α4β7 integrin antibody compositions and methods for treating inflammatory bowel disease

Abstract

Provided herein are variant α4β7 integrin antibodies and methods of use.

Description

Attorney Docket No. 220703-011103 / PCT a407 INTEGRIN ANTIBODY COMPOSITIONS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASECROSS-REFERENCED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 719,066, filed on November 11, 2024, and U.S. Provisional Application No. 63 / 799,310, filed on May 2, 2025, the entire contents of each of which are incorporated herein by reference.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing, which has been submitted via Patent Center. The Sequence Listing titled 220703-011103_PCT_SL.xml, which was created on November 11, 2025, and is 12,164 bytes in size, is hereby incorporated by reference in its entirety.FIELD

[0003] Aspects of the present disclosure relate to anti-a4[37 antibody formulations for the treatment of inflammatory bowel disease and methods of treatment with such antibodies.BACKGROUND

[0004] Integrins are cell-adhesion transmembrane receptors that function as extracellular matrix (ECM)-cytoskeletal 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 a4[37 integrins have been investigated as pharmacological targets for treating various diseases including cancer and inflammatory diseases (e.g., inflammatory bowel disease). However, current integrin therapies have been 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. As such, improved a4[37 therapies are needed.SUMMARY

[0005] Provided herein are methods of upregulating C-C chemokine receptor type 9 (CCR9) gene expression in a human subject. In some embodiments, the methods comprise administering to the human subject either intravenously or subcutaneously at least one dose of a composition comprising an effective amount of an anti-a4[37 antibody having a modified Fc and having an extended half-life compared to an antibody comprising a wild-type Fc, wherein the at least one dose, when administered to the human subject, increases the CCR9 gene expression in whole blood cells for at least twelve days as compared to the CCR9 gene expression prior to the Page 1 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT administering. In some embodiments, the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system. In some embodiments, the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the CCR9 gene expression is determined by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR). In some embodiments, the blood cells are whole blood cells. In some embodiments, the administering of the at least one dose increases the CCR9 gene expression for at least twenty-six days. In some embodiments, the administering of the at least one dose increases the CCR9 gene expression for at least fifty-four days. In some embodiments, wherein the administering of the at least one dose increases the CCR9 gene expression for at least eighty-one days. In some embodiments, the administering of the at least one dose increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.

[0006] In some embodiments, the at least one dose, when administered intravenously or subcutaneously to the human subject, saturates a4[37 receptors of memory T cells circulating in blood for at least twelve days as compared to a baseline occupancy of the a4[37 receptors of memory T cells prior to the administering. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least twenty-six days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least fifty-four days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least eighty-one days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least 24 weeks. a4[37 receptor occupancy saturation was observed at drug concentrations >2 pg / mL. Receptor occupancy appeared to decrease when drug concentrations decreased below 1 pg / mL, e.g., at week 32 in a subset of participants. In some embodiments, the memory T cells are CD8+memory T cells. In some embodiments, the memory T cells are CD4+memory T cells. In some embodiments, the human subject has an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the methods comprise administering the composition subcutaneously. In some embodiments, the methods comprise administering the composition intravenously. In some embodiments, the effective amount comprises at least 100 mg of the antibody. In some embodiments, the effective amount comprises at least 300 mg of the antibody. In some embodiments, the effective amount comprises at least 600 mg of the antibody. In some embodiments, the effective amountPage 2 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT comprises at least 1000 mg of the antibody. In some embodiments, the antibody has an average serum half-life greater than about 60 days in humans. In some embodiments, the antibody has an average serum half-life greater than about 70 days in humans. In some embodiments, the antibody has an average serum half-life of about 80 days in humans. In some embodiments, the antibody has an average serum half-life greater than about 90 days in humans. In some embodiments, the antibody has an average serum half-life is about 100 days or greater in humans.

[0007] In some embodiments, receptor occupancy is determined by a flow cytometry assay. In some embodiments, the at least one dose comprises a single dose. In some embodiments, the methods comprise administering the effective amount of the anti-a4[37 antibody every three months. In some embodiments, the methods comprise administering the effective amount of the anti-a4[37 antibody every six months. In some embodiments, the administering of the at least one dose results in a plasma or serum concentration of the anti-a4[37 antibody of at least about 40 pg / mL for 6 weeks or more.

