lysine residue is expected to reduce solubility or recombinant production yield, it has been found that truncation of the C-terminal lysine in α4β7 binding antibodies results in highly soluble proteins and allows for relatively high yields of α4β7 binding antibodies. In particular, Ab001 achieves surprisingly high yields (greater than 4.5 g / L) and high solubility (greater than 150 g / L).

[0106] In some embodiments, the method provided herein can enhance FcRn binding, wherein the α4β7 binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising the amino acid sequence according to SEQ ID NO: 3 (e.g., Ab001), while exhibiting satisfactory bioavailability when the α4β7 binding antibody is administered subcutaneously.

[0107] In some embodiments, the α4β7 binding antibodies described herein contain modifications to enhance their ability to mediate effector function. Such modifications are known in the art and include fucosylation-free modification or engineering of Fc affinity for activating receptors (primarily FCGR3a, for antibody-dependent cytotoxicity (ADCC)) and for C1q (for complement-dependent cytotoxicity (CDC)).

[0108] In some respects, the antibodies presented herein comprise an IgG1 domain with a reduced fucose content at position Asn 297 (EU number) compared to the naturally occurring IgG1 domain. Such Fc domains are known to have improved ADCC. In some respects, such antibodies do not contain any fucose at position Asn 297.

[0109] In some embodiments, the α4β7 binding antibody provided herein comprises a glycan moiety. In some embodiments, the α4β7 binding antibody provided herein comprises an IgG1 domain having a high total fucose content. The predominant N-glycan types are G0F and G1F. In some embodiments, the α4β7 binding antibody disclosed herein has one or more of the following N-glycan performance analyses: The proportion of G0F can be greater than approximately 40%. For example, the proportion of G0F can range from approximately 40% to approximately 75%. The proportion of G1F can range from about 10% to about 35%; the proportion of Man5 can be less than about 20%.

[0110] In some embodiments, the proportion of Man5 may be in the range of about 1% to about 15%. In some embodiments, the proportion of G0F in the α4β7 binding antibody is about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, and about 70% to about 75%.

[0111] In some embodiments, the proportion of G1F in the α4β7 binding antibody is about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, or about 30% to about 35%.

[0112] In some embodiments, the proportion of Man5 in the α4β7 binding antibody is about 1% to about 5%, about 5% to about 10%, or about 10% to about 15%.

[0113] In some embodiments, the α4β7 binding antibody described herein comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, the antibody provided herein comprises an Fc region having one or more amino acid substitutions at positions 239, 332, and 330.

[0114] In some embodiments, the α4β7-binding antibody described herein comprises an Fc region to which at least one galactose residue of the oligosaccharide is attached. Such antibody variants may have improved CDC function.

[0115] In some embodiments, the α4β7 binding antibody described herein comprises one or more alterations that improve or reduce C1q binding and / or CDC.

[0116] In some embodiments, the Fc region contains one or more amino acid substitutions, wherein said one or more substitutions result in an increase in one or more of the antibody half-life, ADCC activity, ADCP activity, or CDC activity compared to an Fc region without said one or more substitutions. In some embodiments, said one or more amino acid substitutions result in an increase in the antibody half-life at pH 6.0 compared to an antibody containing a wild-type Fc region. In some embodiments, the antibody has a half-life that is approximately 10,000, 1,000, 500, 100, 50, 20, 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1, or 1.05 times longer than that of an antibody containing the wild-type Fc region.

[0117] In some embodiments, the Fc region contains one or more amino acid substitutions, wherein the one or more substitutions result in a reduction of one or more of ADCC activity, ADCP activity, or CDC activity compared to an Fc without the one or more substitutions.

[0118] In some embodiments, the Fc region binds to FcγR receptors selected from the group consisting of: FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In some embodiments, the Fc region binds to the FcγR receptor with higher affinity at pH 6.0 compared to antibodies containing the wild-type Fc region.

[0119] In some embodiments, the α4β7 binding antibody described herein comprises an extended half-life (i.e., serum half-life). In some embodiments, the α4β7 binding antibody described herein comprises a half-life of at least about 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 94, 96 days or greater than 96 days in human vivo. In some embodiments, the α4β7 binding antibody described herein has a half-life in the human body ranging from about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 days to about 56 days, about 28 days to about 42 days, about 35 days to about 96 days, about 35 days to about 84 days, about 35 days to about 70 days, about 35 days to about 56 days, about 35 days to about 42 days, about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, the α4β7 binding antibody described herein has a half-life in the human body ranging from about 42 days to about 56 days. In some embodiments, the α4β7 binding antibody described herein has a half-life of at least about 50 days in the human body. In some embodiments, the α4β7 binding antibody described herein has a half-life of approximately 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 days or more in the human body.

[0120] In some embodiments, the α4β7 binding antibody described herein has a half-life of about 10 to 25 days, about 17 to 23 days, and about 20 to 22 days in non-human primates (NHP). In some embodiments, the NHP is the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 11 to 23 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 17 to 23 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 19 to 23 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 20 to 23 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 17 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 20 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of about 22 days in the cynomolgus monkey. In some embodiments, the α4β7 binding antibody described herein has a half-life of approximately 5 to approximately 15 days or approximately 10 to 12 days in transgenic mice expressing the human neonatal Fc receptor (hFcRn). In some embodiments, the transgenic mice expressing hFcRn are Tg276 mice. In some embodiments, the α4β7 binding antibody described herein has a half-life of approximately 12 days in Tg276 mice.

[0121] Methods for measuring half-life are known in the art. In some embodiments, half-life is measured in rodent models such as Tg276 mice. In some embodiments, half-life is measured in non-human primates such as cynomolgus monkeys. Other animals may also be used to measure the pk-pk ratio of α4β7-binding antibodies. In some embodiments, half-life is measured in humans. In some embodiments, half-life is measured after intravenous administration. In some embodiments, half-life is measured after subcutaneous administration.

[0122] In some embodiments, the α4β7 binding antibody described herein has a half-life at least 20% longer than that of the comparative antibody. In some embodiments, the comparative antibody comprises the same complementarity-determining region and variable region but different Fc regions. In some embodiments, the half-life of the α4β7 binding antibody protein described herein is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, or at least 350% longer than that of the comparative antibody. In some embodiments, the half-life of the α4β7 binding antibody described herein is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 times longer than that of the comparative antibody.

[0123] In some embodiments, the α4β7 binding antibody described herein is present at a concentration of less than or equal to 20 nM, 15 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, 90 pM, 80 pM, 70 pM, 60 pM, 50 pM, 40 pM, 30 pM, 20 pM, or 10 pM. D Combined with α4β7. For example, in some embodiments, the first antigen binding site is at a concentration of about 10 pM to about 1 nM, about 10 pM to about 0.9 nM, about 10 pM to about 0.8 nM, about 10 pM to about 0.7 nM, about 10 pM to about 0.6 nM, about 10 pM to about 0.5 nM, about 10 pM to about 0.4 nM, about 10 pM to about 0.3 nM, about 10 pM to about 0.2 nM, about 10 pM to about 0.1 nM, about 10 pM to about 50 pM, 0.1 nM to about 10 nM, about 0.1 nM to about 9 nM, about 0.1 nM to about 8 nM, about 0.1 nM to about 7 nM, about 0.1 nM to about 6 nM, about 0.1 nM to about 5 nM, about 0.1 nM to about 4 nM, about 0.1 nM to about 3 nM. nM, approximately 0.1 nM to approximately 2 nM, approximately 0.1 nM to approximately 1 nM, approximately 0.1 nM to approximately 0.5 nM, approximately 0.5 nM to approximately 10 nM, approximately 0.5 nM to approximately 9 nM, approximately 0.5 nM to approximately 8 nM, approximately 0.5 nM to approximately 7 nM, approximately 0.5 nM to approximately 6 nM, approximately 0.5 nM to approximately 5 nM, approximately 0.5 nM to approximately 4 nM, approximately 0.5 nM to approximately 3 nM, approximately 0.5 nM to approximately 2 nM, approximately 0.5 nM to approximately 1 nM, approximately 1 nM to approximately 10 nM, approximately 1 nM to approximately 9 nM, approximately 1 nM to approximately 8 nM, approximately 1 nM to approximately 7 nM, approximately 1 nM to approximately 6 nM, approximately 1 nM to approximately 5 nM, approximately 1 nM to approximately 4 nM, approximately 1 nM to approximately 3 nM, approximately 1 K in the range of nM-approximately 2 nM, approximately 2 nM-approximately 10 nM, approximately 3 nM-approximately 10 nM, approximately 4 nM-approximately 10 nM, approximately 5 nM-approximately 10 nM, approximately 6 nM-approximately 10 nM, approximately 7 nM-approximately 10 nM, approximately 8 nM-approximately 10 nM, or approximately 9 nM-approximately 10 nM DCombined with α4β7. In some embodiments, affinity is measured by SPR. In some embodiments, affinity is measured by BLI. In some embodiments, affinity is measured by KinExA. Treatment methods and dosage regimens

[0124] In some embodiments, this document describes methods for treating a disease or condition in a patient in need, the methods comprising administering an effective amount of the α4β7-binding antibody disclosed herein subcutaneously or intravenously to the patient.

[0125] This article provides a method for treating a disease or condition in a patient in need, the method comprising administering to the patient subcutaneously one or more initial doses (also referred to herein as “induction dose”, “induction regimen”, or “induction therapy”) containing an effective amount of α4β7 binding antibody and one or more subsequent doses (also referred herein as “maintenance dose”) containing an effective amount of α4β7 binding antibody.

[0126] This document also provides a method for treating a disease or condition in a patient in need, the method comprising administering intravenously to the patient one or more initial doses (also referred to herein as “induction dose,” “induction regimen,” or “induction therapy”) containing an effective amount of α4β7-binding antibody and one or more subsequent doses (also referred herein as “maintenance dose”) containing an effective amount of α4β7-binding antibody. As used herein, “maintenance dose,” “maintenance regimen,” and “maintenance therapy” are used interchangeably and are administered after the induction dose to continue the response achieved by the induction dose of α4β7-binding antibody.

[0127] In some embodiments, one or more induction doses are administered, followed by a maintenance dose. This disclosure envisions one, two, three, or more induction doses. The induction doses may be administered intravenously or subcutaneously.

[0128] Induction dosing may involve administering a higher dose (higher than the maintenance dose), more frequent (more frequent than the maintenance dose), or both of the α4β7 binding antibody, for example, if it may be twice the maintenance dose. Alternatively, the induction dose may be the same as the maintenance dose.

[0129] In some embodiments, one or more induction doses are greater than the maintenance dose. In some embodiments, the method includes administering a single induction dose greater than the maintenance dose. For example, the induction dose may be 1.5, 2, 3, 4, or 5 times the maintenance dose. Alternatively, one or more induction doses may be the same as the maintenance dose. In some embodiments, one or more induction doses are administered subcutaneously to a patient in need. However, in other embodiments, one or more induction doses are administered intravenously. In some embodiments, the induction dose may need to be administered via one or more subcutaneous injections or infusions on the same day.

[0130] In some embodiments, the method includes administering one or more induction doses, wherein the induction dose is the same as or greater than the maintenance dose and / or administered at a frequency greater than that of the maintenance dose. For example, the method includes administering one, two, three, or four induction doses of the α4β7 binding antibody. In some embodiments, a first dose is administered on day 0, and a second dose is administered on subsequent days (e.g., from day 1 through week 6, such as days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42). In some embodiments, one or more induction doses may require one or more subcutaneous injections or one or more infusions on the same day.

[0131] In some embodiments, the total inducing dose corresponding to the sum of one or more administrations is about 400 mg to about 1000 mg of α4β7-binding antibody. In some embodiments, the total inducing dose corresponding to the sum of one or more administrations is about 500 mg to about 1200 mg of α4β7-binding antibody. In some embodiments, the total dose is about 400 mg of α4β7-binding antibody. In some embodiments, the total dose is about 500 mg of α4β7-binding antibody. In some embodiments, the total dose is about 600 mg of α4β7-binding antibody. In some embodiments, the total dose is about 700 mg of α4β7-binding antibody. In some embodiments, the dose is about 800 mg of α4β7-binding antibody. In some embodiments, the total dose is about 900 mg of α4β7-binding antibody. In some embodiments, the total dose is about 1000 mg of α4β7-binding antibody. In some embodiments, the total dose is about 1100 mg of α4β7-binding antibody. In some embodiments, the total dose is about 1200 mg of α4β7-binding antibody.

[0132] In some embodiments, one or more induction doses are administered subcutaneously to a patient in need. However, in other embodiments, one or more induction doses are administered intravenously.

[0133] In some embodiments, the maintenance regimen comprises a lower dose and / or longer intervals than the induction regimen. In some embodiments, a maintenance dose is administered every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26 weeks or more. In some embodiments, an induction dose of the α4β7 binding antibody is administered subcutaneously on day zero, and a maintenance dose is subsequently administered every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26 weeks or more.

[0134] In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 150 mg to about 1200 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 300 mg to about 900 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 300 mg to about 400 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 400 mg to about 500 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 500 mg to about 600 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 600 mg to about 700 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 700 mg to about 800 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 800 mg to about 900 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 900 mg to about 1000 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 1000 mg to about 1100 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 1100 mg to about 1200 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 150 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 200 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, one or more inducing doses of α4β7-binding antibody, ranging from about 250 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, about 300 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 350 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 400 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 450 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 500 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0.In some embodiments, about 550 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 600 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 650 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 700 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 750 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 800 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 850 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, about 900 mg of one or more inducing doses of α4β7 binding antibody is administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of about 950 mg of α4β7-binding antibody are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of about 1000 mg of α4β7-binding antibody are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of about 1050 mg of α4β7-binding antibody are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of about 1100 mg of α4β7-binding antibody are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of about 1150 mg of α4β7-binding antibody are administered intravenously or subcutaneously on day 0. In some embodiments, one or more induction doses of about 1200 mg of α4β7-binding antibody are administered subcutaneously. In some embodiments, one or more induction doses are administered subcutaneously.

[0135] In some embodiments, the method includes administering two or more induction doses, wherein a first induction dose is greater than a second induction dose, and wherein the two or more induction doses are administered at a frequency greater than that of a maintenance dose. In some embodiments, the first induction dose is greater than both the second induction dose and the maintenance dose, and the second induction dose is the same as or greater than the maintenance dose. In some embodiments, one or more induction doses of α4β7-binding antibody, ranging from about 150 mg to about 1200 mg, are administered intravenously or subcutaneously on day 0. In some embodiments, the method includes administering an α4β7-binding antibody at a first induction dose greater than the second induction dose (e.g., about 600 mg of the first induction dose) intravenously or subcutaneously on day 0, administering a second induction dose (e.g., about 150 mg of the second induction dose) of α4β7-binding antibody on day 14, and thereafter administering a maintenance dose (e.g., about 150 mg) equal to or less than the second induction dose every two weeks. In one example, the induction dose is about 600 mg / mL at week 0 and about 300 mg / mL at week 2, wherein the maintenance dose is about 300 mg / mL every 8 to 12 weeks after the second induction dose. In one example, the induction dose was approximately 600 mg / mL at week 0, approximately 300 mg / mL at week 2, and approximately 300 mg / mL at week 6. In some embodiments, administration of the induction dose may result in plasma or serum C avgW0-W6 The concentration is at least about 65 µg / mL, for example, about 65 µg / mL to about 75 µg / mL or greater, about 65 µg / mL, about 70 µg / mL, about 75 µg / mL or more. In some embodiments, administration of the induction dose may result in plasma or serum C... avgW0-W6 The concentration is approximately 70 µg / mL. In some embodiments, administration of the induction dose may result in plasma or serum C... avgW0-W12 The concentration is at least about 60 µg / mL, for example, about 60 µg / mL to about 70 µg / mL or greater, about 60 µg / mL, about 65 µg / mL, about 70 µg / mL or more. In some embodiments, administration of the inducing dose may result in plasma or serum C... avgW0-W12 The concentration is approximately 65 µg / mL. A maintenance dose may be approximately 300 mg / mL, administered at least every 8 weeks, such as every 12 weeks or every 24 weeks, following the final induction dose. In some embodiments, administration of the induction dose may result in plasma or serum C... avgW30-W40 It is at least about 30 µg / mL, for example about 30 µg / mL, about 40 µg / mL, about 50 µg / mL, about 60 µg / mL, about 70 µg / mL or more.

[0136] In some embodiments, when an effective amount of the α4β7 binding antibody is administered during the induction phase, a plasma or serum concentration of at least about 35 µg / mL (e.g., 35 to 40 µg / mL, 40 to 45 µg / mL, 45 to 50 µg / mL, 50 to 55 µg / mL, 55 to 60 µg / mL, e.g., 36 µg / mL, 41 µg / mL, 46 µg / mL, 51 µg / mL, 56 µg / mL, 60 µg / mL or higher) is achieved in the patient and sustained for at least 4, at least 8, at least 12, at least 16, at least 20, at least 24 weeks or longer (e.g., 4 to 6 weeks, 6 to 8 weeks, 8 to 10 weeks, 10 to 12 weeks, 12 to 14 weeks, 14 to 16 weeks, 16 to 18 weeks, 18 to 20 weeks, 20 to 22 weeks, 22 to 24 weeks or longer) is achieved in the patient.

[0137] In some embodiments, a mean plasma or serum concentration of at least about 35 µg / mL (e.g., 35 to 40 µg / mL, 40 to 45 µg / mL, 45 to 50 µg / mL, 50 to 55 µg / mL, 55 to 60 µg / mL, e.g., 36 µg / mL, 41 µg / mL, 46 µg / mL, 51 µg / mL, 56 µg / mL, 60 µg / mL or higher) is achieved in the patient during the induction period. In some embodiments, a mean plasma or serum concentration of at least about 45 µg / mL is achieved in the patient during the induction period. In some embodiments, a mean plasma or serum concentration of at least about 60 µg / mL is achieved in the patient during the induction period.

[0138] In some embodiments, a maintenance dose of the α4β7-binding antibody is administered subcutaneously for at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks or longer (e.g., 4 to 6 weeks, 6 to 8 weeks, 8 to 10 weeks, 10 to 12 weeks, 12 to 14 weeks, 14 to 16 weeks, 16 to 18 weeks, 18 to 20 weeks, 20 to 22 weeks, 22 to 24 weeks or longer) after administration of the final induction dose. In some embodiments, the maintenance dose is lower than the induction dose (e.g., half, one-third, or less of the induction dose). In some embodiments, the maintenance dose is the same as the induction dose. In some embodiments, a maintenance dose of α4β7-binding antibody is administered subcutaneously every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26 weeks or more. In some embodiments, a maintenance dose of α4β7-binding antibody is administered subcutaneously every 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26 weeks or more. In some embodiments, the maintenance dose comprises an effective amount of α4β7-binding antibody. In some embodiments, the maintenance dose comprises about 150 mg to about 300 mg of α4β7-binding antibody. In some embodiments, the minimum effective serum or plasma concentration of α4β7-binding antibody is achieved when the maintenance dose is administered. In some embodiments, upon administration of the α4β7 binding antibody, a plasma or serum concentration of at least about 6 µg / mL (e.g., about 6 µg / mL to about 10 µg / mL, about 6 µg / mL to about 20 µg / mL, about 6 µg / mL to about 30 µg / mL, e.g., 6 µg / mL, 10 µg / mL, 15 µg / mL, 20 µg / mL, 30 µg / mL or higher) is achieved in the patient for a duration of at least 4, at least 8, at least 12, at least 16, at least 20, at least 24 weeks or longer (e.g., 4 to 6 weeks, 6 to 8 weeks, 8 to 10 weeks, 10 to 12 weeks, 12 to 14 weeks, 14 to 16 weeks, 16 to 18 weeks, 18 to 20 weeks, 20 to 22 weeks, 22 to 24 weeks or longer) is achieved. In some embodiments, the plasma or serum concentration is not lower than 6 µg / mL between maintenance dosing intervals. In some embodiments, the plasma or serum concentration is not less than 10 µg / mL between maintenance dosing intervals. In some embodiments, the plasma or serum concentration is not less than 20 µg / mL between maintenance dosing intervals. In some embodiments, the plasma or serum concentration is not less than 30 µg / mL between maintenance dosing intervals.