[0008] Also, provided herein are methods of occupying a4[37 receptors of memory T cells circulating in blood of a human subject. In some embodiments, the methods comprise administering to the human subject at least one dose of a composition comprising an effective amount of anti-a4[37 antibody having modified Fc and having an extended half-life compared to an antibody comprising a wild-type Fc, and wherein the at least one dose, when administered to the human subject, saturates the a4[37 receptors for at least twelve days as compared to a baseline occupancy of the a4[37 receptors prior to the administering. In some embodiments, the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system. In some embodiments, the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least twenty-six days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least fifty-four days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least eighty-one days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least 24 weeks. a4[37 receptor occupancy (RO) saturation was observed at drug concentrations >2 pg / mL. In some embodiments, the memory T cells are CD8+memory T cells. In some embodiments, the memory T cells are CD4+memory T cells. In some embodiments, the human subject has an inflammatoryPage 3 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the methods comprise administering the composition subcutaneously. In some embodiments, the methods comprise administering the composition intravenously. In some embodiments, the effective amount comprises at least 100 mg of the antibody. In some embodiments, the effective amount comprises at least 300 mg of the antibody. In some embodiments, the effective amount comprises at least 600 mg of the antibody. In some embodiments, the effective amount comprises at least 1000 mg of the antibody. In some embodiments, the antibody has an average serum half-life greater than about 60 days in humans. In some embodiments, the antibody has an average serum half-life greater than about 70 days in humans. In some embodiments, the antibody has an average serum half-life of about 80 days in humans. In some embodiments, the antibody has an average serum half-life greater than about 90 days in humans. In some embodiments, the antibody has an average serum half-life is about 100 days or greater in humans. In some embodiments, receptor occupancy is determined by a flow cytometry assay. In some embodiments, the at least one dose comprises a single dose.

[0009] Also, provided herein are compositions for use in upregulating C-C chemokine receptor type 9 (CCR9) gene expression in a human subject. In some embodiments, the compositions comprise an effective amount of anti-a4[37 antibody having a modified Fc and an extended half-life compared to an antibody having a wild-type Fc, wherein the compositions, when administered to the human subject in at least one dose, increases the CCR9 gene expression in whole blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering. In some embodiments, the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system. In some embodiments, the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the blood cells are whole blood cells. In some embodiments, the effective amount increases the CCR9 gene expression for at least twenty-six days. In some embodiments, the effective amount increases the CCR9 gene expression for at least fifty-four days. In some embodiments, the effective amount increases the CCR9 gene expression for at least eighty-one days. In some embodiments, the effective amount increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering. In some embodiments, the effective amount, when administered to the human subject, saturates a4[37 receptors of memory T cells circulating in blood for at least twelve days as compared to a baseline occupancy of the a4[37 receptors ofPage 4 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT memory T cells prior to the administering as determined by flow cytometry assay. In some embodiments, the effective amount saturates the a4[37 receptors of memory T cells for at least twenty-six days. In some embodiments, the effective amount saturates the a4[37 receptors of memory T cells for at least fifty-four days. In some embodiments, the effective amount saturates the a4p7 receptors of memory T cells for at least eighty-one days. In some embodiments, the memory T cells are CD8+memory T cells. In some embodiments, the memory T cells are CD4+memory T cells. In some embodiments, the human subject has an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the compositions are formulated for subcutaneous administration. In some embodiments, the compositions are formulated for intravenous administration. In some embodiments, the effective amount comprises at least 100 mg of the antibody. In some embodiments, the effective amount comprises at least 300 mg of the antibody. In some embodiments, the effective amount comprises at least 600 mg of the antibody. In some embodiments, the effective amount comprises at least 1000 mg of the antibody. In some embodiments, the antibody has an average serum half-life greater than about 60 days in humans. In some embodiments, the antibody has an average serum half-life greater than about 70 days in humans. In some embodiments, the antibody has an average serum half-life of about 80 days in humans. In some embodiments, the anti-a4p7 antibody has an average serum half-life greater than about 90 days in humans. In some embodiments, the anti-a4p7 antibody has an average serum half-life of about 100 days or greater in humans.