[0139] In some embodiments, the method includes subcutaneously administering one or more induction doses of α4β7-binding antibody to a subject in need, and subcutaneously administering one or more maintenance doses of α4β7-binding antibody to a subject in need. In some embodiments, the amount of α4β7-binding antibody contained in the induction dose is about two or more times that of the maintenance dose. In some embodiments, the induction dose contains about 150 mg to about 1200 mg of α4β7-binding antibody. For example, the induction dose contains about 400 mg to about 600 mg of α4β7-binding antibody and the maintenance dose contains about 150 mg to about 300 mg of α4β7-binding antibody. In another example, the induction dose contains about 400 mg of α4β7-binding antibody, and the maintenance dose contains about 200 mg of α4β7-binding antibody. In some embodiments, the induction dose contains about 500 mg to about 1200 mg of α4β7-binding antibody. For example, in some embodiments, the induction dose contains about 600 mg of α4β7-binding antibody and the maintenance dose contains about 300 mg of α4β7-binding antibody. In another example, the induction dose comprises about 1000 mg of α4β7-binding antibody and the maintenance dose comprises about 300 mg of α4β7-binding antibody. In some embodiments, one or more induction doses comprise about 150 mg to about 1200 mg of α4β7-binding antibody as a total dose. For example, the induction dose comprises one or more induction doses comprising about 400 mg to about 600 mg of α4β7-binding antibody as a total dose, and the maintenance dose comprises about 150 mg to about 300 mg of α4β7-binding antibody. In another example, one or more induction doses comprise about 400 mg of α4β7-binding antibody as a total dose, and the maintenance dose comprises about 200 mg of α4β7-binding antibody. In some embodiments, one or more induction doses comprise about 500 mg to about 1200 mg of α4β7-binding antibody as a total dose. In another example, one or more induction doses comprise about 600 mg of α4β7-binding antibody as a total dose, and the maintenance dose comprises about 300 mg of α4β7-binding antibody. In another instance, one or more induction doses contain a total dose of approximately 1000 mg of α4β7-binding antibody and a maintenance dose contains approximately 300 mg of α4β7-binding antibody.

[0140] In some embodiments, an effective minimum mean serum or plasma concentration of α4β7-binding antibody is achieved during the induction period when one or more induction doses are administered. In some embodiments, a mean serum or plasma concentration of at least about 35 µg / mL of α4β7-binding antibody is achieved in a patient during the induction period, for example, 36 µg / mL. In some embodiments, a serum or plasma concentration of at least about 35 µg / mL of α4β7-binding antibody is achieved in a patient when the induction dose is administered, sustained for at least 12 weeks or longer. In some embodiments, a serum or plasma concentration of at least about 6 µg / mL of α4β7-binding antibody (e.g., about 6 µg / mL to about 10 µg / mL, about 6 µg / mL to about 20 µg / mL, about 6 µg / mL to about 30 µg / mL, such as 6 µg / mL, 10 µg / mL, 15 µg / mL, 20 µg / mL, 30 µg / mL or higher) is achieved in a patient when the maintenance dose is administered, sustained for at least 12 weeks. In some embodiments, when a maintenance dose is administered, a serum or plasma concentration of at least about 10 µg / mL of α4β7-binding antibody is achieved in the patient for at least 12 weeks.

[0141] In some embodiments, this document further describes a method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering about 108 mg or about 300 mg of an α4β7-binding antibody to the patient, wherein the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing an amino acid sequence according to SEQ ID NO: 3; and wherein a plasma or serum concentration of at least about 35 µg / mL of the α4β7-binding antibody is achieved in the patient at the time of administration for at least 2 weeks or longer.

[0142] In some embodiments, a method of treating a disease or condition in a patient in need includes subcutaneously administering one or more induction doses and one or more maintenance doses of an α4β7-binding antibody to the patient, wherein the α4β7-binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain comprising an amino acid sequence according to SEQ ID NO: 3; and wherein a mean serum or plasma concentration of at least about 60 µg / mL of the α4β7-binding antibody is achieved in the patient during the induction period, and wherein a serum or plasma concentration of at least about 10 µg / mL of the α4β7-binding antibody is achieved in the patient upon administration of the maintenance dose for at least 12 weeks.

[0143] In some embodiments, an average plasma or serum concentration of at least about 35 µg / mL, for example about 35 to about 60 µg / mL, was achieved in patients during the induction period.

[0144] In some embodiments, plasma or serum concentrations of at least about 35 µg / mL are achieved in patients upon administration of one or more induction doses, lasting for at least 2 weeks or longer. In some embodiments, plasma or serum concentrations of at least about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 48, 59, 60, or greater than 60 µg / mL are achieved in patients upon administration of one or more induction doses, lasting for at least 2 weeks or longer.

[0145] In some embodiments, upon administration of one or more induction doses and / or one or more maintenance doses of the α4β7-binding antibody, plasma or serum concentrations of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL are achieved in patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more induction doses and / or one or more maintenance doses of the α4β7-binding antibody, plasma or serum concentrations of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 100, 150, or greater than 150 µg / mL are achieved in patients for at least 4 weeks or longer. In some embodiments, upon administration of one or more induction doses and / or one or more maintenance doses of the α4β7-binding antibody, plasma or serum concentrations of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 100, 150, or greater than 150 µg / mL are achieved in patients for at least 6 weeks or longer. In some embodiments, upon administration of one or more induction doses and / or one or more maintenance doses of the α4β7-binding antibody, plasma or serum concentrations of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 100, 150, or greater than 150 µg / mL are achieved in patients for at least 8 weeks or longer. In some embodiments, when one or more induction doses and / or one or more maintenance doses of the α4β7 binding antibody are administered, plasma or serum concentrations of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 100, 150 or greater than 150 µg / mL are achieved in patients for at least 10 weeks or longer.

[0146] In some embodiments, upon administration of one or more inducing doses of the α4β7 binding antibody, a plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 80% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more inducing doses of the α4β7 binding antibody, a plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 85% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more inducing doses of the α4β7 binding antibody, a plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 90% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more inducing doses of the α4β7 binding antibody, a plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 95% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more inducing doses of the α4β7 binding antibody, a plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 99% of patients for at least 2 weeks or longer.

[0147] In some embodiments, upon administration of one or more induction doses, a plasma or serum concentration of at least about 60 µg / mL is achieved in at least about 80% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more induction doses, a plasma or serum concentration of at least about 60 µg / mL is achieved in at least about 85% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more induction doses, a plasma or serum concentration of at least about 60 µg / mL is achieved in at least about 90% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more induction doses, a plasma or serum concentration of at least about 60 µg / mL is achieved in at least about 95% of patients for at least 2 weeks or longer. In some embodiments, upon administration of one or more induction doses, a plasma or serum concentration of at least about 60 µg / mL is achieved in at least about 99% of patients for at least 2 weeks or longer.

[0148] In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 80% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 85% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 90% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 95% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 35 µg / mL was achieved in at least about 99% of patients.

[0149] In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 60 µg / mL was achieved in at least about 80% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 60 µg / mL was achieved in at least about 85% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 60 µg / mL was achieved in at least about 90% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 60 µg / mL was achieved in at least about 95% of patients. In some embodiments, during the induction period, a mean plasma or serum concentration of at least about 60 µg / mL was achieved in at least about 99% of patients.

[0150] In some embodiments, this document further describes a method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering to the patient about 75 mg to about 300 mg of an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing an amino acid sequence according to SEQ ID NO: 3; and wherein a maintenance concentration of at least about 6 µg / mL of α4β7-binding antibody is achieved in the patient at the time of administration. 谷 The duration is at least 2 weeks or longer. In some embodiments, the α4β7 antibody is a long-acting engineered α4β7-binding antibody consisting of a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 and a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In other embodiments, the dosage and frequency of administration provide a sustained maintenance C of at least about 6 µg / mL of α4β7-binding antibody in the patient at the time of administration. 谷The dosing frequency is no higher than once every 4 weeks, or alternatively once every 8 weeks, or alternatively once every 12 weeks, or alternatively once every 16 weeks, or alternatively once every 26 weeks. In the examples, the dose is sufficient for annual (Q52) dosing. In other examples, the dose and frequency of administration provide a sustained C-level of at least about 10 µg / mL of α4β7-binding antibody in the patient at the time of administration. 谷 The dosing frequency is no more than once every 4 weeks, or alternatively once every 8 weeks, or alternatively once every 12 weeks, or alternatively once every 16 weeks, or alternatively once every 26 weeks. The method can be administered intravenously (IV) or subcutaneously (SC), or both (one or more IV induction doses and one or more SC maintenance doses); a particular advantage of this disclosure is that it provides subcutaneous administration of both the induction and maintenance doses.

[0151] In some embodiments, a maintenance concentration of at least about 6 µg / mL (e.g., 10 µg / mL) was achieved in patients when one or more maintenance doses were administered. 谷 In some embodiments, at the time of administration, a maintenance concentration of at least about 2, 4, 6, 8, 10, 12, 14, 16, or greater than 16 µg / mL was achieved in patients. 谷 This lasts for at least two weeks or longer. In some embodiments, at the time of administration, a maintenance concentration of at least about 2, 4, 6, 8, 10, 12, 14, 16, or greater than 16 µg / mL was achieved in patients. 谷 This lasts for at least 4 weeks or longer. In some embodiments, at the time of administration, a maintenance concentration of at least about 2, 4, 6, 8, 10, 12, 14, 16, or greater than 16 µg / mL was achieved in patients. 谷 The maintenance effect lasts for at least 6 weeks or longer. In some embodiments, at the time of administration, a maintenance effect of at least about 2, 4, 6, 8, 10, 12, 14, 16, or greater than 16 µg / mL is achieved in patients, lasting for at least 8 weeks or longer. In some embodiments, at the time of administration, a maintenance effect of at least about 2, 4, 6, 8, 10, 12, 14, 16, or greater than 16 µg / mL is achieved in patients. 谷 This should last for at least 10 weeks or longer.

[0152] In some embodiments, at the time of administration, a maintenance concentration of at least about 6 µg / mL was achieved in at least about 80% of patients. 谷 This lasts for at least two weeks or longer. In some embodiments, a maintenance concentration of at least about 6 µg / mL was achieved in at least about 85% of patients at the time of administration. 谷This lasts for at least two weeks or longer. In some embodiments, a maintenance concentration of at least about 6 µg / mL was achieved in at least about 90% of patients at the time of administration. 谷 This lasts for at least two weeks or longer. In some embodiments, a maintenance concentration of at least about 6 µg / mL was achieved in at least about 95% of patients at the time of administration. 谷 This lasts for at least 2 weeks or longer. In some embodiments, a maintenance concentration of at least about 6 µg / mL was achieved in at least about 99% of patients at the time of administration. 谷 This will last for at least two weeks or longer.

[0153] In some embodiments, a concentration of at least about 30 µg / mL of C was achieved in patients. 6周, 诱导 In some embodiments, a concentration of at least about 35 µg / mL of C was achieved in patients. 6周, 诱导 In some embodiments, a Cg concentration of at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL was achieved in patients. 6周, 诱导 In some embodiments, a Cg concentration of at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL was achieved in patients. 7周, 诱导 In some embodiments, a Cg concentration of at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL was achieved in patients. 8周, 诱导 In some embodiments, a Cg concentration of at least 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL was achieved in patients. 9周, 诱导 In some embodiments, a Cg of at least about 20, 25, 30, 35, 40, 45, 50, 55, 60 or greater than 60 µg / mL was achieved in patients. 10周, 诱导 In some embodiments, a Cg concentration of at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL was achieved in patients. 11周, 诱导 In some embodiments, a Cg concentration of at least about 20, 25, 30, 35, 40, 45, 50, 55, 60, or greater than 60 µg / mL was achieved in patients. 12周, 诱导 .

[0154] In some embodiments, a C concentration of at least about 35 µg / mL was achieved in at least about 80% of patients. 6周, 诱导 In some embodiments, a C concentration of at least about 35 µg / mL was achieved in at least about 85% of patients. 6周, 诱导 In some embodiments, a C concentration of at least about 35 µg / mL was achieved in at least about 90% of patients. 6周, 诱导In some embodiments, a concentration of at least about 35 µg / mL of C was achieved in at least about 95% of patients. 6周, 诱导 In some embodiments, a concentration of at least about 35 µg / mL of C was achieved in at least about 99% of patients. 6周, 诱导 .

[0155] In some embodiments, a C concentration of at least about 60 µg / mL was achieved in at least about 80% of patients. 6周, 诱导 In some embodiments, a concentration of at least about 60 µg / mL of C was achieved in at least about 85% of patients. 6周, 诱导 In some embodiments, a concentration of at least about 60 µg / mL of C was achieved in at least about 90% of patients. 6周, 诱导 In some embodiments, a concentration of at least about 60 µg / mL of C was achieved in at least about 95% of patients. 6周, 诱导 In some embodiments, a concentration of at least about 60 µg / mL of C was achieved in at least about 99% of patients. 6周, 诱导 This article provides a method for achieving 60 µg / mL to 70 µg / mL or greater α4β7 binding antibody C in subjects in need. avgW0-W12 The method comprises administering at least 600 mg of a first dose of an α4β7-binding antibody to the subject of need, wherein the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3.

[0156] In some embodiments, administration leading to C avgW0-W12 The concentration is at least 60 µg / mL. In some embodiments, administration leads to C avgW0-W12 It is approximately 65 µg / mL.

[0157] In some embodiments, administration includes administering a first dose of at least 600 mg of the α4β7 binding antibody to a subject in need, and administering a second dose of at least 300 mg of the α4β7 binding antibody at least two weeks after administering the first dose.

[0158] In some embodiments, the method includes intravenous administration of at least 600 mg of a first dose of α4β7 binding antibody and subcutaneous administration of at least 300 mg of a second dose of α4β7 binding antibody.

[0159] In some embodiments, the method includes a first dose of at least 600 mg of α4β7-binding antibody administered subcutaneously and a second dose of at least 300 mg of α4β7-binding antibody administered subcutaneously.

[0160] In some embodiments, the method further includes administering at least 300 mg of one or more doses of the α4β7 binding antibody to a subject in need at least four weeks after administration of the second dose of the α4β7 binding antibody. In some embodiments, one or more doses of the α4β7 binding antibody are administered subcutaneously.

[0161] In some embodiments, the method includes administering at least 600 mg of α4β7-binding antibody to the subject in need every twenty-six weeks following the administration of a second dose of the α4β7-binding antibody.

[0162] This article provides a method for achieving 65 µg / mL to 75 µg / mL or greater α4β7 binding antibody C in subjects in need. avgW0-W6 The method comprises administering at least 600 mg of a first dose of an α4β7-binding antibody to the subject of need, wherein the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3.

[0163] In some embodiments, administration leading to C avgW0-W6 It is approximately 70 µg / mL. In some embodiments, administration leads to C avgW0-W12 It is approximately 65 µg / mL.

[0164] In some embodiments, the administration includes administering a first dose of at least 600 mg of α4β7 binding antibody to a subject in need, and administering a second dose of at least 300 mg of α4β7 binding antibody at least two weeks after administering the first dose of at least 600 mg of α4β7 binding antibody.

[0165] In some embodiments, the method includes intravenous administration of a first dose of α4β7-binding antibody and subcutaneous administration of a second dose of α4β7-binding antibody.

[0166] In some embodiments, the method includes subcutaneous administration of a first dose and a second dose of the α4β7-binding antibody.

[0167] In some embodiments, the method further includes administering one or more additional doses of at least 300 mg of the α4β7 binding antibody to a subject in need at least four weeks after administering the second dose of the α4β7 binding antibody.

[0168] In some embodiments, the method includes subcutaneous administration of one or more additional doses of the α4β7-binding antibody.

[0169] In some embodiments, the method further includes administering at least 600 mg of α4β7-binding antibody to the subject in need every twenty-six weeks following the administration of a second dose of the α4β7-binding antibody.

[0170] In some embodiments, administration of one or more doses of the α4β7-binding antibody leads to C avg The concentration is 40 µg / mL to 50 µg / mL or greater. In some embodiments, administration of one or more doses of the α4β7-binding antibody results in C... avg It is approximately 45 µg / mL.

[0171] This article provides a C-level assay that achieves 35 µg / mL or greater of the α4β7-binding antibody in subjects six weeks after administration of the antibody to those in need. 谷 The method comprises administering at least 600 mg of the α4β7-binding antibody to the subject in need, wherein the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3.

[0172] In some embodiments, administration of at least 600 mg of α4β7-binding antibody resulted in serum C avgW0-W12 The concentration is at least 60 μg / mL. In some embodiments, administration of at least 600 mg of α4β7-binding antibody results in serum C... avgW30-W40 The concentration should be at least 30 μg / mL.

[0173] In some embodiments, at least 600 mg of α4β7-binding antibody is administered intravenously. In other embodiments, at least 600 mg of α4β7-binding antibody is administered subcutaneously.

[0174] In some embodiments, the method further includes administering about 120 to about 450 mg of α4β7-binding antibody to a subject in need, wherein the administration of about 120 to about 450 mg of α4β7-binding antibody leads to a steady-state C0. 谷 The concentration is at least 6 µg / mL. In some embodiments, the method further includes administering at least 120 mg of α4β7-binding antibody to a subject in need, wherein the administration of at least 120 mg of α4β7-binding antibody results in a steady-state Cg. 谷 The concentration is at least 6 µg / mL. In some embodiments, the method further includes administering at least 300 mg of α4β7-binding antibody to a subject in need, wherein the administration of at least 300 mg of α4β7-binding antibody results in a steady-state Cg. 谷 The concentration is at least 6 µg / mL.

[0175] In some embodiments, the method further comprises administering at least 300 mg of α4β7-binding antibody to a subject in need, resulting in a mean serum concentration of α4β7-binding antibody greater than 35 μg / mL for ten weeks following administration of at least 300 mg of α4β7-binding antibody. In some embodiments, the method results in serum C avgW0-W12 The concentration is at least 60 μg / mL. In some embodiments, administration of at least 300 mg of α4β7-binding antibody results in serum C... avgW30-W40 The concentration should be at least 30 μg / mL.

[0176] In some embodiments, the method further includes administering at least 300 mg of α4β7 binding antibody to a subject in need, resulting in a mean serum concentration of α4β7 binding antibody greater than 35 μg / mL for ten weeks following administration of at least 300 mg of α4β7 binding antibody.

[0177] In some embodiments, the method further includes subcutaneously administering at least 300 mg of α4β7-binding antibody to a subject in need four weeks after the administration of the last dose of the α4β7-binding antibody.

[0178] In some embodiments, the method further includes administering a maintenance dose of at least 600 mg of α4β7-binding antibody subcutaneously to the subject every twenty-six weeks after the administration of the last dose of the α4β7-binding antibody.

[0179] This document provides a multi-dose regimen for use in treating a disease in a subject of need, the multi-dose regimen comprising: a first injectable liquid formulation comprising a total dose of at least 500 mg of α4β7-binding antibody; and a second injectable liquid formulation comprising a total dose of at least 120 mg of α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the second injectable liquid formulation comprises a total dose of about 300 mg of α4β7-binding antibody. In some embodiments, the first injectable liquid formulation is for intravenous administration. In some embodiments, the first injectable liquid formulation is a single-dose or multi-dose formulation. In some embodiments, the second injectable liquid formulation is for subcutaneous administration. In some embodiments, the second injectable liquid formulation is a single-dose or multi-dose formulation.

[0180] This document provides a multi-dose regimen for use in treating a disease in a subject of need, the multi-dose regimen comprising: (a) a first injectable liquid formulation comprising a total dose of at least 500 mg of α4β7-binding antibody; and (b) a second injectable liquid formulation comprising a total dose of at least 300 mg of α4β7-binding antibody, wherein the α4β7-binding antibody comprises: (i) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (ii) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0181] In some embodiments, the first injectable liquid formulation comprises a total dose of about 600 mg of α4β7 binding antibody. In some embodiments, the first injectable liquid formulation comprises a total dose of about 1000 mg of α4β7 binding antibody.

[0182] In some embodiments, the second injectable liquid formulation comprises a total dose of about 300 mg of α4β7 binding antibody.

[0183] In some embodiments, the first injectable liquid formulation is for intravenous administration. In some embodiments, the first injectable liquid formulation is a single-dose or multi-dose formulation. In some embodiments, the second injectable liquid formulation is for subcutaneous administration. In some embodiments, the second injectable liquid formulation is a single-dose or multi-dose formulation.

[0184] This document provides a dosing regimen for use in treating a disease in a subject of need, the dosing regimen comprising: a first formulation for administration to the subject comprising a total dose of at least about 5500 mg of α4β7-binding antibody; and a second formulation for subcutaneous administration to the subject following the first formulation, comprising a total dose of at least about 120 mg of α4β7-binding antibody, and thereafter as a maintenance dose for at least eight weeks following administration of the second formulation, wherein the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a first injectable liquid formulation comprises a total dose of about 500 mg to about 1200 mg of α4β7-binding antibody. In some embodiments, a first injectable liquid formulation comprises a total dose of about 600 mg of α4β7-binding antibody. In some embodiments, the first injectable liquid formulation comprises about 1000 mg of α4β7-binding antibody in total. In some embodiments, the second injectable liquid formulation comprises about 120 mg to about 450 mg of α4β7-binding antibody in total. In some embodiments, the second injectable liquid formulation comprises about 300 mg of α4β7-binding antibody in total. In some embodiments, the second formulation is administered at least two weeks after the first formulation and thereafter as a maintenance dose at least eight weeks after the administration of the second formulation.

[0185] This document provides a dosing regimen for use in treating a disease in a subject in need, the dosing regimen comprising: (a) a first preparation for administration to the subject comprising at least about 600 mg of a total dose of α4β7-binding antibody; and (b) a second preparation for subcutaneous administration to the subject at least two weeks after administration of the first preparation, comprising at least about 300 mg of a total dose of α4β7-binding antibody, and thereafter as a maintenance dose at least eight weeks after administration of the second preparation, wherein the α4β7-binding antibody comprises: (i) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1, and (ii) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0186] In some embodiments, the first formulation is for subcutaneous administration. In other embodiments, the first formulation is for intravenous administration.

[0187] In some embodiments, the first preparation comprises a total dose of about 600 mg of α4β7 binding antibody. In some embodiments, the second preparation comprises a total dose of about 300 mg of α4β7 binding antibody.

[0188] In some embodiments, the first formulation dosing regimen includes a single or multiple injections. In some embodiments, the second formulation dosing regimen includes a single or multiple injections.

[0189] In some embodiments, the first and second formulations are free of citrate. In some embodiments, the first or second formulation or both formulations comprise one or more of the following: histidine; arginine or a salt thereof; ethylenediaminetetraacetic acid (EDTA); and polysorbate 80.

[0190] This document provides an injectable formulation of an α4β7-binding antibody comprising: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3, wherein the α4β7-binding antibody has a mean serum half-life of greater than 6 days in cynomolgus monkeys. In some embodiments, the α4β7-binding antibody has a mean serum half-life of greater than 10 days in cynomolgus monkeys. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3.

[0191] In some embodiments, the mean serum half-life in cynomolgus monkeys is about 17 days or longer. In some embodiments, the mean serum half-life in cynomolgus monkeys is 22 days.

[0192] In some embodiments, the injectable formulation comprises at least about 100 mg / ml, at least about 150 mg / ml, at least about 180 mg / ml, or at least about 200 mg / ml of an α4β7 binding antibody. For example, injectable formulations contain at least about 100 mg / ml to at least 110 mg / ml, at least about 110 mg / ml to at least 120 mg / ml, at least about 120 mg / ml to at least 130 mg / ml, at least about 130 mg / ml to at least 140 mg / ml, at least about 140 mg / ml to at least 150 mg / ml, at least about 150 mg / ml to at least 160 mg / ml, at least about 160 mg / ml to at least 170 mg / ml, at least about 170 mg / ml to at least 180 mg / ml, at least about 180 mg / ml to at least 190 mg / ml, at least about 190 mg / ml to at least 200 mg / ml, at least about 200 mg / ml to at least 210 mg / ml or more of α4β7 binding antibody.

[0193] In some embodiments, the injectable formulation comprises about 600 mg of α4β7-binding antibody. In other embodiments, the injectable formulation comprises about 1000 mg of α4β7-binding antibody.

[0194] In some embodiments, the injectable dosage form is an injectable liquid formulation. In some embodiments, the injectable liquid formulation is citrate-free. In some embodiments, the injectable liquid formulation comprises one or more of the following: histidine; arginine or a salt thereof; ethylenediaminetetraacetic acid (EDTA); and polysorbate 80.

[0195] This document provides a method for treating a disease in a subject in need, the method comprising administering to the subject in need (a) an effective amount of an induction dose of an α4β7-binding antibody, and (b) an effective amount of one or more maintenance doses of the α4β7-binding antibody, wherein the one or more maintenance doses are administered subcutaneously at intervals of at least eight weeks. In some embodiments, the α4β7-binding antibody comprises: (i) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and (ii) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0196] In some embodiments, the effective amount of each of the one or more maintenance doses of the α4β7 binding antibody is at least about 120 mg. In some embodiments, the effective amount of each of the one or more maintenance doses of the α4β7 binding antibody is at least about 300 mg. In some embodiments, the effective amount of the induction dose of the α4β7 binding antibody is about 600 mg. In some embodiments, the effective amount of the induction dose of the α4β7 binding antibody is about 1000 mg. In some embodiments, an effective amount of the induction dose of the α4β7 binding antibody is administered subcutaneously. In some embodiments, the effective amount of the induction dose of the α4β7 binding antibody is administered intravenously. In some embodiments, the one or more maintenance doses are administered subcutaneously at intervals of about 12 weeks. In some embodiments, the one or more maintenance doses are administered subcutaneously at intervals of about 26 weeks. In some embodiments, the dose of the α4β7 binding antibody included in the induction dose is about 2 times or more the dose of each of the one or more maintenance doses.

[0197] In some embodiments, administration of the α4β7-binding antibody follows a biphasic decrease in serum concentration. In some embodiments, repeated administration of the α4β7-binding antibody has no significant effect on clearance (CL) and steady-state volume of distribution (Vss). In some embodiments, pharmacokinetics are unaffected by the patient's disease state.

[0198] In some embodiments, the α4β7 binding antibody provided herein and the α4β7 binding antibody in the regimens, injectable formulations, and methods provided herein have one or more of the following characteristics: (a) The mean serum half-life in cynomolgus monkeys is greater than about 6 days. (b) The mean serum half-life in cynomolgus monkeys was 22 days. (c) The chain-breaking temperature TmOnset is greater than approximately 55°C. (d) The chain-breaking temperature TmOnset is greater than 56.2°C. (e) The proportion of G0F is approximately 55.1% to approximately 60.4%. (f) The proportion of G1F is approximately 16.6% to approximately 18.8%. (g) The proportion of Man5 is approximately 7.3% to approximately 8.8%. (h) Does not induce T cell activation markers CD25 or CD69. (i) Does not result in the release of cytokines at least 6 hours after administration, said cytokines including one or more of IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70 and TNF. (j) Complement-dependent cytotoxicity (CDC) in primary human PBMCs and human β-lymphocytes expressing α4β7 is not induced. (k) Does not induce antibody-dependent cytotoxicity (ADCC) in human NK cells, and (l) Does not affect the inhibitory activity of regulatory T cells expressing α4β7 integrin, wherein the inhibitory activity is measured by the presence of elevated CD71, CD25, Ki67, granzyme B or OX40.

[0199] In some embodiments, methods for treating inflammatory gastrointestinal diseases in patients in need are described herein. As used herein, the term “inflammatory gastrointestinal disease” refers to a gastrointestinal disease involving an inflammatory pathway. For example, inflammatory gastrointestinal diseases include, but are not limited to, inflammatory bowel disease, ulcerative colitis (with or without exposure to anti-tumor necrosis factor (anti-TNF)), Crohn's disease (including fistula Crohn's disease), chronic pouchitis, collagenous gastritis, microscopic or collagenous colitis, colitis (including immune-mediated colitis), and sclerosing cholangitis (including in subjects with underlying inflammatory bowel disease, celiac disease, or ileitis). In other aspects of this disclosure, this article provides methods for treating acute intestinal graft-versus-host disease (aGVHD) (e.g., in subjects undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT)), steroid-refractory acute intestinal graft-versus-host disease (GvHD) (e.g., in subjects undergoing Allo-HSCT), type 1 diabetes (T1D) (e.g., with or without anti-TNF pretreatment), and immune checkpoint inhibitor-associated colitis in subjects with urogenital cancers or melanoma.

[0200] In some embodiments, the disease is an inflammatory gastrointestinal disease. In some embodiments, the disease is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0201] In some embodiments, the subject in need has moderate to severe active ulcerative colitis. The Mayo score is a commonly used index of disease activity in UC. The full Mayo score consists of four parts: rectal bleeding, stool frequency, physician assessment, and endoscopic appearance, each scored from 0 to 3, for a total score of 0 to 12. In some embodiments, the subject in need has a Mayo score of 6 to 12 and an endoscopic score ≥ 2. In some embodiments, administration of an α4β7-binding antibody results in a clinical response defined as a reduction of 3 or more points and 30% in the full Mayo score relative to baseline (or, if the full Mayo score was not performed at the visit, a reduction of 2 or more points and 25% or more in the partial Mayo score relative to baseline), accompanied by a reduction in the rectal bleeding sub-score to 1 or 0. In some embodiments, administration of an α4β7-binding antibody results in clinical remission, for example, a full Mayo score of 2 or lower with no individual sub-score greater than 1. Alternatively, a modified or adapted Mayo score may be used for inclusion and for clinical remission endpoints in UC. According to the modified or adapted Mayo score, clinical remission is defined as: a bowel frequency subscore of 0 or 1 and not greater than baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1 with no fragility.

[0202] In some embodiments, the subjects in need have moderate to severe active Crohn's disease. The Crohn's Disease Activity Index (CDAI) is a commonly used disease activity index in Crohn's disease (CD) and is calculated from eight independent variables. "Clinical remission" in Crohn's disease is defined as a CDAI score of 150 or lower. The American Gastroenterological Association and the European Crohn's Disease and Colitis Organization define CDAI < 150, 250–220, 220–450, and > 450 as reflecting remission, mild disease activity, moderate disease activity, and severe disease activity, respectively. In some embodiments, administration of an α4β7-binding antibody results in a clinical response, defined as a reduction in the CDAI score of ≥ 100 points relative to baseline. In some embodiments, administration of an α4β7-binding antibody results in clinical remission, defined as a CDAI score of 150 or lower.

[0203] In some embodiments, this document describes a method for treating inflammatory bowel disease in a patient in need, the method comprising administering an effective amount of an α4β7-binding antibody subcutaneously or intravenously to the patient, the α4β7-binding antibody comprising: a) a heavy chain comprising an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising an amino acid sequence according to SEQ ID NO: 3.

[0204] In some embodiments, inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0205] In some embodiments, this document describes a method for treating inflammatory bowel disease in a patient in need, the method comprising administering an effective amount of an α4β7-binding antibody subcutaneously or intravenously to the patient, the α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody is a long-acting engineered α4β7-binding antibody consisting of a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 and a light chain comprising the amino acid sequence according to SEQ ID NO: 3.

[0206] In some embodiments, the α4β7 binding antibody is administered at a dose of about 75 mg to about 150 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 150 mg to about 300 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 250 mg to about 750 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 700 mg to about 900 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 400 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 400 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 500 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 700 mg to about 900 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at doses of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg.

[0207] In some embodiments, the α4β7 binding antibody is administered intravenously, intratumorally, intramuscularly, subcutaneously, intralesionally, intraenterically, intracolonally, intrarectally, intrapocketly, or intraperitoneally. In some embodiments, the α4β7 binding antibody is administered via a parenteral route, such as intravenously, intramuscularly, subcutaneously, intraarterially, or intraperitoneally. In some embodiments, the α4β7 binding antibody is administered intravenously or subcutaneously. In some embodiments, the α4β7 binding antibody is administered intravenously. In some embodiments, the α4β7 binding antibody is administered subcutaneously.

[0208] Administration of the α4β7 binding antibody can occur at various intervals. In some embodiments, the α4β7 binding antibody is administered to the patient at least once at intervals of more than 8 weeks. In some embodiments, the interval is about 8 to about 12 weeks. In some embodiments, the interval is about 8 to about 16 weeks. In some embodiments, the interval is about 8 to about 20 weeks. In some embodiments, the interval is about 8 to about 24 weeks. In some embodiments, the interval is about 12 to about 26 weeks. In some embodiments, the interval is about 12 to about 22 weeks. In some embodiments, the interval is about 12 to about 18 weeks. In some embodiments, the interval is about 12 to about 14 weeks. In some embodiments, the interval is about 16 to about 26 weeks. In some embodiments, the interval is about 16 to about 22 weeks. In some embodiments, the interval is about 16 to about 18 weeks. In some embodiments, the interval is about 20 to about 26 weeks. In some embodiments, the interval is about 20 to about 22 weeks. In some embodiments, the interval is about 22 to about 26 weeks. In some embodiments, the interval is about 24 to about 26 weeks. In some embodiments, the interval is about 12 weeks. In some embodiments, the interval is about 14 weeks. In some embodiments, the interval is about 13 weeks. In some embodiments, the interval is approximately 16 weeks. In some embodiments, the interval is approximately 17 weeks. In some embodiments, the interval is approximately 18 weeks. In some embodiments, the interval is approximately 19 weeks. In some embodiments, the interval is approximately 20 weeks. In some embodiments, the interval is approximately 21 weeks. In some embodiments, the interval is approximately 22 weeks. In some embodiments, the interval is approximately 23 weeks. In some embodiments, the interval is approximately 24 weeks. In some embodiments, the interval is approximately 25 weeks. In some embodiments, the interval is approximately 26 weeks. In the embodiments, the dosage is sufficient for annual (Q52) dosing.

[0209] In some embodiments, this document describes a method of treating a disease or condition in a patient in need, the method comprising subcutaneously administering to the patient about 108 mg or about 300 mg of an α4β7-binding antibody every four or six weeks, wherein the α4β7-binding antibody comprises a heavy chain containing an amino acid sequence according to SEQ ID NO: 4 and a light chain containing an amino acid sequence according to SEQ ID NO: 5; and wherein no intermediate subcutaneous administration of the α4β7-binding antibody occurs during the four or six weeks. In some embodiments, the α4β7-binding antibody is administered at doses of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In some embodiments, the α4β7-binding antibody is administered every week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, ten weeks, twelve weeks, fourteen weeks, sixteen weeks, thirteen weeks, sixteen weeks, seven weeks, eight weeks, ten weeks, twelve weeks, fourteen weeks, sixteen weeks, sixteen weeks, thir ...

[0210] In some embodiments, the induction dose comprises about 400 mg to about 1000 mg of α4β7 binding antibody, and the maintenance dose comprises about 150 to about 300 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 600 mg of α4β7 binding antibody, and the maintenance dose comprises about 300 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 1000 mg of α4β7 binding antibody, and the maintenance dose comprises about 300 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 400 mg of α4β7 binding antibody, and the maintenance dose comprises about 200 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 600 mg of α4β7 binding antibody, and the maintenance dose comprises about 600 mg of α4β7 binding antibody.

[0211] In some embodiments, the method includes subcutaneously administering an induction dose of approximately 600 mg of α4β7-binding antibody to the subject at week 0 and subcutaneously administering a maintenance dose of approximately 600 mg of α4β7-binding antibody to the subject at week 26.

[0212] In some embodiments, upon administration of one or more induction doses, a mean serum or plasma concentration of at least about 35 µg / mL of α4β7-binding antibody is achieved in patients during the induction period. In some embodiments, upon administration of one or more maintenance doses, serum or plasma concentrations of at least about 6 µg / mL and at least about 10 µg / mL of α4β7-binding antibody are achieved in patients for at least 2 weeks or longer. Pharmaceutical Composition

[0213] This disclosure is further characterized by pharmaceutical compositions containing a therapeutically effective amount of the α4β7-binding antibody described herein. The compositions can be formulated for use in a variety of drug delivery systems. The compositions may also contain one or more physiologically acceptable excipients or carriers, as suitably formulated. Suitable formulations for use in this disclosure can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th edition, 1985. For a brief overview of drug delivery methods, see, for example, Langer (Science 249:1527-1533, 1990).

[0214] In some embodiments, the pharmaceutical composition is a liquid composition. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the liquid composition is colorless to brown; in some embodiments, the liquid composition is clear to milky white. In some embodiments, the liquid composition contains at least 150 mg / ml, or at least 180 mg / ml, or at least 200 mg / ml of α4β7 binding antibody. In some embodiments, the liquid composition contains about 150 mg / ml to about 160 mg / ml, about 160 mg / ml to about 170 mg / ml, about 170 mg / ml to about 10 mg / ml, about 180 mg / ml to about 190 mg / ml, about 190 mg / ml to about 200 mg / ml or more of α4β7 binding antibody.

[0215] In some embodiments, the pharmaceutical composition may contain formulation materials for altering, maintaining, or preserving, for example, the composition's pH, osmotic pressure, viscosity, transparency, color, isotonicity, odor, sterility, stability, dissolution or release rate, absorption, or permeation. In such embodiments, suitable formulation materials include, but are not limited to, amino acids or their salts (such as glycine, glutamine, asparagine, arginine (e.g., arginine-HCl), histidine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids); fillers (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA), pentiformin (DTPA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); filler monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); colorants, flavorings, and diluents; emulsifiers; and hydrophilic polymers (such as polyvinylpyrrolidone). Low molecular weight peptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerol, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronic, PEG, dehydrated sorbitol esters, polysorbates (such as polysorbate 20, polysorbate 80), triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancers (such as sucrose or sorbitol); tension enhancers (such as alkali metal halides, preferably sodium chloride or potassium chloride, mannitol or sorbitol); delivery media; diluents; excipients and / or adjuvants (see Remington's) Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

[0216] In some embodiments, the pharmaceutical composition is free of citrate. In some embodiments, the pharmaceutical composition may contain nanoparticles, such as polymer nanoparticles, liposomes, or micelles.

[0217] In some embodiments, the pharmaceutical composition may contain a sustained-release or controlled-release formulation. Techniques for formulating sustained-release or controlled-release methods, such as liposome carriers, bio-erosive microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release formulations may include porous polymeric microparticles or semi-permeable polymeric matrices in the form of, for example, molded articles (e.g., membranes or microcapsules). Sustained-release matrices may include polyesters, hydrogels, polylactide, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained-release compositions may also contain liposomes, which may be prepared by any of several methods known in the art.

[0218] Pharmaceutical compositions containing the α4β7 binding antibody disclosed herein may be available in dosage units and may be prepared by any suitable method. The pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), subcutaneous (SC), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal, and rectal administration. In some embodiments, the α4β7 binding antibody disclosed herein is administered intravenously. In some embodiments, the α4β7 binding antibody disclosed herein is administered intravenously or subcutaneously. In a specific embodiment, the α4β7 binding antibody disclosed herein is administered subcutaneously.

[0219] This disclosure relates to injectable formulations of α4β7-binding antibodies. In some embodiments, the α4β7-binding antibody comprises a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody consists of a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the injectable formulation is a liquid preparation. In some embodiments, the liquid preparation comprises one or more of histidine, arginine or a salt thereof, EDTA, and polysorbate 80. In some embodiments, the injectable liquid preparation is free of citrate.

[0220] In some embodiments, a subcutaneous dosage form comprising at least about 150 mg of an α4β7-binding antibody is described herein, the α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the subcutaneous dosage form comprises at least about 300 mg of an α4β7-binding antibody, the α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3.

[0221] In some embodiments, this document provides a subcutaneous dosage form comprising at least about 150 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In some embodiments, this document provides a subcutaneous dosage form comprising at least about 150 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3.

[0222] In some embodiments, this document provides a subcutaneous dosage form comprising at least about 300 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In some embodiments, this document provides a subcutaneous dosage form comprising at least about 300 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3.

[0223] Useful formulations can be prepared using methods known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Components suitable for parenteral administration include: sterile diluents such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates, or phosphates; and tonic agents such as sodium chloride or dextran. In some embodiments, formulations for parenteral administration do not contain citrates.

[0224] For intravenous or subcutaneous administration, suitable carriers include physiological saline, antibacterial water, Cremophor ELTM (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage and should be protected against microbial contamination. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0225] Intravenous or subcutaneous drug delivery formulations may be contained in syringes, pens, or pouches. In some embodiments, the pouch is connected to a channel containing a tube and / or needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation. In some embodiments, the formulation is a liquid formulation. Various devices can be used to deliver liquid formulations via the subcutaneous administration route, including on-body infusion devices, autoinjector devices, pre-filled syringes, and syringes. Typically, administration time depends on volume and device and can range from seconds to minutes.

[0226] These compositions can be sterilized using conventional sterilization techniques or aseptically filtered. The resulting aqueous solution can be packaged for use as is or lyophilized, with the lyophilized formulation combined with a sterile aqueous carrier prior to application.

[0227] The formulation may also contain a polyol that acts as a tonic and can stabilize α4β7-binding antibodies. The amount of polyol added to the formulation may vary depending on the desired isotonicity of the formulation. In some embodiments, aqueous formulations are isotonic. The amount of polyol added may also vary depending on the molecular weight of the polyol. For example, a lower amount of monosaccharide (e.g., mannitol) may be added compared to a disaccharide (such as trehalose). In some embodiments, the polyol used as a tonic in the formulation is mannitol.