[0010] Also, provided herein are compositions for use in saturating a4p7 receptors of memory T cells circulating in blood of a human subject. In some embodiments, the compositions comprise an effective amount of anti-a4p7 antibody having a modified Fc and having an extended half-life compared to an antibody comprising a wild-type Fc, wherein an effective amount of the compositions, when administered to the human subject in at least one dose, saturates the a4p7 receptors of memory T cells for at least twelve days as compared to a baseline occupancy of a4p7 receptors of memory T cells prior to the administering. In some embodiments, the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system. In some embodiments, the anti-a4p7 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3. In some embodiments, the effective amount, when administered to the human subject, saturates the a4[37 receptors of memory T cells for at least twenty-six days. In somePage 5 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT embodiments, the effective amount, when administered to the human subject, saturates the a4[37 receptors of memory T cells for at least fifty-four days. In some embodiments, the effective amount, when administered to the human subject, saturates the a4[37 receptors of memory T cells for at least eighty-one days. In some embodiments, the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least 24 weeks. a4[37 receptor occupancy (RO) saturation was observed at drug concentrations >2 pg / mL. In some embodiments, the memory T cells are CD8+memory T cells. In some embodiments, the memory T cells are CD4+memory T cells. In some embodiments, the effective amount, when administered to the human subject, increases C-C chemokine receptor type 9 (CCR9) gene expression in blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering. In some embodiments, the effective amount increases the CCR9 gene expression for at least twenty-six days. In some embodiments, the effective amount increases the CCR9 gene expression for at least fifty-four days. In some embodiments, the effective amount increases the CCR9 gene expression for at least eighty-one days. In some embodiments, the effective amount increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering. In some embodiments, the human subject has an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the compositions are formulated for subcutaneous administration. In some embodiments, the compositions are formulated for intravenous administration. In some embodiments, the effective amount comprises at least 100 mg of the antibody. In some embodiments, the effective amount comprises at least 300 mg of the antibody. In some embodiments, the effective amount comprises at least 600 mg of the antibody. In some embodiments, the effective amount comprises at least 1000 mg of the antibody. In some embodiments, the antibody has an average serum half-life greater than about 60 days in humans. In some embodiments, the antibody has an average serum half-life greater than about 70 days in humans. In some embodiments, the antibody has an average serum half-life of about 80 days in humans. In some embodiments, the anti-a4[37 antibody has an average serum half-life greater than about 90 days in humans. In some embodiments, the anti-a4[37 antibody has an average serum half-life of about 100 days or greater in humans.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1A shows results of single ascending dose (SAD) study of antibody AbOOl in subjects treated with AbOOl. Data shown are mean + / - SD of serum concentration in subjectsPage 6 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT dosed with AbOOl at 100 mg SC (N=6), AbOOl at 300 mg SC (N=6), AbOOl at 600 mg SC (N=6), AbOOl at 1000 mg SC (n=6), AbOOl at 1000 mg IV (N=6); AbOOl at 600 mg IV (N=8), and an additional cohort of AbOOl at 600 mg SC (N=8). FIG. IB shows results of a multiple ascending dose (MAD) study of antibody AbOOl in subjects. Data shown are mean + / - SD of serum concentration in subjects dosed with AbOOl twice each at 300 mg SC (N=6), and AbOOl at 600 mg IV (N=6).

[0012] FIGS. 2A-2E show results of the ability of antibody AbOOl to bind a4[37 receptors present on immune cells. Specifically, FIG. 2A and 2B show percentage of a4[37 receptors as demonstrated by binding of ACT-1 (murine antibody to 0.4(17) on CD4+Memory T cells and CD8+ Memory T cells, respectively, in human subjects treated with AbOOl. Data shown are mean percentage + / - SD of percent ACT-1 bound receptors in human subjects dosed with AbOOl at 300 mg SC (n=5-6), human subjects dosed with AbOOl at 600 mg SC (n=6), human subjects dosed with AbOOl at 1000 mg SC (n=6), or pooled placebo (n=2-6). Additionally, FIG. 2C and 2E show mean percentage (+ / - SD) of a4(37 bound by MAdCAM-1 (Mucosal addressin cell adhesion molecule 1) on CD4+Memory T cells and CD8+ Memory T cells, respectively, in human subjects treated with single doses of AbOOl. Data shown are Mean ± SD for each cohort at each visit; pooled placebo, (n): Placebo (4-10), 100 mg SC (6), 300 mg SC (5-6), 600 mg SC (5-6), 1,000 mg SC (6), 1,000 mg IV (5-6). FIG. 2D shows mean percentage (+ / - SD) of a4(37 bound by MAdCAM-1 on CD4+Memory T cells in human subjects treated with two doses of AbOOl either 300 mg SC or 600 mg IV. Data shown are Mean ± SD for each cohort at each visit; pooled placebo, (n): Placebo (n=2-4), 300 mg x 2 SC (n=6), 600 mg x 2 IV (n=6).