[0228] Detergents or surfactants may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g., polysorbate 20, 80, etc.) or poloxamers (e.g., poloxamer 188). The amount of detergent added is such that it reduces the aggregation of the formulated antibody and / or minimizes the formation of particles in the formulation and / or reduces adsorption. In some embodiments, the formulation may contain a surfactant, which is a polysorbate. In some embodiments, the formulation may contain the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) dehydrated sorbitan monooleate (see Fiedler, Lexikon der Hifsstoffe [Dictionary of Additives], Editio Cantor Verlag Aulendorf [Elendor Cantor Publishers], 4th edition, 1996).

[0229] In embodiments, the protein product disclosed herein is formulated as a liquid preparation. In some embodiments, the liquid preparation is prepared in combination with a stable level of sugar. In some embodiments, the liquid preparation is prepared in an aqueous carrier. In some embodiments, the amount of stabilizer added is not greater than an amount that would result in an undesirable or unsuitable viscosity for intravenous administration. In some embodiments, the sugar is a disaccharide, such as sucrose. In some embodiments, the liquid preparation may also contain one or more of a buffer, a surfactant, and a preservative.

[0230] In some embodiments, the pH of the liquid formulation is set by adding a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide. In some embodiments, the pH of the liquid formulation is about 3.5 to 9, 5.5 to 6.5, for example 6.0. In some embodiments, the pH of the liquid formulation is about 6.

[0231] The aqueous carriers of interest in this article are pharmaceutically acceptable (safe and non-toxic to humans) and suitable for the preparation of liquid formulations. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), pH buffers (e.g., phosphate-buffered saline), sterile saline solutions, Ringer's solution, or dextran solution.

[0232] Preservatives may optionally be added to the formulations described herein to reduce bacterial activity. The addition of preservatives may, for example, facilitate the production of formulations intended for multiple use (multiple doses).

[0233] The α4β7-binding antibody can be lyophilized to produce a lyophilized formulation containing a protein and a lyophilization protectant. The lyophilization protectant can be a sugar, such as a disaccharide. In some embodiments, the lyophilization protectant is sucrose or maltose. The lyophilized formulation may also contain one or more of a buffer, surfactant, filler, and / or preservative.

[0234] The amount of sucrose or maltose used to stabilize the lyophilized pharmaceutical product may be at least 1:2 in weight ratio of protein to sucrose or maltose. In some embodiments, the weight ratio of protein to sucrose or maltose is 1:2 to 1:5. In some embodiments, the pH of the formulation is set by adding a pharmaceutically acceptable acid and / or base prior to lyophilization. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0235] In some embodiments, the α4β7 binding antibody is administered at a dose of about 75 mg to about 150 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 250 mg to about 750 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 700 mg to about 900 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 600 mg to about 1200 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 400 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 400 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg to about 500 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 500 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg or more. In some embodiments, the α4β7-binding antibody is administered at a dose of about 300 mg. The actual dose level of the active ingredient in the pharmaceutical compositions disclosed herein may be about 250 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg, in order to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and administration method without toxicity to the patient.

[0236] The specific dose can be a uniform dose per patient, i.e., approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, or more of α4β7 binding antibody. Alternatively, the dose can be customized for each patient based on their approximate weight or surface area. Other factors in determining the appropriate dose may include the disease or symptom to be treated or prevented, the severity of the disease, the route of administration, and the patient's age, sex, and medical condition. Further refinement of the calculations required to determine the appropriate therapeutic dose is routinely performed by those skilled in the art, particularly in accordance with the dosing information and assays disclosed herein. The dose can also be determined using known assays used to determine the dose used in conjunction with appropriate dose-response data. The dose can be adjusted for individual patients as the progression of the disease is monitored. Blood levels of targetable constructs or complexes can be measured in patients to determine whether dose adjustments are needed to achieve or maintain effective concentrations. Pharmacogenomics can be used to determine which targetable constructs and / or complexes and their doses are most likely to be effective for a given individual (Schmitz et al., Clinica Chimica Acta 308: 43-53, 2001; Steimer et al., Clinica Chimica Acta 308:33-41, 2001). medicine box

[0237] This article provides a kit for treating a disease in a subject in need, the kit comprising: (a) an injectable liquid formulation containing an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3; and (b) instructions for administering about 500 mg to about 1200 mg of the α4β7-binding antibody, instructions for administering about 120 mg to about 450 mg of the α4β7-binding antibody at least two weeks after administering about 500 mg to about 1200 mg of the α4β7-binding antibody, and instructions for administering about 120 mg to about 450 mg of the α4β7-binding antibody at least four weeks thereafter. In some embodiments, the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0238] This article provides a kit for treating a disease in a subject in need, the kit comprising: (a) an injectable liquid formulation containing an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3; and (b) instructions for administering at least 600 mg of the α4β7-binding antibody, administering at least 300 mg of the α4β7-binding antibody at least two weeks after administering the 600 mg of the α4β7-binding antibody, and administering at least 300 mg of the α4β7-binding antibody at least four weeks thereafter. In some embodiments, the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3.

[0239] This article provides a kit for treating a disease in a subject in need, the kit comprising: (a) an injectable subcutaneous liquid formulation containing an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3; and (b) instructions for subcutaneous administration of at least 600 mg of the α4β7-binding antibody, subcutaneous administration of at least 300 mg of the α4β7-binding antibody at least two weeks after administration of the 600 mg α4β7-binding antibody, and subcutaneous administration of at least 300 mg of the α4β7-binding antibody at least four weeks thereafter. In some embodiments, the α4β7-binding antibody comprises a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Preparation method

[0240] The aforementioned α4β7 binding antibody can be prepared using recombinant DNA techniques well known to those skilled in the art. For example, one or more isolated polynucleotides encoding the α4β7 binding antibody can be linked to other suitable nucleotide sequences, including, for example, constant region coding sequences and expression control sequences, to produce a conventional gene expression construct (i.e., an expression vector) encoding the desired α4β7 binding antibody. The generation of the determined gene construct is within the scope of conventional techniques in this art.

[0241] Nucleic acid encoding the desired α4β7-binding antibody can be incorporated (ligated) into an expression vector, which can be introduced into host cells using conventional transfection or transformation techniques. Exemplary host cells include *E. coli* cells that do not normally produce IgG proteins, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, young hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells. Transformed host cells can grow under conditions that allow host cells to express the gene encoding the α4β7-binding antibody. In some embodiments, the nucleic acid comprises the sequence shown in SEQ ID NO: 12-17.

[0242] Specific expression and purification conditions will vary depending on the expression system used. For example, if a gene is to be expressed in *E. coli*, it is first cloned into an expression vector by positioning the engineered gene downstream of a suitable bacterial promoter (e.g., Trp or Tac) and a prokaryotic signaling sequence. The expressed protein can be secreted. The expressed protein can accumulate in refractive bodies or inclusion bodies, which can be harvested after disrupting the cells using a French press or sonication. The refractive bodies are then dissolved, and the protein can be refolded and / or cleaved using methods known in the art.

[0243] To express an engineered gene in a eukaryotic host cell (e.g., CHO cells), it is first inserted into an expression vector containing a suitable eukaryotic promoter, secretion signal, poly A sequence, and stop codon. Optionally, the vector or gene construct may contain enhancers and introns. In embodiments involving fusion proteins comprising an α4β7-binding antibody or a portion thereof, the expression vector optionally contains a sequence encoding all or part of a constant region, thereby enabling expression of all or part of the heavy or light chain. The gene construct can be introduced into eukaryotic host cells using conventional techniques.

[0244] In some embodiments, the protein construct includes an N-terminal signal sequence for expressing the α4β7 binding antibody. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgGκ light chain, trypsinogen, serum albumin, and prolactin.

[0245] Following transfection, single clones can be isolated using methods known in the art (such as limiting dilution, ELISA, FACS, microscopy, or Clonepix) for cell bank generation. Clones can be cultured under conditions suitable for scale-up and maintenance expression in a bioreactor adapted for α4β7-binding antibodies.

[0246] α4β7 binding antibodies can be isolated and purified using methods known in the art, including centrifugation, deep filtration, cell lysis, homogenization, freeze-thaw, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography. Other embodiments

[0247] In some embodiments, this document describes a subcutaneous dosage form comprising an effective amount of an α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the effective amount achieves a mean serum or plasma concentration of about 35 µg / mL and a serum or plasma trough concentration of at least about 6 µg / mL (e.g., about 10 µg / mL). In some embodiments, the heavy chain comprises the amino acid sequence according to SEQ ID NO: 1, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the heavy chain comprises the amino acid sequence according to SEQ ID NO: 2, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the subcutaneous dosage form comprises about 75 mg to about 900 mg or more of the α4β7-binding antibody. In some embodiments, the subcutaneous dosage form comprises about 75 mg, 100 mg, 150 mg, 200 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg or more of α4β7-binding antibody. In some embodiments, the subcutaneous dosage form comprises an induction dose of about 300 mg to about 1200 mg and a maintenance dose of about 150 mg to 350 mg of α4β7-binding antibody.

[0248] In some embodiments, methods of administering one or more of the dosage forms described herein are described herein. More specifically, for maintenance therapy following one to three doses of induction therapy, the administration frequency of one or more dosage forms described herein is no more than once every eight weeks (Q8 administration), or no more than once every twelve weeks (Q12 administration), or no more than once every sixteen weeks (Q16 administration), and in some embodiments, no more than twice a year (Q26 administration). In some embodiments, the dosage is sufficient for annual (Q52) administration. The administration method may further include an induction dose containing a dose that is two or more times the dose of the α4β7 binding antibody disclosed herein. The method may be administered intravenously (IV) or subcutaneously (SC), or both (one or more IV induction doses and SC maintenance doses); a particular advantage of this disclosure is that it provides subcutaneous administration of both the induction dose and the maintenance dose.

[0249] In some embodiments, this document describes a method of treating inflammatory bowel disease in a patient in need, the method comprising administering, subcutaneously or intravenously, an effective amount of an α4β7-binding antibody to the patient, the α4β7-binding antibody comprising: a) a heavy chain comprising an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the heavy chain comprises an amino acid sequence according to SEQ ID NO: 1, and the light chain comprises an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the heavy chain comprises an amino acid sequence according to SEQ ID NO: 2, and the light chain comprises an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the administration of the α4β7-binding antibody is subcutaneous. In some embodiments, the administration of the α4β7-binding antibody is intravenous. In some embodiments, the α4β7-binding antibody is administered at a dose of about 100 mg to about 900 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 100 mg to about 600 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 100 mg to about 300 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg. In some embodiments, the α4β7 binding antibody is administered at a dose of about 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg or more.

[0250] In some embodiments, this document describes a method of treating a disease or condition in a patient in need, the method comprising administering, at least once, an effective amount of an α4β7-binding antibody to the patient at intervals of more than 8 weeks, the α4β7-binding antibody comprising: a) a heavy chain comprising an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) a light chain comprising an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the interval is about 12 to about 26 weeks. In some embodiments, the interval is about 12 weeks. In some embodiments, the interval is about 16 weeks. In some embodiments, the interval is about 26 weeks. In some embodiments, the disease or condition is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the heavy chain comprises an amino acid sequence according to SEQ ID NO: 1, and the light chain comprises an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the heavy chain comprises an amino acid sequence according to SEQ ID NO: 2, and the light chain comprises an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7 binding antibody is administered subcutaneously. In some embodiments, the α4β7 binding antibody is administered intravenously. In some embodiments, the α4β7 binding antibody is administered at a dose of about 300 mg. In some embodiments, the α4β7 binding antibody is administered at doses of about 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or more. In some embodiments, the disease or condition is inflammatory bowel disease, and the α4β7 binding antibody is administered subcutaneously with an induction dose of about 600 mg (by intravenous or subcutaneous administration) and a maintenance dose of about 300 mg.

[0251] In some embodiments, this document describes a method for treating a disease or condition in a patient in need, the method comprising administering to the patient approximately 108 mg or approximately 300 mg of an α4β7 binding antibody every four or six weeks, wherein the α4β7 binding antibody comprises a heavy chain containing an amino acid sequence according to SEQ ID NO: 4 and a light chain containing an amino acid sequence according to SEQ ID NO: 5; and wherein subcutaneous administration of the intermediate α4β7 binding antibody does not occur during the four or six weeks.

[0252] In some embodiments, this document describes a method for treating a disease or condition in a patient in need, the method comprising administering to the patient about 108 mg or about 300 mg of an α4β7 binding antibody, wherein the α4β7 binding antibody comprises a heavy chain containing an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing an amino acid sequence according to SEQ ID NO: 3; and wherein a serum or plasma concentration of at least about 35 µg / mL of the α4β7 binding antibody is achieved in the patient at the time of administration for at least 2 weeks or longer.

[0253] In some embodiments, this document describes a method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering to the patient an induction dose of about 150 mg to about 1200 mg (e.g., about 300 mg to about 1000 mg) of an α4β7 binding antibody, wherein the α4β7 binding antibody comprises a heavy chain containing an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing an amino acid sequence according to SEQ ID NO: 3; and wherein a serum or plasma concentration of at least about 35 µg / mL of the α4β7 binding antibody is achieved in the patient at the time of administration, lasting for at least 2 weeks or longer, and a serum or plasma trough concentration of at least about 6 µg / mL, for example, 10 µg / mL.

[0254] In some embodiments, this document describes a method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering to the patient about 108 mg or about 300 mg of an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain containing the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing the amino acid sequence according to SEQ ID NO: 3; and wherein a maintenance concentration of at least about 6 µg / mL (e.g., about 10 µg / mL) of the α4β7-binding antibody is achieved in the patient at the time of administration. 谷 In another embodiment, the dosage and frequency of administration provide, at the time of administration, at least about 6 µg / mL (e.g., about 10 µg / mL) of the α4β7-binding antibody C30 in the patient for sustained administration. 谷 And the dosing frequency should not exceed once every 4 weeks, or alternatively once every 8 weeks, or alternatively once every 12 weeks, or alternatively once every 16 weeks, or alternatively once every 26 weeks.

[0255] In one embodiment, one or more induction doses are administered, followed by a maintenance dose. The induction dose may be administered intravenously or subcutaneously. The induction dose may be higher than or more frequently than the maintenance dose, for example, if it may be twice the maintenance dose. Aspects of this disclosure envision one, two, three, or more induction doses. In one example, the induction dose is 600 mg / mL at week 0 and 300 mg / mL at week 2, wherein the maintenance dose is 300 mg / mL every 12 weeks following the second induction dose.

[0256] This disclosure relates to isolated nucleic acids, expression vectors containing nucleic acid sequences, or recombinant host cells containing nucleic acid sequences encoding the heavy and / or light chains of the α4β7 binding antibody described herein. In some embodiments, the nucleic acid sequence encodes SEQ ID NO: 1. In some embodiments, the nucleic acid sequence encodes SEQ ID NO: 3.

[0257] This disclosure relates to an α4β7-binding antibody comprising: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain comprising the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the α4β7-binding antibody comprises: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3.

[0258] This disclosure relates to an α4β7-binding antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of the amino acid sequence according to SEQ ID NO: 1. In some embodiments, the light chain consists of the amino acid sequence according to SEQ ID NO: 3.

[0259] According to aspects of this disclosure, the α4β7 binding antibody has an extended half-life compared to an α4β7 binding antibody comprising a heavy chain sequence consisting of SEQ ID NO: 4. In some embodiments, the α4β7 binding antibody has a half-life of 42 to 56 days or longer in the human body.

[0260] This disclosure relates to a pharmaceutical composition comprising an α4β7-binding antibody and a pharmaceutically acceptable carrier, the α4β7-binding antibody comprising: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the pharmaceutical composition comprises an α4β7-binding antibody and a pharmaceutically acceptable carrier, the α4β7-binding antibody comprising: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the pharmaceutical composition is citrate-free.

[0261] This disclosure relates to a subcutaneous dosage form comprising at least about 150 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the subcutaneous dosage form comprises at least about 150 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a light chain consisting of the amino acid sequence according to SEQ ID NO: 3. In some embodiments, the dosage form is citrate-free. In some embodiments, the subcutaneous dose comprises about 150 mg to about 900 mg of the α4β7-binding antibody.

[0262] A method is provided for treating inflammatory bowel disease in a subject of need. In some embodiments, the method includes subcutaneous administration of one or more dosage forms of the aspects disclosed herein to the subject. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0263] In some embodiments, a method of treating inflammatory bowel disease in a subject of need includes subcutaneous administration of an effective amount of an α4β7-binding antibody comprising a heavy chain and a light chain to the subject, wherein the heavy chain consists of the amino acid sequence according to SEQ ID NO: 1; and the light chain comprises the variable region of SEQ ID NO: 3.

[0264] In some embodiments, a method for treating inflammatory bowel disease in a subject of need includes subcutaneous administration of an effective amount of an α4β7-binding antibody comprising a heavy chain and a light chain to the subject, wherein the heavy chain consists of the amino acid sequence according to SEQ ID NO: 1; and the light chain consists of the variable region of SEQ ID NO: 3.

[0265] In some embodiments, the α4β7 binding antibody is administered at a dose of about 150 mg to about 900 mg. In some embodiments, the method includes administering an effective amount of the α4β7 binding antibody to the subject at intervals of more than 8 weeks (e.g., about 12 to about 26 weeks, about 12 weeks, about 16 weeks, about 26 weeks).

[0266] In some embodiments, inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0267] In some embodiments, an average serum or plasma or serum concentration of at least about 35 µg / mL of α4β7-binding antibody was achieved in subjects during the induction period.

[0268] In some embodiments, a maintenance C-level of at least about 6 µg / mL of α4β7-binding antibody was achieved in subjects. 谷 .

[0269] This disclosure relates to a method for treating inflammatory bowel disease in a subject of need, the method comprising: (a) subcutaneously administering to the subject one or more induction doses comprising an effective amount of an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence according to SEQ ID NO: 1; and the light chain consists of a variable region of SEQ ID NO: 3; and (b) subcutaneously administering to the subject one or more maintenance doses comprising an effective amount of the α4β7-binding antibody.

[0270] In some embodiments, one or more maintenance doses of the α4β7-binding antibody are administered at intervals of more than 8 weeks.

[0271] In some embodiments, the amount of α4β7-binding antibody contained in the induction dose is about two or more times that of the maintenance dose.

[0272] In some embodiments, the induction dose comprises about 400 mg to about 600 mg of α4β7 binding antibody, and the maintenance dose comprises about 150 to about 300 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 600 mg of α4β7 binding antibody, and the maintenance dose comprises about 300 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 400 mg of α4β7 binding antibody, and the maintenance dose comprises about 200 mg of α4β7 binding antibody. In some embodiments, the induction dose comprises about 600 mg of α4β7 binding antibody, and the maintenance dose comprises about 600 mg of α4β7 binding antibody.

[0273] In some embodiments, the method includes subcutaneously administering an induction dose of approximately 600 mg of α4β7-binding antibody to the subject at week 0 and subcutaneously administering a maintenance dose of approximately 600 mg of α4β7-binding antibody to the subject at week 26.

[0274] In some embodiments, upon administration of one or more induction doses, a mean serum or plasma concentration of at least about 35 µg / mL of α4β7-binding antibody is achieved in patients during the induction period. In some embodiments, upon administration of one or more maintenance doses, a serum or plasma concentration of at least about 6 µg / mL of α4β7-binding antibody is achieved in patients for at least 2 weeks or longer.

[0275] While this disclosure provides for subcutaneous administration of the α4β7-binding antibody, it can also be administered via an intravenous route (i.e., by infusion). Further, it is envisioned that one or more induction or loading doses can be administered via subcutaneous (SC) or intravenous (IV) administration. Specific Implementation

[0276] The following describes specific, non-limiting embodiments, each of which is considered to be within the scope of this disclosure. Example 1. A multi-dosing regimen comprising a liquid formulation for use in treating a disease in a subject in need, the multi-dosing regimen comprising: (a) A first injectable liquid formulation comprising at least 500 mg of a total dose of a long-acting α4β7-targeting molecule; and (b) A second injectable liquid formulation comprising at least 300 mg of the long-acting α4β7-targeting molecule. The long-acting α4β7 targeting molecule comprises: (i) A heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1, and (ii) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 2. A multi-dose regimen as described in Example 1, wherein the first injectable liquid formulation comprises a total dose of the long-acting α4β7 targeting molecule of about 500 mg to about 1200 mg. Example 3. A multi-dose regimen as described in Example 1, wherein the first injectable liquid formulation comprises a total dose of approximately 600 mg of the long-acting α4β7 targeting molecule. Example 4. A multi-dose regimen as described in Example 1, wherein the first injectable liquid formulation comprises a total dose of approximately 1000 mg of the long-acting α4β7 targeting molecule. Example 5. A multi-dose regimen as described in any one of Examples 1-4, wherein the second injectable liquid formulation comprises a total dose of the long-acting α4β7 targeting molecule of about 300 mg to about 450 mg. Example 6. A multi-dose regimen as described in any one of Examples 1-4, wherein the second injectable liquid formulation comprises a total dose of approximately 300 mg of the long-acting α4β7 targeting molecule. Example 7. A multi-dose regimen as described in any one of Examples 1-6, wherein the first injectable liquid formulation is for intravenous administration. Example 8. A multi-dosing regimen as described in any one of Examples 1-6, wherein the first injectable liquid formulation is for subcutaneous administration. Example 9. A multi-dose regimen as described in Example 8, wherein the first injectable liquid formulation is a single-dose or multi-dose formulation. Example 10. A multi-dosing regimen as described in any one of Examples 1-9, wherein the second injectable liquid formulation is for subcutaneous administration. Example 11. The multi-dosing regimen as described in Example 10, wherein the second injectable liquid formulation is suitable for single or multiple injection administration. Example 12. A multi-dose regimen as described in any one of Examples 1-11, wherein the disease is an inflammatory gastroenteritis. Example 13. A multi-dose regimen as described in any one of Examples 1-11, wherein the disease is inflammatory bowel disease. Example 14. A multi-dose regimen as described in Example 13, wherein the inflammatory bowel disease is Crohn's disease. Example 15. A multi-dose regimen as described in Example 13, wherein the inflammatory bowel disease is ulcerative colitis. Example 16. A dosing regimen for use in treating a disease in a subject in need, the dosing regimen comprising: (a) A first preparation comprising at least about 600 mg of a long-acting α4β7-targeting molecule for administration to the subject; (b) A second formulation comprising at least about 300 mg of the long-acting α4β7-targeting molecule, for subcutaneous administration to the subject at least two weeks after administration of the first formulation, and thereafter as a maintenance dose at least eight weeks after administration of the second formulation. The long-acting α4β7 targeting molecule comprises: (i) A heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1, and (ii) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 17. The dosing regimen as described in Example 16, wherein the first preparation is for subcutaneous administration. Example 18. The dosing regimen as described in Example 16, wherein the first preparation is for intravenous administration. Example 19. A dosing regimen as described in any one of Examples 16-18, wherein the first formulation comprises a total dose of about 600 mg to about 1200 mg of the long-acting α4β7 targeting molecule. Example 20. A dosing regimen as described in any one of Examples 16-18, wherein the first formulation comprises a total dose of about 600 mg of the long-acting α4β7 targeting molecule. Example 21. A dosing regimen as described in any one of Examples 16-20, wherein the second formulation comprises a total dose of about 300 mg to about 450 mg of the long-acting α4β7 targeting molecule. Example 22. A dosing regimen as described in any one of Examples 16-20, wherein the second formulation comprises a total dose of about 300 mg of the long-acting α4β7 targeting molecule. Example 23. A dosing regimen as described in Example 19 or Example 20, wherein the first preparation is suitable for single or multiple injections. Example 24. A dosing regimen as described in any one of Examples 16-23, wherein the second preparation is a single-dose or multi-dose injectable preparation. Example 25. A dosing regimen as described in any one of Examples 16-24, wherein the first formulation and the second formulation are free of citrate. Example 26. The dosing regimen as described in Example 25, wherein the first formulation or the second formulation or both formulations comprise one or more of the following: (a) Histidine; (b) Arginine or its salts; (c) EDTA; and (d) Polysorbate 80. Example 27. The dosing regimen as described in any one of Examples 16-26, wherein the disease is an inflammatory gastroenteritis. Example 28. The dosing regimen as described in any one of Examples 16-26, wherein the disease is inflammatory bowel disease. Example 29. The dosing regimen as described in Example 28, wherein the inflammatory bowel disease is Crohn's disease. Example 30. The dosing regimen as described in Example 28, wherein the inflammatory bowel disease is ulcerative colitis. Example 31. An injectable formulation of an α4β7 binding antibody, wherein the α4β7 binding antibody comprises: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and a) A light chain, said light chain consisting of an amino acid sequence according to SEQ ID NO. The α4β7 binding antibody described therein has an average serum half-life of more than 6 days in cynomolgus monkeys. Example 32. An injectable formulation as described in Example 31, wherein the mean serum half-life in cynomolgus monkeys is about 17 days or longer. Example 33. An injectable dosage form as described in Example 31 or 32, comprising at least 100 mg / ml of the long-acting α4β7 targeting molecule. Example 34. An injectable dosage form as described in Example 31 or 32, comprising at least 180 mg / ml of the α4β7 binding antibody. Example 35. An injectable dosage form as described in Example 31 or 32, comprising at least 150 mg / ml of the long-acting α4β7 targeting molecule. Example 36. An injectable dosage form as described in Example 31 or Example 32, comprising at least 200 mg / ml of the long-acting α4β7 targeting molecule. Example 37. An injectable dosage form as described in any one of Examples 31-32, comprising about 600 mg to about 1200 mg of the long-acting α4β7 targeting molecule. Example 38. An injectable dosage form as described in any one of Examples 31-32, comprising about 600 mg of the long-acting α4β7 targeting molecule. Example 39. An injectable dosage form as described in any one of Examples 31-32, comprising about 1000 mg of the long-acting α4β7 targeting molecule. Example 40. An injectable dosage form as described in any one of Examples 31-39, wherein the injectable dosage form is an injectable liquid formulation. Example 41. An injectable dosage form as described in Example 40, wherein the injectable liquid formulation is free of citrate. Example 42. An injectable dosage form as described in Example 41, wherein the injectable liquid formulation comprises one or more of the following: (a) Histidine; (b) Arginine or its salts; (c) EDTA; and (d) Polysorbate 80. Example 43. An injectable liquid formulation as described in any one of Examples 1-30 or Examples 40-42, wherein the injectable liquid formulation is a pharmaceutical composition. Example 44. A method of treating a disease in a patient in need, the method comprising: administering to a subject in need (a) an effective amount of an induction dose of a long-acting α4β7-targeting molecule, and (b) an effective amount of one or more maintenance doses of the long-acting α4β7-targeting molecule, wherein the one or more maintenance doses are administered subcutaneously at intervals of at least eight weeks. The long-acting α4β7 targeting molecule comprises: (i) a heavy chain consisting of an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and (ii) a light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 45. The method as described in Example 44, wherein the disease is an inflammatory gastroenteritis. Example 46. The method as described in Example 44, wherein the disease is inflammatory bowel disease. Example 47. The method as described in Example 45, wherein the inflammatory bowel disease is Crohn's disease. Example 48. The method as described in Example 45, wherein the inflammatory bowel disease is ulcerative colitis. Example 49. The method as described in any one of Examples 44-48, wherein the effective amount of each of the one or more maintenance doses of the long-acting α4β7 targeting molecule is at least about 300 mg. Example 50. The method as described in any one of Examples 44-48, wherein the effective amount of each of the one or more maintenance doses of the long-acting α4β7 targeting molecule is about 300 mg to about 450 mg. Example 51. The method as described in any one of Examples 44-48, wherein the effective amount of the inducing dose of the long-acting α4β7 targeting molecule is about 600 mg. Example 52. The method as described in any one of Examples 44-48, wherein the effective amount of the inducing dose of the long-acting α4β7 targeting molecule is about 1000 mg. Example 53. The method as described in any one of Examples 44-48, wherein the effective amount of the inducing dose of the long-acting α4β7 targeting molecule is 600 mg to about 1200 mg. Example 54. The method as described in any one of Examples 51-53, comprising administering an effective amount of the induction dose in a single or multiple injections. Example 55. The method as described in any one of Examples 44-54, wherein the effective amount of the induction dose of the long-acting α4β7 targeting molecule is administered subcutaneously. Example 56. The method as described in any one of Examples 44-54, wherein the effective amount of the induction dose of the long-acting α4β7 targeting molecule is administered intravenously. Example 57. The method as described in any one of Examples 44-56, wherein one or more maintenance doses are administered subcutaneously at intervals of approximately 12 weeks. Example 58. The method as described in any one of Examples 44-56, wherein one or more maintenance doses are administered subcutaneously at intervals of approximately 26 weeks. Example 59. The method as described in any one of Examples 44-58, wherein the dose of the long-acting α4β7 targeting molecule included in the induction dose is about two or more times the dose of each of the one or more maintenance doses. Example 60. The method as described in any one of Examples 44-59, wherein: (a) The long-acting α4β7 targeting molecule follows a biphasic decrease in serum concentration; (b) Repeated administration of the long-acting α4β7-targeting molecule had no significant effect on clearance (CL) and steady-state volume of distribution (Vss); (c) The pharmacokinetics are not affected by the patient's disease state; or (d) Its combination. Example 61. A C-type long-acting α4β7-targeting molecule that achieves 60 µg / ml to 70 µg / ml or greater in subjects in need. avgW0-W12 The method comprises administering at least 600 mg of the α4β7-binding antibody as a first dose to the subject in need, wherein the long-acting α4β7-targeting molecule comprises: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 62. The method as described in Example 61, wherein the application leads to C avgW0-W12 It is approximately 65 µg / ml. Example 63. The method as described in Example 62, wherein the administration comprises administering at least 600 mg of the long-acting α4β7 targeting molecule to the subject in need, and administering at least 300 mg of the long-acting α4β7 targeting molecule at least two weeks after administering the first dose. Example 64. The method as described in Example 63, comprising intravenous administration of at least 600 mg of the long-acting α4β7 targeting molecule and subcutaneous administration of at least 300 mg of the long-acting α4β7 targeting molecule. Example 65. The method as described in Example 63, comprising subcutaneous administration of a first dose of at least 600 mg of the long-acting α4β7 targeting molecule and subcutaneous administration of a second dose of at least 300 mg of the long-acting α4β7 targeting molecule. Example 66. The method of any one of Examples 61-65, further comprising administering at least 300 mg of one or more doses of the long-acting α4β7-targeting molecule to the subject in need at least four weeks after administration of a second dose of the long-acting α4β7-targeting molecule. Example 67. The method as described in Example 66, comprising subcutaneous administration of one or more doses of the long-acting α4β7 targeting molecule. Example 68. The method as described in any one of Examples 61-67, comprising administering at least 600 mg of the long-acting α4β7 targeting molecule to the subject in need every twenty-six weeks following administration of a second dose of the long-acting α4β7 targeting molecule. Example 69. A C-type long-acting α4β7-targeting molecule that achieves 65 µg / ml to 75 µg / ml or greater in subjects in need. avgW0-W6 The method comprises administering at least 600 mg of the long-acting α4β7-targeting molecule as a first dose to the subject in need, wherein the long-acting α4β7-targeting molecule comprises: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 70. The method as described in Example 69, wherein the application results in C avgW0-W6 It is approximately 70 µg / ml. Example 71. The method as described in Example 69, wherein the application results in C avgW0-W6 It is approximately 65 µg / ml. Example 72. The method of any one of Examples 69-71, wherein the administration comprises administering at least 600 mg of the long-acting α4β7 targeting molecule to the subject in need, and administering at least 300 mg of the long-acting α4β7 targeting molecule at least two weeks after administering at least 600 mg of the first dose of the long-acting α4β7 targeting molecule. Example 73. The method as described in Example 72, comprising intravenous administration of a first dose of the long-acting α4β7 targeting molecule and subcutaneous administration of a second dose of the long-acting α4β7 targeting molecule. Example 74. The method as described in Example 72, comprising subcutaneous administration of a first dose and a second dose of the long-acting α4β7 targeting molecule. Example 75. The method as described in any one of Examples 72-74, further comprising administering at least 300 mg of one or more additional doses of the long-acting α4β7-targeting molecule to the subject in need at least four weeks after administration of the second dose of the long-acting α4β7-targeting molecule. Example 76. The method as described in Example 75, comprising subcutaneous administration of one or more additional doses of the long-acting α4β7 targeting molecule. Example 77. The method as described in Example 75 or Example 68, further comprising administering at least 600 mg of the long-acting α4β7 targeting molecule to the subject in need every twenty-six weeks following administration of a second dose of the long-acting α4β7 targeting molecule. Example 78. The method as described in any one of Examples 66-68 or 75-77, wherein administration of one or more doses of the long-acting α4β7 targeting molecule results in C avg The concentration is 40 µg / ml to 50 µg / ml or greater. Example 79. The method as described in any one of Examples 66-68 or 75-77, wherein administration of one or more doses of the long-acting α4β7 targeting molecule results in C avg It is approximately 45 µg / ml. Example 80. A C-type of the long-acting α4β7-targeting molecule achieving 35 µg / ml or greater in said long-acting α4β7-targeting molecule in said patients six weeks after administration to subjects in need. 谷 The method includes administering at least 600 mg of the long-acting α4β7-targeting molecule to the patient in need, wherein the long-acting α4β7-targeting molecule comprises: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 81. The method as described in Example 80, wherein administration of at least 600 mg of the long-acting α4β7 targeting molecule resulted in serum C avgW0-W12 The concentration should be at least 60 μg / ml. Example 82. The method as described in Example 80, wherein administration of at least 600 mg of the long-acting α4β7 targeting molecule resulted in serum C avgW30-W40 The concentration should be at least 30 μg / ml. Example 83. The method as described in Example 80, wherein at least 600 mg of the long-acting α4β7 targeting molecule is administered intravenously. Example 84. The method as described in Example 80, wherein at least 600 mg of the long-acting α4β7 targeting molecule is administered subcutaneously. Example 85. The method as described in any one of Examples 80-84, further comprising administering at least 300 mg of the long-acting α4β7 targeting molecule to the subject in need, wherein administration of at least 300 mg of the long-acting α4β7 targeting molecule results in steady-state C 谷 The concentration is at least 6 µg / ml. Example 86. The method as described in any one of Examples 80-84, further comprising administering at least 300 mg of the long-acting α4β7 targeting molecule to the subject in need, thereby resulting in a mean serum concentration of α4β7 binding antibody greater than 35 μg / ml for ten weeks following administration of at least 300 mg of the long-acting α4β7 targeting molecule. Example 87. The method as described in any one of Examples 85-86, further comprising subcutaneously administering at least 300 mg of the long-acting α4β7 targeting molecule to the subject in need four weeks after administration of the last dose of the long-acting α4β7 targeting molecule. Example 88. The method as described in any one of Examples 85-86, further comprising administering at least 600 mg of maintenance dose of α4β7 binding antibody subcutaneously to the patient every twenty-six weeks after administration of the last dose of the long-acting α4β7 targeting molecule. Example 89. A long-acting α4β7-targeting molecule, comprising: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 90. An isolated nucleic acid encoding the heavy and / or light chains of the long-acting α4β7 targeting molecule as described in Example 89. Example 91. The isolated nucleic acid as described in Example 90, encoded as SEQ ID NO: 1. Example 92. The isolated nucleic acid as described in Example 90, encoded by SEQ ID NO: 3. Example 93. A recombinant host cell comprising the isolated nucleic acid as described in any one of Examples 90-92, or an expression vector comprising the isolated nucleic acid as described in any one of Examples 90-92. Example 95. A medicine box for treating a disease in a subject in need, the medicine box comprising: (a) An injectable liquid formulation comprising a long-acting α4β7 targeting molecule, wherein the long-acting α4β7 targeting molecule comprises: (i) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (ii) a light chain, said light chain consisting of the amino acid sequence according to SEQ ID NO: 3, and (b) Instructions for use of at least 600 mg of the long-acting α4β7-targeting molecule, at least 300 mg of the long-acting α4β7-targeting molecule at least two weeks after administration of 600 mg of the long-acting α4β7-targeting molecule, and at least 300 mg of the long-acting α4β7-targeting molecule at least four weeks thereafter. Example 96. A medicine box for treating a disease in a subject in need, the medicine box comprising: (a) An injectable subcutaneous liquid formulation containing a long-acting α4β7 targeting molecule. The long-acting α4β7 targeting molecule comprises: (i) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (ii) a light chain, said light chain consisting of the amino acid sequence according to SEQ ID NO: 3, and (b) Instructions for use of at least 600 mg of the long-acting α4β7-targeting molecule administered subcutaneously, at least 300 mg of the long-acting α4β7-targeting molecule administered subcutaneously at least two weeks after administration of 600 mg of the long-acting α4β7-targeting molecule, and at least 300 mg of the long-acting α4β7-targeting molecule administered subcutaneously at least four weeks thereafter. Example 97. A medicine box as described in Example 95 or Example 96, wherein the disease is an inflammatory gastroenteritis. Example 98. A medicine box as described in Example 95 or Example 96, wherein the disease is inflammatory bowel disease, optionally Crohn's disease or ulcerative colitis. Example 99. A long-acting α4β7 targeting molecule as described in Example 89, a long-acting α4β7 targeting molecule of any of the schemes described in Examples 1-30, a long-acting α4β7 targeting molecule of an injectable dosage form described in any of Examples 31-42, a long-acting α4β7 targeting molecule of a method described in any of Examples 44-88, or a long-acting α4β7 targeting molecule of a kit described in any of Examples 95-98, wherein the long-acting α4β7 targeting molecule comprises one or more of the following properties: i. The average serum half-life in cynomolgus monkeys is greater than approximately 6 days. ii. The mean serum half-life in cynomolgus monkeys is approximately 17 days or longer. iii. The chain-breaking temperature TmOnset is greater than approximately 55°C. iv. The chain-breaking temperature TmOnset is greater than 56.2°C. v. Does not induce T cell activation markers CD25 or CD69. vi. Does not result in the release of cytokines at least 6 hours after administration, said cytokines including one or more of IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70, and TNF. vii. Complement-dependent cytotoxicity (CDC) in primary human PBMCs and human β-lymphocytes expressing α4β7 is not induced. viii. Does not induce antibody-dependent cytotoxicity (ADCC) in human NK cells. ix. Does not affect the inhibitory activity of regulatory T cells expressing α4β7 integrin, wherein the inhibitory activity is measured by the presence of elevated CD71, CD25, Ki67, granzyme B, or OX40. The proportion of x.G0F is approximately 55.1% to approximately 60.4%. The proportion of xi.G1F was approximately 16.6% to approximately 18.8%. The proportion of xii.Man5 is approximately 7.3% to approximately 8.8%. Example 100. A subcutaneous dosage form comprising at least about 300 mg of an α4β7 binding antibody, said α4β7 binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) A light chain comprising the amino acid sequence according to SEQ ID NO: 3. Example 101. The dosage form as described in Example 100, wherein the heavy chain comprises the amino acid sequence according to SEQ ID NO: 1, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. Example 102. The dosage form as described in Example 100, wherein the heavy chain comprises the amino acid sequence according to SEQ ID NO: 2, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. Example 103. A dosage form as described in any one of Examples 100-102, comprising about 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg or 700 mg of the α4β7 binding antibody. Example 104. A method of administering one or more dosage forms as described in any one of Examples 100-103. Example 105. A method for treating inflammatory bowel disease in a patient in need, the method comprising administering an effective amount of an α4β7-binding antibody subcutaneously or intravenously to the patient, the α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) A light chain comprising the amino acid sequence according to SEQ ID NO: 3. Example 106. The method as described in Example 105, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. Example 107. The method as described in Example 105, wherein the inflammatory bowel disease is ulcerative colitis. Example 108. The method of any one of Examples 105-107, wherein the heavy chain comprises the amino acid sequence according to SEQ ID NO: 1, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. Example 109. The method of any one of Examples 105-108, wherein the heavy chain comprises the amino acid sequence according to SEQ ID NO: 2, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. Example 110. The method as described in any one of Examples 105-109, wherein the α4β7 binding antibody is administered subcutaneously. Example 111. The method as described in any one of Examples 105-110, wherein the α4β7 binding antibody is administered intravenously. Example 112. The method as described in any one of Examples 105-111, wherein the α4β7 binding antibody is administered at a dose of about 300 mg. Example 113. The method of any one of Examples 105-112, wherein the α4β7 binding antibody is administered at a dose of about 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg or 700 mg. Example 114. A method of treating a disease or condition in a patient in need, the method comprising administering, at least once at intervals of more than 8 weeks, an effective amount of an α4β7-binding antibody, the α4β7-binding antibody comprising: a) a heavy chain comprising the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and b) A light chain comprising the amino acid sequence according to SEQ ID NO: 3. Example 115. The method as described in Example 114, wherein the interval is about 12 to about 26 weeks. Example 116. The method as described in Example 115, wherein the interval is approximately 12 weeks. Example 117. The method as described in Example 115, wherein the interval is approximately 16 weeks. Example 118. The method as described in Example 115, wherein the interval is approximately 26 weeks. Example 119. The method as described in Example 115, wherein the disease or symptom is inflammatory bowel disease. Example 120. The method as described in Example 119, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. Example 121. The method as described in Example 119, wherein the inflammatory bowel disease is ulcerative colitis. Example 122. The method of any one of Examples 115-121, wherein the heavy chain comprises the amino acid sequence according to SEQ ID NO: 1, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. Example 123. The method of any one of Examples 115-121, wherein the heavy chain comprises the amino acid sequence according to SEQ ID NO: 2, and the light chain comprises the amino acid sequence according to SEQ ID NO: 3. Example 124. The method as described in any one of Examples 115-123, wherein the α4β7 binding antibody is administered subcutaneously. Example 125. The method as described in any one of Examples 115-123, wherein the α4β7 binding antibody is administered intravenously. Example 126. The method as described in any one of Examples 115-125, wherein the α4β7 binding antibody is administered at a dose of about 300 mg. Example 127. The method of any one of Examples 115-125, wherein the α4β7 binding antibody is administered at a dose of about 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg or 700 mg. Example 128. The method as described in any one of Examples 115-127, wherein the disease or condition is inflammatory bowel disease, and the α4β7 binding antibody is administered at a dose of about 300 mg and is administered subcutaneously. Example 129. A method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering approximately 108 mg or approximately 300 mg of an α4β7-binding antibody to the patient every four or six weeks. The α4β7 binding antibody comprises a heavy chain containing the amino acid sequence according to SEQ ID NO: 4 and a light chain containing the amino acid sequence according to SEQ ID NO: 5; and Subcutaneous administration of the α4β7 binding antibody, which occurs between the four and six weeks mentioned above, does not occur. Example 130. A method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering about 108 mg or about 300 mg of an α4β7 binding antibody to the patient. The α4β7 binding antibody comprises a heavy chain containing the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing the amino acid sequence according to SEQ ID NO: 3; and The α4β7 binding antibody achieved a plasma concentration of at least about 35 µg / mL in the patients at the time of administration, lasting for at least 2 weeks or longer. Example 131. A method for treating a disease or condition in a patient in need, the method comprising subcutaneously administering about 108 mg or about 300 mg of an α4β7 binding antibody to the patient. The α4β7 binding antibody comprises a heavy chain containing the amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2 and a light chain containing the amino acid sequence according to SEQ ID NO: 3; and The α4β7-binding antibody achieved a C1 concentration of at least approximately 6 µg / mL in the patients upon administration. 谷 This will last for at least two weeks or longer. Example 132. The method as described in any one of Examples 130-131, wherein the condition is inflammatory bowel disease. Example 133. The method as described in any one of Examples 130-131, wherein the condition is Crohn's disease or ulcerative colitis. Example 134. An isolated nucleic acid, wherein the nucleic acid encodes the heavy chain and / or light chain of the α4β7 binding antibody as described in any one of Examples 100-134. Example 135. The isolated nucleic acid as described in Example 134, wherein the nucleic acid sequence encodes SEQ ID NO:1. Example 136. The isolated nucleic acid as described in Example 134, wherein the nucleic acid encodes SEQ ID NO: 3. Example 137. A recombinant host cell comprising the nucleic acid sequence as described in any one of Examples 135-136, or an expression vector comprising the nucleic acid sequence as described in any one of Examples 135-136. Example 138. An α4β7 binding antibody, comprising: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and b) A light chain comprising the amino acid sequence according to SEQ ID NO: 3. Example 139. An α4β7 binding antibody, comprising: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 140. An α4β7 binding antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence according to SEQ ID NO: 1. Example 141. An α4β7 binding antibody as described in Example 140, wherein the light chain consists of an amino acid sequence according to SEQ ID NO:3. Example 142. An α4β7 binding antibody as described in any of Examples 138-141, wherein the α4β7 binding antibody has an extended half-life compared to an α4β7 binding antibody comprising a heavy chain sequence consisting of SEQ ID NO: 4. Example 143. An α4β7 binding antibody as described in any one of Examples 138-142, wherein the α4β7 binding antibody has a half-life of 42 to 56 days or longer in the human body. Example 144. A pharmaceutical composition comprising an α4β7-binding antibody and a pharmaceutically acceptable carrier, said α4β7-binding antibody comprising: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and b) A light chain comprising the amino acid sequence according to SEQ ID NO: 3. Example 145. A pharmaceutical composition comprising an α4β7-binding antibody and a pharmaceutically acceptable carrier, said α4β7-binding antibody comprising: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 146. A pharmaceutical composition as described in any one of Examples 144-145, wherein the composition is free of citrate. Example 147. A subcutaneous dosage form comprising at least about 150 mg of an α4β7-binding antibody, said α4β7-binding antibody comprising: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and b) A light chain comprising the amino acid sequence according to SEQ ID NO: 3. Example 148. A subcutaneous dosage form comprising at least about 150 mg of an α4β7 binding antibody, said α4β7 binding antibody comprising: a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and b) A light chain consisting of an amino acid sequence according to SEQ ID NO: 3. Example 149. A subcutaneous dosage form as described in Example 147 or Example 148, wherein the dosage form is free of citrate. Example 150. A subcutaneous dosage form as described in Examples 147, 148 or 149, comprising about 150 mg to about 900 mg of the α4β7 binding antibody. Example 151. A method for treating inflammatory bowel disease in a subject of need, the method comprising subcutaneously administering one or more dosage forms as described in any one of Examples 147-150 to the subject. Example 152. The method as described in Example 151, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. Example 153. The method as described in Example 151, wherein the inflammatory bowel disease is ulcerative colitis. Example 154. A method for treating inflammatory bowel disease in a subject in need, the method comprising subcutaneously administering an effective amount of an α4β7-binding antibody comprising a heavy chain and a light chain to the subject, wherein the heavy chain comprises an amino acid sequence according to SEQ ID NO:1; and the light chain comprises a variable region of SEQ ID NO:3. Example 155. A method for treating inflammatory bowel disease in a subject in need, the method comprising subcutaneously administering an effective amount of an α4β7-binding antibody comprising a heavy chain and a light chain to the subject, wherein the heavy chain consists of the amino acid sequence according to SEQ ID NO: 1; and the light chain consists of the variable region of SEQ ID NO: 3. Example 156. The method as described in Example 154 or Example 155, wherein the α4β7 binding antibody is administered at a dose of about 150 mg to about 900 mg. Example 157. The method as described in Example 154 or Example 155, comprising administering an effective amount of α4β7 binding antibody to the subject at intervals of more than 8 weeks. Example 158. The method as described in Example 157, wherein the interval is about 12 to about 26 weeks. Example 159. The method as described in Example 157, wherein the interval is approximately 12 weeks. Example 160. The method as described in Example 157, wherein the interval is approximately 16 weeks. Example 161. The method as described in Example 157, wherein the interval is approximately 26 weeks. Example 162. The method as described in Example 157, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. Example 163. The method as described in Example 157, wherein the inflammatory bowel disease is ulcerative colitis. Example 164. The method as described in Example 155 or Example 156, wherein an average plasma or serum concentration of at least about 35 µg / mL of the α4β7 binding antibody is achieved in the subject during the induction period. Example 165. The method as described in Example 154 or Example 155, wherein a maintenance C-level of at least about 6 µg / mL of the α4β7 binding antibody is achieved in the subject upon administration. 谷 . Example 166. A method for treating inflammatory bowel disease in a subject of need, the method comprising: (a) subcutaneously administering to the subject one or more induction doses comprising an effective amount of an α4β7-binding antibody, wherein the α4β7-binding antibody comprises a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence according to SEQ ID NO: 1; and the light chain consists of a variable region of SEQ ID NO: 3; and (b) subcutaneously administering to the subject one or more maintenance doses comprising an effective amount of the α4β7-binding antibody. Example 167. The method as described in Example 166, wherein the amount of the α4β7 binding antibody contained in the induction dose is about two or more times that of the maintenance dose. Example 168. The method as described in Example 166, wherein the induction dose comprises about 400 mg to about 600 mg of the α4β7 binding antibody, and wherein the maintenance dose comprises about 150 to about 300 mg of the α4β7 binding antibody. Example 169. The method as described in Example 166, wherein the induction dose comprises about 600 mg of the α4β7 binding antibody, and wherein the maintenance dose comprises about 300 mg of the α4β7 binding antibody. Example 170. The method as described in Example 166, wherein the induction dose comprises about 400 mg of the α4β7 binding antibody, and wherein the maintenance dose comprises about 200 mg of the α4β7 binding antibody. Example 171. The method as described in Example 166, wherein the induction dose comprises about 600 mg of the α4β7 binding antibody, and wherein the maintenance dose comprises about 600 mg of the α4β7 binding antibody. Example 172. The method as described in any one of Examples 166-171, wherein, upon administration of the one or more induction doses, a mean serum or plasma concentration of at least about 35 µg / mL of the α4β7 binding antibody is achieved in the patient during the induction period. Example 173. The method as described in any one of Examples 166-171, wherein, upon administration of the one or more maintenance doses, a serum or plasma concentration of at least about 6 µg / mL of the α4β7 binding antibody is achieved in the patient for at least 2 weeks or longer. Example 174. The method as described in any one of Examples 166-171, wherein the one or more maintenance doses of the α4β7 binding antibody are administered at intervals of more than 8 weeks. Example

[0277] The present disclosure, which is now generally described, will be more readily understood by referring to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the disclosure and are not intended to limit the disclosure. Example 1: Efficacy of α4β7-binding antibody

[0278] This example illustrates the efficacy of the α4β7 binding antibody described in this article.

[0279] PBMCs contain cell types expressing α4β7 integrin, and CD4+ helper T cells are associated with inflammatory bowel disease. The ability of the α4β7-binding antibody described in this paper (i.e., α4β7-binding antibody Ab001, which contains a heavy chain containing the sequence according to SEQ ID NO: 1 and a light chain containing the sequence according to SEQ ID NO: 3) to bind to PBMCs was analyzed. Cell binding to PBMCs isolated from three human donors was determined by staining with various increasing concentrations of comparative antibody (solid lines; solid shapes) or Ab001 (dashed lines; hollow shapes). Figure 1A and Figure 1B ). Figure 1C The receptor occupancy on peripheral blood mononuclear cells expressing α4β7 is shown. The comparative antibody described in this and other examples comprises a heavy chain containing the sequence according to SEQ ID NO: 4 and a light chain containing the sequence according to SEQ ID NO: 5. Basic immunophenotype T cell assays showed that both the comparative antibody and the α4β7-binding antibody exhibited binding to the CD3+CD4+CD45RO+ population of memory T helper cells. EC50 of the comparative antibody and the α4β7-binding antibody... 50 The values ​​are shown in Table 2A, and the EC values ​​of the two antibodies are also shown. 50 The value corresponds well with previously reported EC50 values ​​associated with the same population: EC 50 It is approximately 0.3 nM. Table 2A. EC50 data combined with PBMC

[0280] The IC50 for competitive inhibition was determined by titrating unlabeled Ab001 into a sample equilibrated with fluorescently labeled Ab001 at an EC50 concentration. 50 Values. Ab001 and comparative antibody receptor occupancy (IC50) on CD4+, CD20+, and CD45RO+ cells from human and monkey donors. 50 The results are shown in Table 2B. Table 2B. Receptor occupancy rate by cell type

[0281] α4β7 integrin is a ligand for mucosal addressin cell adhesion molecule 1 (MAdCAM1), and the interaction between these two molecules leads to intestinal homing of lymphocytes. Blocking this interaction is a therapeutic target for inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. α4β7-mediated MAdCAM-1 adhesion was tracked in cells treated with various ascending concentrations of α4β7-binding antibody Ab001 or a comparative antibody to determine the percentage inhibition of total MAdCAM-1 adhesion. Figure 2A The α4β7-binding antibody Ab001 was as effective as the comparative antibody. α4β1 integrin is a related integrin that is a ligand for VCAM-1, which mediates lymphocyte homing to the vascular endothelium. Importantly, in similar assays tracking VCAM-1 adhesion, the α4β7-binding antibody Ab001 did not block VCAM-1 adhesion. As a positive control, antibodies targeting α4β1 integrin did indeed inhibit VCAM-1 adhesion. Figure 2B The α4β7-binding antibody Ab001 was evaluated in human whole blood assays designed to detect its effects on cytokine release and T cell activation. In whole blood assays from three human donors, as measured by FACS, the α4β7-binding antibody Ab001 did not induce the T cell activation markers CD25 or CD69. Furthermore, no cytokine release (Luminex assays of IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70, and TNF) was observed at 6 or 24 hours after the addition of the α4β7-binding antibody Ab001 (400 μg / mL) to the sample. In contrast, these markers were induced when human whole blood was incubated with lipopolysaccharide (LPS) or phytohemagglutinin (PHA), known mitogens that target T and B cells and activate cytokine release.

[0282] The ability of the α4β7-binding antibody Ab001 to induce CDC was evaluated in primary human PBMCs and the α4β7-expressing human B lymphocyte line RPMI-8866. PBMCs were incubated with a series of concentrations up to 10 μg / mL for 4 h, including (i) the α4β7-binding antibody Ab001, (ii) a comparative antibody, (iii) OKT3 (known to induce CDC in T cells), and (iv) an IgG1 isotype negative control antibody. RPMI-8866 cells were incubated with (i) the α4β7-binding antibody Ab001, (ii) a comparative antibody, (iii) rituximab (known to induce CDC in B cells), and (iv) the same IgG1 isotype negative control antibody as used in the PBMC assay for 4 h. Cell viability was measured in both the PBMC and RPMI-8866 assays, and complement-induced specific death (%) was reported against the test antibody concentration for all experimental conditions. Like the comparative antibody, Ab001 did not induce CDC in PBMC or RPMI-8866 cells.

[0283] The ability of the α4β7-binding antibody Ab001 to induce ADCC in human NK cells was evaluated. Primary human NK cells were isolated and used as effector cells, and the α4β7-expressing human B lymphocyte line (RPMI-8866) was used as the target cell population. Effector NK cells and RPMI-8866 cells were incubated with (i) the α4β7-binding antibody Ab001, (ii) a comparative antibody, (iii) rituximab (known to induce ADCC), and (iv) an IgG1 isotype negative control antibody at a series of concentrations from 300 pg / mL to 10 μg / mL (3 h). Cell viability was measured, and ADCC-induced specific cell death (%) was reported against the test antibody concentration for all experimental conditions. Neither the α4β7-binding antibody Ab001 nor the comparative antibody induced NK cell-mediated ADCC in RPMI-8866 cells. The α4β7-binding antibody Ab001 showed a similar range of cell death as the comparative antibody.

[0284] The ability of the α4β7-binding antibody Ab001 to affect the normal activity of regulatory T cells (Tregs) was tested using human PBMCs. Regulatory T cells expressing α4β7 integrin were isolated by FACS and co-cultured with CD8+ T-responding cells in or without the test antibody and T-cell stimulation reagent. Markers of T-cell activation (CD71, CD25, Ki67, granzyme B, or OX40) were measured. The α4β7-binding antibody Ab001 did not affect Treg inhibitory activity at concentrations greater than 10-fold of its known EC50. As the Treg cell count increased from a ratio of 0:16 (none) to 8:16 Treg:CD8+, a marker of T-cell activation (CD25) was measured. + Stimulated CD8+ cells were inhibited. Similar results were observed when treated with α4β7-binding antibody Ab001, culture medium alone, IgG1 isotype negative control, and comparative antibody. Similar results were also observed for Treg inhibitory activity when measured by markers CD71, Ki67, granzyme B, and OX40.

[0285] The ability of the α4β7-binding antibody Ab001 to bind to and induce the internalization of α4β7 integrin was measured using CD4+ memory T cells. Human memory CD4+ T cells were exposed to fluorescently labeled test antibodies, including the α4β7-binding antibody Ab001-A647 and a comparative antibody, at concentrations ranging from 0 nM to 100 nM, and then incubated for 24 h at allowable (37°C) or restrictive (4°C) temperatures for receptor internalization. Cells were then washed with either FACS buffer or mild acid (0.5 M NaCl + 0.2 M acetic acid) to remove membrane-bound antibodies and associated fluorescent signals. Cells incubated with the A647-labeled Ab001 at internalization conditions (37°C) retained greater fluorescence after acid washing compared to cells stained and incubated at restrictive internalization conditions (4°C). This indicates that the α4β7 integrin is internalized upon binding to the fluorescent comparative antibody.

[0286] The ability of functional α4β7 to rapidly express after antibody-induced internalization was determined by incubating human PBMCs with α4β7-binding antibody Ab001 or a comparative antibody at concentrations of 0 nM (control), 0.11 nM, 0.33 nM, or 1.0 nM (at 37°C for 24 h). After incubation, cells were washed twice with PBS to remove unbound, unlabeled test antibody in order to allow internalization. Cells were then resuspended in suitable medium (RPMI 1640 + 10% fetal bovine serum) and incubated with either fluorescently labeled α4β7-binding antibody Ab001 or a comparative antibody for 96 h, with fluorescence monitored at 0 h, 24 h, and 96 h. The results for α4β7-binding antibody Ab001 and the comparative antibody were similar, demonstrating that functional α4β7 can be re-expressed on lymphocytes within 24 to 96 hours of antibody-induced internalization.

[0287] The half-life of Ab001 was studied using non-human primates (NHPs). Comparative antibody or Ab001 was administered intravenously to NHPs, and normalized concentrations of each protein were calculated at multiple time points over 21 days post-injection. Figure 3 It also plotted data from external studies using comparative antibodies (t). 1 / 2 ≈ 10 days). β-elimination half-life (t) of α4β7-binding antibody Ab001 1 / 2 (≈17 days) This is 70% longer than the half-life observed for antibodies against the comparison antibody. YTE modification of the α4β7-binding antibody Ab001 described herein typically increases the half-life of mAbs in NHP and humans by 2–4 times relative to the wild type. The human mAb half-life is at least approximately twice that of the NHP half-life. Therefore, based on the initial allometric expansion based on these data, the human half-life is estimated to be 43–56 days.

[0288] In separate experiments, the prolonged half-life was evaluated by pharmacokinetic analysis in Tg276 transgenic mice (human FcRn hemizygotes) following a single intravenous bolus dose of α4β7-binding antibody Ab001 (10 mg / kg, 5 mg / kg, 1 mg / kg) and in cynomolgus monkeys following a single bolus dose of α4β7-binding antibody Ab001 (150 mg / kg) administered intravenously (IV) and subcutaneously (SC). Human PK simulations were based on allometric expansion of α4β7-binding antibody Ab001 clearance observed in cynomolgus monkeys and performed in MATLAB.

[0289] In Tg276 mice, the half-life of the α4β7-binding antibody Ab001 was 10–11 days across all dose cohorts, compared to approximately 3 days for the comparative antibody. In cynomolgus monkeys, the half-life of α4β7-binding antibody Ab001 was 19–23 days following a single IV or SC infusion, a significant increase compared to the 10-day half-life reported for the comparative antibody in cynomolgus monkeys. Based on the allometric expansion of α4β7-binding antibody Ab001 clearance observed in this study, predictive simulations of α4β7-binding antibody Ab001 pharmacokinetics in humans suggest that, for simulated patients, 300 mg Q8W–Q12W SC administration would be able to achieve C 6周, 诱导 ≥ 35 μg / mL and C 谷, ss ≥ 6 μg / mL. Example 2: Subcutaneous dosing regimen of α4β7 binding antibody

[0290] Pharmacokinetic (PK)-pharmacodynamic (PD) modeling and simulation were performed to determine the subcutaneous dose and regimen that would maintain certain serum concentrations above specific levels at a given time during the regimen or at steady state. Achieving these thresholds has proven to be an important indicator of clinical remission in patients with ulcerative colitis. Specifically, maintaining trough C60 concentrations 6 weeks after induction was crucial. 谷 ≥ 35 µg / mL was significantly associated with a higher remission rate in ulcerative colitis.

[0291] Dosing regimens were determined using a two-compartment linear model with the following parameters: central volume of distribution (Vc), peripheral volume of distribution (Vp), clearance from the central volume (Cl), first-order absorption rate constant from the subcutaneous reservoir to the central volume (ka), and subcutaneous bioavailability relative to intravenous administration. Given that the α4β7-binding antibody disclosed herein is expected to have a longer serum half-life than normal IgG, an effective human half-life of 53 days was used in these models.

[0292] To achieve a higher overall clinical response, the minimum concentration of ≥ 35 µg / mL at 6 weeks (Table 3) or ≥ 6 µg / mL C at steady state was determined for > 95% of patients. 谷 The dosing regimen is shown in Table 4. The model was further refined by adding the effects of covariates including body weight and serum albumin.

[0293] To simulate serum α4β7-binding antibody concentrations over time in a large cohort of patients using a specified dosing regimen, body weight and serum albumin concentration were uniquely assigned to 1000 patients. These two covariates were independently assigned and randomly selected using a cumulative distribution function (CDF) of body weight and a separate CDF of serum albumin concentration. To derive each CDF, a generalized extreme value distribution was fitted using percentiles of body weight and serum albumin concentration reported in clinical trials of the comparative antibody, allowing for various probability distribution behaviors that might be expected in real-world clinical trials. Body weight values ​​were logarithmically transformed, while serum albumin concentration values ​​were used directly. Table 3. Minimum induction regimens that allow >95% of patients to achieve serum concentrations ≥ 35 µg / mL at 6 weeks. Table 4. >90% of patients are allowed to achieve serum C ≥ 6 µg / mL at steady state. 谷 Minimum maintenance plan Example 3: Dose-response relationship of α4β7 binding antibody

[0294] This example illustrates the dose-response relationship of the α4β7-binding antibody described herein.

[0295] Using an induction protocol, a simulated trial involving 1000 patients was conducted with intravenous doses of 300 mg, 350 mg, and 400 mg of a YTE-modified α4β7-binding antibody (such as α4β7-binding antibody Ab001) to determine C6 levels at 6 weeks post-induction. 谷 value( Figure 4 Data generated in a clinical trial of the comparative antibody administered intravenously at 300 mg are also presented. The comparative antibody was also run using the same simulations. In these simulations, a human half-life of 25.5 days was used for the comparative antibody and a human half-life of 50 days was used for Ab001. At 6 weeks post-induction, up to 25% of patients receiving the comparative antibody achieved C. 谷 The threshold was ≥ 35 µg / ml. In contrast, the vast majority of surrogate patients receiving all tested concentrations of Ab001 maintained C 谷 ≥ 35 µg / ml.

[0296] Best-in-class efficacy of the comparative antibody maintenance dosing is based on the area under the steady-state curve (AUC) of a 300 mg Q8W IV maintenance dosing regimen. ss )data( Figure 5When administered subcutaneously, the comparative antibody could only be administered at 108 mg Q2W without falling below the clinically relevant AUC. In contrast, Ab001 is expected to maintain the clinically relevant AUC through quarterly subcutaneous maintenance dosing. These data were generated using the 35- and 50-day human half-lives of Ab001 and plotted together with the comparative antibody data. Figure 5 Based on the human body's half-life, this can be achieved even more rarely than Q16W.

[0297] Post-hoc analysis of comparative antibody test data indicated that C during treatment 谷 Conservative targets of ≥ 6 µg / mL maintain long-term efficacy. Best-in-class 300 mg IV Q8W antibody dosing showed 75% C in patients. 谷 ≥ 6 µg / mL. A trial simulating 1000 patients was conducted using a comparative antibody administered subcutaneously at 108 mg (half-life 25.5 days), a comparative antibody administered intravenously at 300 mg (half-life 25.5 days), and Ab001 administered subcutaneously at 300 mg (half-life 43, 53, or 56 days). Figure 6 Similar to clinical results, 65% of Q8W IV dummy patients achieved C. 谷 ≥ 6 µg / mL (65% marked with a dashed line). Ab001, with a minimum half-life of 43 days, enables Q12W SC dosing. This matches the analogous comparative antibody IVQ8W dosing. Ab001 has a half-life of 50 days when administered Q12W SC, resulting in C in over 90% of patients. 谷 ≥ 6 µg / mL. Figure 5 Maintaining clinically relevant AUC ss The dosing frequency is indicated by an asterisk.

[0298] In summary, these data demonstrate that Ab001, with a half-life of at least 35 days, can be administered subcutaneously at a Q12W frequency while maintaining clinically relevant control levels. 谷 and AUC ss . Example 4: Binding affinity of α4β7-binding antibodies

[0299] This example describes the binding affinity of α4β7 to antibody Ab001.

[0300] In short, the binding affinity of the α4β7-binding antibody Ab001 to α4β7 was determined by kinetic exclusion assay (KinExA) and flow cytometry, and functional activity was determined by inhibiting MAdCAM-mediated cell adhesion.

[0301] α4β7 Binding: The α4β7-binding antibody Ab001 specifically binds to α4β7 but not to the associated integrins α4β1 and αEβ7. In cell assays, Ab001 binds to α4β7 on the surface of RPMI-8866 cells with an affinity matching that of the comparative antibody, but it does not bind to Ramos cells expressing α4β1. α4β7 Binding: The α4β7-binding antibody Ab001 exhibits a high affinity for α4β7, with K as determined by KinExA. D The value is 836 pM. Functionally, α4β7 binds to the α4β7-binding antibody Ab001 with an IC50 comparable to that of the comparative antibody. 50 It strongly inhibits MAdCAM-1-mediated cell adhesion, but has no inhibitory activity on VCAM-1-mediated cell adhesion. Example 5: Simulation of serum concentrations of α4β7-binding antibodies

[0302] The induction protocol was simulated as follows: (1) the mean serum concentration during the 12-week induction period was determined by subcutaneous doses of 600 mg at week 0 (W0) and 300 mg at week 2 (W2) using the α4β7-binding antibody described herein (such as Ab001); (2) the intravenous dose of 300 mg at weeks 0, 2 and 6 using the comparative antibody; and (3) the intravenous dose of 300 mg at weeks 0 and 2 and the subcutaneous dose of 108 mg Q2W starting from week 6 using the comparative antibody. Figure 7A Display Ab001's C avgW0-12 C of the antibody greater than that of the comparison antibody avgW0-12 . Figure 7C Display Ab001's C avgW0-12 C of the antibody greater than that of the comparison antibody avgW0-12 Simulated patients with Q12W SC achieved C 谷 ≥ 36 µg / mL, which is higher than the C of simulated patients who received IV administration of the comparative antibody. 谷 And higher than the C of simulated patients who received the comparative antibody at IV / SC. 谷 Furthermore, surrogate patients with Q12W SC achieved and maintained C during the induction period. 谷 ≥ 36 µg / mL.

[0303] Figure 7B Serum concentrations were depicted based on the antibody half-life, with respect to a 300 mg Q8W IV dose of a comparative antibody and a 300 mg Q12W SC dose of an α4β7-binding antibody (such as Ab001) as described herein. Figure 7BThe results show that Q12W SC administration of the α4β7 binding antibody (such as Ab001) described herein resulted in maintenance of target C. 谷 ≥ 6 µg / mL.

[0304] Figure 7D and Figure 7E The simulated patients with Q12W SC achieved the lowest effective mean serum or plasma concentrations of the α4β7 binding antibodies (such as Ab001) described in this article.

[0305] Figure 7F The study depicted serum concentrations based on antibody half-life, on administration of the comparative antibody at an intravenous dose of 300 mg in weeks 0 and 2 and on administration at a subcutaneous dose of 108 mg Q2W starting in week 6 (26 injections per year for maintenance), and on administration of the α4β7 binding antibody described herein (such as Ab001) at a subcutaneous dose of 300 mg Q12W (4–6 injections per year for maintenance). Figure 7F The α4β7 binding antibodies described in this article (such as Ab001) exhibit excellent steady-state curves in patients. Example 6: PK simulation of serum concentrations of α4β7-binding antibodies

[0306] Figures 8A-8C This is a graph showing a human PK simulation (simulated using a dose of 75 mg / kg NHP-SC (n = 6, M / F)). Figure 8A This is a graph showing the simulated human curve of the α4β7 binding antibody (such as Ab001) described herein at 600 mg. Figure 8B This is a graph showing the simulated human curve of the α4β7 binding antibody (such as Ab001) described herein at 600 mg Q26W. Figure 8C This is a graph showing the simulated human curves of the α4β7 binding antibody (such as Ab001) described herein at 400 mg, 200 mg, and Q12W.

[0307] Figure 8A The study showed that a single 600 mg dose maintained concentrations above the induction threshold for 12 weeks, and then decreased to below the maintenance concentration at 32 weeks.

[0308] Figure 8B This demonstrates simulated dosing of 600 mg of the α4β7-binding antibody (such as Ab001) Q26W (Q6M) described herein to maintain induction and maintenance concentrations.

[0309] Figure 8C This demonstrates simulated dosing of 400 mg and 200 mg of the α4β7-binding antibody (such as Ab001) Q12W described herein to maintain induction and maintenance concentrations. Example 7: Summary of key binding properties, preclinical in vitro and in vivo studies of α4β7-binding antibody Ab001 Table 5. Summary of Research K D The equilibrium dissociation constant between an antibody and its antigen. IC 50 : half-maximum inhibitory concentration EC 50 : half of the maximum effective concentration MAdCAM-1: Mucosal vascular addressing cell adhesion molecule 1 VCAM-1: Vascular cell adhesion protein 1 Example 8: Preparations

[0310] The deglycosylated molecular weight of the α4β7 binding antibody Ab001 active pharmaceutical ingredient is 146,698.3 Daltons. Its solubility is greater than 200 mg / mL, and it is a colorless to brown, transparent to milky white liquid.

[0311] The α4β7 binding antibody Ab001 active pharmaceutical ingredient is a sterile liquid for injection, packaged in 2 mL glass vials. Each single-use vial contains a nominal volume of 2 mL of an aqueous solution of 150 mg / mL Ab001 with histidine, arginine, disodium ethylenedinitrate tetraacetate dihydrate (EDTA), and polysorbate 80. Example 9: Toxicology and toxicokinetics of α4β7-binding antibody Ab001

[0312] Toxicokinetic assessments were performed over 27 days following single intravenous (IV) and subcutaneous (SC) administration of α4β7-binding antibody Ab001 at doses of 30, 75, and 150 mg / kg in male and female cynomolgus monkeys. No PK anomalies were observed, therefore all animals were considered in the statistical analysis. In male monkeys administered intravenously (IV), the serum concentration-time curve for α4β7-binding antibody Ab001 showed a biphasic decrease, with the mean terminal t... 1 / 2 The duration was 6.19 ± 1.72 days, with a mean AUC of last The mean daily active ingredient (Vss) was 27200 ± 4880 days • µg / mL, and the mean Vss was 53.0 ± 4.30 mL / kg. A sharp increase in CL was observed after 14 days, consistent with the development of ADA. When SC was administered to male and female monkeys, T... max The value ranges between 1 day and 7 days. When considering C... max and AUC last At that time, Ab001 exhibited a linear dose-proportioning relationship. Mean terminal t 1 / 2The value ranges from 10.2 to 24.2 days. When considering C... max At AUC, there was no statistically significant difference in exposure between male and female monkeys at a dose of 75 mg / kg (t-test, p = 0.05).

[0313] In male monkeys administered IV (150 mg / kg), the serum concentration-time curve of the α4β7-binding antibody Ab001 showed a biphasic decrease, with the mean (±SD) terminal t 1 / 2 The duration was 6.19 ± 1.72 days, with a mean (±SD) AUC last The mean CL was 27200 ± 3200 days • µg / mL, and the mean (± SD) Vss was 53.0 ± 4.30 mL / kg. In this cohort, a sharp increase in CL was observed after 14 days, suggesting the possible formation of ADA.

[0314] T in male and female monkeys administered SC max The value ranges between 1 day and 7 days. When considering C... max and AUC last At that time, the α4β7-binding antibody Ab001 exhibited approximately dose-linear pharmacokinetics. Mean terminal t 1 / 2 The value ranges from 10.2 to 24.2 days. When considering C... max and AUC last At that time, there was no statistically significant difference in exposure between male and female monkeys at 75 mg / kg (t-test, p = 0.05).

[0315] Overall, when considering C max (Maximum average concentration) and AUC last Serum exposure to α4β7-binding antibody Ab001 after SC administration was dose-proportional (Table 15) at concentration / time area under the curve from 0 to 648 h. Mean (±SD) C max The values ​​ranged from 297 ± 46.9 to 1780 ± 315 μg / mL, and the AUC last The range was 4590 ± 600 to 30500 ± 6460 days • μg / mL. Following a 75 mg / kg SC dose, the exposure (AUC) of male and female animals was... last and C max Similar. Administration of 150 mg / kg of Ab001 IV resulted in a mean AUC. last The exposure was 27200 ± 3200 days • μg / mL, and the average C max It was 3670 ± 433 μg / mL.

[0316] The α4β7-binding antibody Ab001 was then administered to male and female cynomolgus monkeys (n = 3 / sex / group) at 0 (SC and IV; mediator control), 25 (SC), 80 (SC), 160 (SC), and 160 mg / kg (IV) every two weeks (Q2W) (dose on day 1, day 15, and day 29) for one month. All animals survived to the planned dissection day, day 30 of the study. Bioanalytical samples were collected, processed, and analyzed using a validated GyroLab® bioanalytical method, and toxicokinetic parameters were determined using non-compartmental assays. AUC was determined after Q2W SC doses of 25, 80, and 160 mg / kg. 0-28d and C max Increased in a manner slightly greater than the dose ratio. No sex difference in exposure was observed. Median T was observed between 3.00 and 7.00 days after administration at different dose levels following a single SC administration. max The value, and the T value after the 15th day of dosing. max Values ​​ranged between 1.00 and 7.00 days. Mean (±SD) AUC after SC administration every two weeks. 0-28d Exposure (combined sex) was 6180 ± 2950, ​​28200 ± 2260, and 71500 ± 17000 days • μg / mL, respectively. C after the SC dose on day 15 max The mean AUCs (±SD) were 430 ± 291, 1380 ± 151, and 4040 ± 1380 μg / mL, respectively. Following intravenous administration of 160 mg / kg every two weeks, the mean AUCs were... 0-28d (±SD) Exposure (combined sex) was 73200 ± 12500 days • μg / mL, while C max The mean accumulation ratio (±SD) was 4980 ± 905 μg / mL. For all doses, the mean accumulation ratio after the second bi-weekly dose was ≤ 1.4 (AUC).

[0317] Anti-α4β7 binding antibody Ab001 was associated with reduced exposure in two female and one male animals at a 25 mg / kg SC dose, but these animals were still included in the TK calculation for this dose. ADA formation had no effect on exposure at either 80 mg / kg or 160 mg / kg doses (NOAEL). Throughout the study evaluation, serum α4β7 binding antibody Ab001 concentrations (for a 25 mg / kg dose, at C...) were... min The saturable binding EC50 of Ab001 is at least 3300 times that of Ab001. Exposure (C max and AUC 0-28d The dose ratio was slightly higher than the dose ratio, and no gender-related differences were observed.

[0318] Mean (±SD) AUC after SC administration every two weeks at 25, 80, and 160 mg / kg: 0-28d Exposure (combined sex) was 6180 ± 2950, ​​28200 ± 2260, and 71500 ± 17000 days • μg / mL, respectively. The mean (±SD) C after the SC dose on day 15 at 25, 80, and 160 mg / kg was... max The mean (±SD) AUCs were 430 ± 291, 1380 ± 151, and 4040 ± 1380 μg / mL, respectively. Following intravenous administration of 160 mg / kg every two weeks, the mean (±SD) AUCs were... 0-28d The exposure (combined sex) was 73200 ± 12500 days • μg / mL, while the mean (± SD) C max The concentration was 4980 ± 905 μg / mL. For all doses, the mean accumulation ratio after the second bi-weekly dose was ≤ 1.40 (AUC).

[0319] It remains unclear whether the α4β7-binding antibody Ab001 will exhibit toxicity due to its prolonged half-life. Results indicate that despite this initial uncertainty, no macroscopic (e.g., organ) or microscopic (e.g., cell / tissue) findings were observed at any dose. Example 10: Human vs. Human

[0320] For single and multiple SC and IV injections of α4β7-binding antibody Ab001 in the dose range of 100 to 1000 mg, serum concentration-time curves of α4β7-binding antibody Ab001 in humans were predicted. Steady-state serum exposure to α4β7-binding antibody Ab001 was predicted using the following two resources: (1) PK parameters of α4β7-binding antibody Ab001 in cynomolgus monkeys, where CL parameters were extrapolated interspecies using the allometric growth index of published half-life engineered monoclonal antibodies; and (2) literature values ​​of PK parameters reported for vedelizumab (an approved therapeutic human IgG1 monoclonal antibody targeting α4β7) (Rosario et al. 2016, Clinical Drug Investigation 36 (11): 913-23).

[0321] The following hypotheses regarding α4β7-binding antibody were made: (i) Ab001 followed a biphasic decline after administration; (ii) pharmacokinetic parameters, including CL and Vss, remained unchanged with repeated dosing and in a 70 kg human body within a dose range of 100 to 1000 mg (consistent with vedelizumab observations); (iii) disease status had no significant effect on PK; (iv) target-mediated drug disposal (TMDD) had a minimal effect on PK; and (v) there would be no production of anti-α4β7-binding antibody Ab001, or if present, anti-α4β7-binding antibody Ab001 had no effect on α4β7-binding antibody Ab001 PK.

[0322] Based on the above assumptions, the predicted terminal phase t of the α4β7-binding antibody Ab001 in the human body is... 1 / 2 The value was approximately 64 days, consistent with the expected extended half-life resulting from the incorporation of the YTE mutation into the Fc domain. The reported human half-life of vedelizumab is 25.5 days (Rosario et al. 2015, Alimentary Pharmacology & Therapeutics [Digestive Pharmacology and Therapeutics] 42(2): 188-202; Rosario et al. 2016). The predicted steady-state C-value of the α4β7-binding antibody Ab001 in humans for single and multiple IV and SC administrations... max The AUC values ​​are shown in Table 6. Table 6. Predicted human exposure after single and multiple administrations of SC and IV.

[0323] AUC x-yd = Area under the serum concentration-time curve from time x to time y after dosing (i.e., AUC within the dosing interval); AUC 0-inf = Area under the serum concentration-time curve from time zero to infinity; C max = Maximum serum concentration within 28 days; IV = intravenous; SC = subcutaneous; Q2W = once every two weeks. Example 11: PK-induced simulation of serum concentration of α4β7 binding antibody

[0324] The following induction protocols were used for simulation: (1) simulations were performed using the α4β7-binding antibody described herein (such as Ab001) at subcutaneous doses of 600 mg in week 0 (W0) and 300 mg in week 2 (W2) to determine the mean serum concentration during the 12-week induction period; (2) simulations were performed using the α4β7-binding antibody described herein (such as Ab001) at subcutaneous doses of 600 mg in week 0 (W0), 300 mg in week 2 (W2) and 300 mg in week 6 (W6) to determine the mean serum concentration during the 12-week induction period; (3) simulations were performed using the comparative antibody at intravenous doses of 300 mg in weeks 0 (W0), 2 (W2) and 6 (W6) to determine the mean serum concentration during the 12-week induction period.

[0325] Figure 10A Analysis showed that at subcutaneous induction doses of 600 mg in week 0 (W0) and 300 mg in week 2 (W2), the C of Ab001 was... maxW0-12 C minW0-12 and C avgW0-12 The calculated values ​​were 89.7 µg / mL, 37.4 µg / mL, and 60.7 µg / mL, respectively. Figure 10B Analysis showed that at subcutaneous induction doses of 600 mg in week 0 (W0), 300 mg in week 2 (W2), and 300 mg in week 6 (W6), the C of Ab001 was... maxW0-12 C minW0-12 and C avgW0-12 The calculated values ​​were 94.7 µg / mL, 57.6 µg / mL, and 73.9 µg / mL, respectively. Figure 10C Analysis showed that at an intravenous dose of 300 mg in weeks 0 (W0), 2 (W2), and 6 (W6), the C-value of the comparative antibody was [missing information]. maxW0-12 C minW0-12 and C avgW0-12 The calculated values ​​were 164 µg / mL, 22.9 µg / mL, and 65.1 µg / mL, respectively. Example 12: PK maintenance simulation of serum concentration of α4β7 binding antibody

[0326] The following maintenance protocols were used for simulation: (1) simulation with a subcutaneous dose of 600 mg of the α4β7-binding antibody described herein (such as Ab001) every 26 weeks to determine the mean serum concentration during the maintenance period from week 30 to week 60; (2) simulation with a subcutaneous dose of 300 mg of the α4β7-binding antibody described herein (such as Ab001) every 12 weeks to determine the mean serum concentration during the maintenance period from week 30 to week 60; (3) simulation with a comparative antibody at an intravenous dose of 300 mg every 8 weeks to determine the mean serum concentration during the maintenance period from week 30 to week 60; and (4) simulation with a comparative antibody at a subcutaneous dose of 108 mg every 2 weeks to determine the mean serum concentration during the maintenance period from week 30 to week 60.

[0327] Figure 11A Analysis showed that at a subcutaneous maintenance dose of 600 mg every 26 weeks, the C of Ab001 was... maxW30-60 C minW30-60 and C avgW30-60 The calculated values ​​were 74.8 µg / mL, 7.13 µg / mL, and 31.2 µg / mL, respectively. Figure 11B Analysis showed that at a subcutaneous maintenance dose of 300 mg every 12 weeks, the C of Ab001 was... maxW30-60 C minW30-60 and C avgW30-60 The calculated values ​​were 50.6 µg / mL, 17.8 µg / mL, and 31.3 µg / mL, respectively. Figure 11C Analysis showed that, at an intravenous dose of 300 mg every 8 weeks, the C-value of the comparative antibody was [missing information]. maxW30-60 C minW30-60 and C avgW30-60 The calculated values ​​were 136 µg / mL, 10.1 µg / mL, and 37.6 µg / mL, respectively. Figure 11D Analysis showed that at a subcutaneous dose of 108 mg every 2 weeks, the C-value of the comparative antibody was... maxW30-60 C minW30-60 and C avgW30-60 The calculated values ​​were 33.7 µg / mL, 27.2 µg / mL, and 31.1 µg / mL, respectively. Example 13: Simulation of a single escalation dose of α4β7 binding antibody

[0328] Single-increment dose simulations were performed for two regimens: (1) simulations were performed with 600 mg of the α4β7-binding antibody described herein (such as Ab001) to determine the serum concentration of Ab001 over an 84-day period from administration; and (2) simulations were performed with 300 mg of the α4β7-binding antibody described herein (such as Ab001) to determine the serum concentration of Ab001 over an 84-day period from administration.

[0329] Figure 12 The comparison of simulated serum concentrations of Ab001 at doses of 600 mg and 300 mg is shown. Figure 12 Analysis showed that, in both regimens, serum concentrations of Ab001 remained within the range of 10 µg / mL and 40 µg / mL after 84 days of administration. Example 14: Simulation of multiple escalation doses of α4β7 binding antibody

[0330] Multiple escalation dose simulations were performed for both regimens: (1) simulations were performed using the α4β7 binding antibody described herein (such as Ab001) with a subcutaneous dose of 600 mg on day 0 (D0) followed by a subcutaneous dose of 600 mg on day 14 (D14) to determine the serum concentration of Ab001 over a period of 56 days from administration; and (2) simulations were performed using the α4β7 binding antibody described herein (such as Ab001) with a subcutaneous dose of 600 mg on day 0 (D0) followed by a subcutaneous dose of 600 mg on day 14 (D14) to determine the serum concentration of Ab001 over a period of 56 days from administration.

[0331] Figure 13 The comparison of simulated serum concentrations of Ab001 at doses of 600 mg and 300 mg is shown. Figure 13 Analysis showed that, in both regimens, the serum concentration of Ab001 remained above 40 µg / mL 56 days after administration. Example 15: Clinical efficacy of α4β7 binding antibodies

[0332] Vedelizumab has been shown to be effective in treating ulcerative colitis (UC) and Crohn's disease (CD) (ENTYVIO Product Monograph). The serum half-life of this antibody in human subjects is 26 days (25 days according to the product insert). Several factors can increase vedelizumab clearance, including albumin, body weight, fecal calprotectin, prior TNF antagonist therapy, and the presence of anti-vedelizumab antibodies. In patients who received 300 mg vedelizumab via 30-minute intravenous infusion at weeks 0 and 2, the median serum trough concentration at week 6 was 25.6 mcg / mL (range 0.9 to 140.0) for ulcerative colitis and 24.5 mcg / mL (range 1.1 to 177.0) for Crohn's disease. In patients with ulcerative colitis and Crohn's disease, the median steady-state serum trough concentrations were 9.8 mcg / mL (range 2.4 to 42.8) and 11.2 mcg / mL (range 0.4 to 54.5) when 300 mg vedelizumab was administered intravenously every eight weeks starting from week 6.

[0333] Clinical trials evaluated the efficacy and safety of intravenous (for induction) and intravenous or subcutaneous vedelizumab for maintenance therapy in adult patients with moderate to severe active ulcerative colitis (Mayo score 6 to 12, endoscopic score ≥ 2). The primary endpoint during induction was the proportion of patients achieving a clinical response at week 6. The primary endpoint during the subcutaneous study was the proportion of patients achieving a clinical remission at week 52 (complete Mayo score ≤ 2 and no individual score > 1). Secondary endpoints included mucosal healing at week 52 (Mayo endoscopic score ≤ 1); durable clinical response (clinical response at weeks 6 and 52); durable clinical remission (clinical remission at weeks 6 and 52); and corticosteroid-free clinical remission at week 52 (patients who were on oral corticosteroids at baseline and had discontinued corticosteroids and were in clinical remission).

[0334] In a randomized, double-blind, placebo-controlled study evaluating efficacy endpoints at week 6 (induction) and week 52 (maintenance), vedelizumab was assessed intravenously (for induction) and subcutaneously (for maintenance) in adult patients with moderate to severe active Crohn's disease (CDAI score 220 to 450). The primary endpoint was the proportion of patients achieving clinical response (CDAI score ≤ 150). Secondary endpoints included enhanced clinical response; no corticosteroid response; and clinical response in TNFα-antagonist-naïve patients at week 52.

[0335] The α4β7-binding antibody Ab001 was evaluated in clinical trials in patients with ulcerative colitis and Crohn's disease with various primary and secondary endpoints, such as clinical remission in both ulcerative colitis and Crohn's disease, endoscopic improvement (mucosal healing) in ulcerative colitis, durable clinical response in ulcerative colitis, durable clinical remission in ulcerative colitis, enhanced clinical response in Crohn's disease, clinical remission in patients previously untreated with advanced therapy (such as TNFα antagonists) in Crohn's disease, and steroid-free clinical remission in both ulcerative colitis and Crohn's disease. Biomarker testing was performed at week 6, including C-reactive protein (CRP), fecal calprotectin, and symptoms.

[0336] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in a higher proportion of patients achieving clinical remission in both ulcerative colitis and Crohn's disease than previously observed with vedelizumab.

[0337] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in greater endoscopic improvements in ulcerative colitis than previously observed with vedelizumab.

[0338] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in greater mucosal healing in ulcerative colitis than previously observed with vedelizumab.

[0339] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in a more durable clinical response in ulcerative colitis than previously observed with vedelizumab.

[0340] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in a more durable clinical response in ulcerative colitis than previously observed with vedelizumab.

[0341] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in an enhanced clinical response in Crohn's disease compared to the previously observed response to vedelizumab.

[0342] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in a greater clinical response in TNFα antagonist-naïve patients with Crohn's disease than previously observed with vedelizumab.

[0343] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in a greater than previously observed response to vedelizumab in both ulcerative colitis and Crohn's disease without corticosteroids.

[0344] In a clinical study, the properties of the α4β7-binding antibody Ab001 resulted in improvements in biomarkers (including CRP, fecal calprotectin, and symptoms) at week 6 compared to previous observations with vedelizumab. Example 16: Two-room PK model

[0345] To guide the first-in-human dosing of Ab001, a two-compartment pharmacokinetic (PK) model was established and calibrated based on data from cynomolgus monkeys (N = 34). The model included mechanisms for intercompartmental transport and elimination of the drug, and addressed target-mediated drug disposal (TMDD) using an empirical Michaelis-Menten elimination function. The model parameters were allometrically extended to humans using an expansion exponent specific to YTE-containing mAbs. Simulations were performed for single IV and SC administrations, as well as bi-weekly administrations. PK parameters, including maximum drug concentration (C001), were calculated for each dosing regimen. max ), area under the PK curve (AUC) and trough concentration (C min ), and report here.

[0346] For two drug molecules, Ab001 and a comparative antibody, a two-compartment PK model was calibrated based on a preclinical PK dataset from cynomolgus monkeys. The parameters Thalf, Vmax, and Km were fitted to the mean measurements of the IV administration dataset for Ab001. For the SC administration dataset, the parameter Thalf... 1 / 2 V max and K m The data were derived from IV fitting and optimized for 100% bioavailability (F) and absorption half-life (T). 1 / 2 The SC (intra- ...

[0347] For preclinical fitting of the comparative antibody, datasets of 10 and 50 mg / kg were available for both IV and SC administration routes. Data from the 10 mg / kg IV dose group for ≥ 20 days were not included in the calibration because these points showed abnormally elevated serum drug levels. For parameter T... 1 / 2 V max K m P dist12 and V c A fitting was performed to capture the IV administration dataset. It was found that the optimized center volume value of the comparator antibody was low, which was the C value for capturing the IV dataset. max Required. For the SC application dataset, parameter T 1 / 2 V max K m P dist12 and V cData were taken from IV calibration and model simulations were overlaid onto preclinical SC data. Bioavailability (F) and absorption half-life (T) were compared. 1 / 2 The bioavailability and absorption half-life of the SC are set from the Ab001 SC dose calibration values.

[0348] The half-life of Ab001 in cynomolgus monkeys was estimated to be 17.1 days, and the half-life of the comparative antibody was estimated to be 9.74 days. Based on the corresponding values ​​for each antibody and applying allometric expansion, the half-life in humans in this study was estimated to be 63.7 days, and the critical concentration was estimated to be 8 μg / mL, beyond which the effect of TMDD was negligible. In previous analyses, the half-life of Ab001 in humans was estimated to be 54 days using the FcRn expansion factor. In this study, the half-life of the comparative antibody in human serum was estimated to be 38.5 days. By invoking and incorporating

[0349] All publications and patents (including all patents, patent applications, scientific publications, manufacturer specifications, and instructions) cited throughout this specification, whether above or below, are incorporated herein by reference in their entirety for all purposes. Where any material incorporated by reference conflicts or is inconsistent with this specification to any extent, this specification shall supersede any such material. equivalent

[0350] This disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. Therefore, the foregoing embodiments should be considered illustrative in all respects and not limiting of the disclosure herein. Consequently, the scope of this disclosure is indicated by the appended claims rather than the foregoing description, and all variations falling within the equivalent meaning and scope of the claims are intended to be included therein.

Claims

1. A multi-dose regimen for use in treating a disease in a subject in need, the multi-dose regimen comprising: (a) A first injectable liquid formulation comprising at least 500 mg of a total dose of α4β7-binding antibody; and (b) A second injectable liquid formulation comprising at least 120 mg of the α4β7-binding antibody in total dose. The α4β7 binding antibody is composed of the following: (i) A heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1, and (ii) A light chain consisting of an amino acid sequence according to SEQ ID NO:

3.

2. The multi-dosing regimen of claim 1, wherein the first injectable liquid formulation comprises a total dose of the α4β7 binding antibody of about 500 mg to about 1200 mg, and the second injectable liquid formulation comprises a total dose of the α4β7 binding antibody of about 120 mg to about 450 mg.

3. The multi-dosing regimen of claim 1 or claim 2, wherein the first injectable liquid formulation comprises a total dose of about 600 mg of the α4β7 binding antibody, and the second injectable liquid formulation comprises a total dose of about 300 mg of the α4β7 binding antibody.

4. The multi-dosing regimen of any one of claims 1-3, wherein the first injectable liquid formulation is for intravenous administration.

5. The multi-dosing regimen of any one of claims 1-3, wherein the first injectable liquid formulation is for subcutaneous administration.

6. The multi-dosing regimen of claim 5, wherein the first injectable liquid formulation is suitable for single or multiple injection administration.

7. The multi-dosing regimen of any one of claims 1-6, wherein the second injectable liquid formulation is for subcutaneous administration.

8. The multi-dosing regimen of claim 7, wherein the second injectable liquid formulation is suitable for single or multiple injection administration.

9. The multi-dose regimen of any one of claims 1-8, wherein the disease is inflammatory bowel disease.

10. The multi-dosing regimen of claim 9, wherein the inflammatory bowel disease is Crohn's disease.

11. The multi-dosing regimen of claim 9, wherein the inflammatory bowel disease is ulcerative colitis.

12. A dosing regimen for use in treating a disease in a subject in need, the dosing regimen comprising: (a) A first preparation for administration to the subject, comprising at least about 500 mg of total dose of α4β7 binding antibody; (b) A second preparation, comprising at least about 120 mg of the α4β7 binding antibody, administered subcutaneously to the subject after the first preparation, and subsequently administered as a maintenance dose for at least eight weeks after administration of the second preparation. The α4β7 binding antibody is composed of the following: (i) A heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1, and (ii) A light chain consisting of an amino acid sequence according to SEQ ID NO:

3.

13. The administration regimen of claim 12, wherein the first preparation is for subcutaneous administration.

14. The dosing regimen of claim 12, wherein the first preparation is for intravenous administration.

15. The dosing regimen of any one of claims 12-14, wherein the first preparation comprises a total dose of about 500 mg to about 1200 mg of the α4β7 binding antibody.

16. The dosing regimen of any one of claims 12-14, wherein the first preparation comprises a total dose of about 600 mg of the α4β7 binding antibody.

17. The dosing regimen of any one of claims 12-16, wherein the second formulation comprises a total dose of the α4β7 binding antibody of about 120 mg to about 450 mg.

18. The dosing regimen of any one of claims 12-16, wherein the second formulation comprises a total dose of about 300 mg of the α4β7 binding antibody.

19. The dosing regimen of any one of claims 12-18, wherein the second formulation is administered at least two weeks after the first formulation, and thereafter as a maintenance dose at least eight weeks after the administration of the second formulation.

20. The dosing regimen of any one of claims 12-20, wherein the first preparation is suitable for single or multiple injections.

21. The dosing regimen of any one of claims 12-20, wherein the second preparation is suitable for single or multiple injection administration.

22. The dosing regimen of any one of claims 12-21, wherein the first formulation and the second formulation are free of citrate.

23. The dosing regimen of any one of claims 12-22, wherein the disease is inflammatory bowel disease.

24. The dosing regimen of claim 23, wherein the inflammatory bowel disease is Crohn's disease.

25. The dosing regimen of claim 23, wherein the inflammatory bowel disease is ulcerative colitis.

26. An injectable formulation of an α4β7-binding antibody, said α4β7-binding antibody comprising: a) A heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; as well as b) A light chain, said light chain consisting of the amino acid sequence according to SEQ ID NO: 3, The α4β7 binding antibody described therein has an average serum half-life of more than about 10 days in cynomolgus monkeys.

27. The injectable formulation of claim 26, wherein the mean serum half-life in cynomolgus monkeys is about 17 days or longer.

28. The injectable dosage form of claim 26 or claim 27, wherein the injectable dosage form is an injectable liquid formulation.

29. The injectable formulation of claim 28, wherein the α4β7 binding antibody is present at a concentration of at least 180 mg / mL.

30. The injectable dosage form of claim 28, wherein the injectable liquid formulation is free of citrate.

31. A method for treating a disease in a patient in need, the method comprising: Administer to subjects in need (a) an effective induction dose of the α4β7-binding antibody, and (b) an effective dose of one or more maintenance doses of the α4β7-binding antibody, wherein the one or more maintenance doses are administered subcutaneously at intervals of at least eight weeks. The α4β7 binding antibody is composed of the following: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO:

3.

32. The method of claim 31, wherein the disease is inflammatory bowel disease.

33. The method of claim 32, wherein the inflammatory bowel disease is Crohn's disease.

34. The method of claim 33, wherein the inflammatory bowel disease is ulcerative colitis.

35. The method of any one of claims 31-34, wherein the effective amount of the induction dose of the α4β7 binding antibody is at least 600 mg, and wherein the effective amount of each of the one or more maintenance doses of the α4β7 binding antibody is at least 300 mg.

36. The method of claim 35, wherein the effective amount of the induction dose of the α4β7 binding antibody is about 600 mg, and wherein the effective amount of each of the one or more maintenance doses of the α4β7 binding antibody is about 300 mg.

37. The method of any one of claims 31-36, wherein the effective amount of the α4β7 binding antibody is administered subcutaneously.

38. The method of any one of claims 31-36, wherein the effective amount of the α4β7 binding antibody is administered intravenously.

39. The method of any one of claims 31-36, wherein the one or more maintenance doses are administered subcutaneously at intervals of approximately 12 weeks.

40. The method of any one of claims 31-36, wherein the one or more maintenance doses are administered subcutaneously at intervals of approximately 26 weeks.

41. The method of any one of claims 31-40, wherein the dose of the α4β7 binding antibody included in the induction dose is about two or more times the dose of each of the one or more maintenance doses.

42. A C10 assay that achieves 35 µg / mL or greater of the α4β7-binding antibody in a subject six weeks after administration of the α4β7-binding antibody to a subject in need. 谷 The method comprises administering at least about 600 mg of the α4β7 binding antibody to the subject in need, wherein the α4β7 binding antibody comprises the following: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO:

3.

43. The method of claim 42, wherein about 600 mg to about 1200 mg of the α4β7 binding antibody is administered intravenously.

44. The method of claim 42, wherein about 600 mg to about 1200 mg of the α4β7 binding antibody is administered subcutaneously.

45. The method of claim 43, wherein about 600 mg of the α4β7 binding antibody is administered intravenously.

46. ​​The method of claim 44, wherein about 600 mg of the α4β7 binding antibody is administered subcutaneously.

47. The method of any one of claims 42-46, further comprising administering at least about 300 mg of the α4β7-binding antibody to the subject in need, wherein administering at least about 300 mg of the α4β7-binding antibody results in a steady-state Cg. 谷 The concentration is at least 6 µg / mL.

48. The method of claim 47, which results in serum C avgW0-W12 The concentration should be at least 60 μg / mL.

49. The method of claim 47, wherein administration of at least about 600 mg of the α4β7 binding antibody results in serum C avgW30-W40 The concentration should be at least 30 μg / mL.

50. The method of any one of claims 42-49, further comprising administering at least about 300 mg of the α4β7 binding antibody to the subject in need, wherein the administration results in an average serum concentration of the α4β7 binding antibody above 35 μg / mL for ten weeks following the administration of at least about 300 mg of the α4β7 binding antibody.

51. The method of any one of claims 42-49, further comprising administering at least about 300 mg of the α4β7 binding antibody subcutaneously to the subject in need four weeks after administration of the last dose of the α4β7 binding antibody.

52. The method of any one of claims 42-49, further comprising administering, every twenty-six weeks, at least about 600 mg of the α4β7-binding antibody subcutaneously to the subject.

53. An α4β7 binding antibody, comprising the following: (a) a heavy chain, said heavy chain consisting of the amino acid sequence according to SEQ ID NO: 1; and (b) A light chain consisting of an amino acid sequence according to SEQ ID NO:

3.

54. An isolated nucleic acid encoding the heavy and / or light chain of the α4β7 binding antibody as described in claim 53.

55. The isolated nucleic acid as described in claim 54, encoded as SEQ ID NO:

1.

56. The isolated nucleic acid as described in claim 54, encoded as SEQ ID NO:

3.

57. A recombinant host cell comprising the isolated nucleic acid as described in any one of claims 54-56, or an expression vector comprising the isolated nucleic acid as described in any one of claims 54-56.

58. The multi-dosing regimen of claim 1, the dosing regimen of claim 11, the injectable formulation of claim 26, or the method of claim 31, wherein the disease is a gastroenteritis.

59. The multi-dose regimen of any one of claims 1-11, the dosing regimen of any one of claims 12-25, the method of any one of claims 31-41, the method of any one of claims 42-52, or the antibody of claim 53, wherein the α4β7 binding antibody has a mean serum half-life of more than about 10 days in cynomolgus monkeys.

60. The multi-dose regimen of any one of claims 1-11, the dosing regimen of any one of claims 12-25, the method of any one of claims 31-41, the method of any one of claims 42-52, or the antibody of claim 53, wherein the mean serum half-life in cynomolgus monkeys is about 17 days or longer.

61. The multi-dose regimen of any one of claims 1-11, the dosing regimen of any one of claims 12-25, the injectable dosage form of any one of claims 26-30, the method of any one of claims 31-41, the method of any one of claims 42-52, or the antibody of claim 53, wherein the α4β7 binding antibody has one or more of the following properties: (a) The chain-breaking temperature TmOnset is greater than approximately 55°C. (b) The chain-breaking temperature TmOnset is greater than 56.2°C. (c) The proportion of G0F was approximately 55.1% to approximately 60.4%. (d) The proportion of G1F was approximately 16.6% to approximately 18.8%. (e) The proportion of Man5 is approximately 7.3% to approximately 8.8%. (f) Does not induce T cell activation markers CD25 or CD69. (g) Does not result in the release of cytokines, said cytokines being one or more of IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70, and TNF. (h) Does not induce complement-dependent cytotoxicity in primary human PBMCs and human β-lymphocytes expressing α4β7 in CDC. (i) Does not induce antibody-dependent cytotoxic ADCC in human NK cells, and (j) Does not affect the inhibitory activity of regulatory T cells expressing α4β7 integrin, wherein the inhibitory activity is measured by the presence of elevated CD71, CD25, Ki67, granzyme B or OX40.

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