[0013] FIGS. 3A-3B show effects of antibody AbOO 1 treatment on gene expression level of normalized CCR9, relative to baseline. FIG. 3A shows changes in CCR9 gene expression in whole blood over time. Data shown are mean of the relative CCR9 gene expression + / - SD in human subjects subcutaneously administered with 300 mg of AbOOl (n=4-6), 600 mg or AbOOl (n=6), or pooled placebo (n=2-6). FIG. 3B shows comparison of CCR9 gene expression at visits across the different treatment groups of AbOO 1. The statistical test performed was t-test with Bonferroni correction for multiple comparisons.

[0014] FIG. 4A shows simulation of serum concentrations of anti-a4(37 antibody described herein (e.g., AbOOl) based on intravenous induction dosing regimen at W0 and W4. For comparison, vedolizumab is shown with induction dosing regimen at W0, W2 and maintenance dosing regimen at every 2 weeks beginning at W6. FIG. 4B summarizes the result of simulations of anticipated % of all human subjects treated with AbOOl or vedolizumab that will have Week 6 Trough Concentration of at least 40 pg / mL. FIG. 4C shows simulation of serum concentrations of anti-a4(37 antibody described herein (e.g., AbOOl) based on intravenous induction dosing Page 7 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT regimen at WO and W4, and subcutaneous maintenance dosing regimen at every 3 months (Q12W or Q3M) or every 6 months (Q24W or Q6M). For comparison, vedolizumab is shown with induction dosing regimen at WO and W2, and maintenance dosing regimen at every 2 weeks beginning at W6.

[0015] FIG. 5 shows target engagement at varying serum concentrations of AbOO 1.DETAILED DESCRIPTION

[0016] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0017] The term, “antibody,” as used herein, is understood to mean an intact antibody (e.g., an intact 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 an intact antibody, antigen-binding fragment, or Fc fragment that has been modified, engineered, or chemically conjugated. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CHI, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs can be defined. The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. Naturally occurring antibodies can be used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g., scFv), minibodies, and diabodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies).

[0018] The terms, “variable domain” and “variable region,” are used interchangeably and refer to the portions of the antibody or immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody. Variability is not evenly distributed throughout the variable domains of antibodies; it isPage 8 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT concentrated in sub-domains of each of 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 domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface.

[0019] The term, “Fc polypeptide,” as used herein, refers to one of the two polypeptides forming the dimeric Fc domain, i.e., a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, a, y, and p, respectively. Several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgG2, IgG.v IgG-i. IgAi, and IgA2.

[0020] The terms, “Fc receptor” and “FcR,” as used herein, refer to a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. FcyRIIA and FcyRIIB have an immunoreceptor tyrosine-based activation motif (ITAM) and an immunoreceptor tyrosine-based inhibition motif (ITIM), respectively. The term, FcR, also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus.

[0021] The terms, “recipient,” “individual,” “subject,” “host” and “patient”, are used interchangeably and in some embodiments, refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys etc. In some embodiments, the mammal is human. None of these terms require the supervision of medical personnel.

[0022] The term, “effective amount,” as used herein, refers to the amount of a compound (e.g., a compound of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.Page 9 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0023] The term, “treating,” as used herein, includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0024] The term, “pharmaceutical composition,” as used herein, refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0025] The term, “pharmaceutically acceptable carrier,” as used herein, refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives.

[0026] The terms, “a” and “an,” as used herein, mean “one or more” and include the plural unless the context is inappropriate.

[0027] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000-fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.

[0028] The term, “about” a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0029] The term, “percent (%) identity,” as used herein, refers to the extent to which two sequences (nucleotide or amino acid) have the same residue at the same positions in an alignment. For example, “an amino acid sequence is X% identical to SEQ ID NO: Y” refers to % identity of the amino acid sequence to SEQ ID NO: Y and is elaborated as X% of residues in the amino acid sequence are identical to the residues of sequence disclosed in SEQ ID NO: Y. Generally, computer programs are employed for such calculations. Exemplary programs that compare and align pairs of sequences, include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990) and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0030] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are Page 10 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0031] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.Compositions

[0032] Provided herein are compositions comprising polypeptides that have a binding specificity for human a4[37 integrin. Polypeptides described herein may have specificity for a4[37 and not related integrins including cx4[31 and aE[37. In some embodiments, compositions described herein comprise an anti-a4[37 antibody. In some embodiments, the anti-a4[37 antibody comprises two heavy chain polypeptides, and two light chain polypeptides.

[0033] In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a heavy chain polypeptide comprises an amino acid sequence having 100% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiment, a heavy chain polypeptide comprises or consists of an amino acid sequence having 100% sequence identity with an amino acid sequence according to SEQ ID NO: 1.Page 11 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0034] In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a light chain polypeptide comprises an amino acid sequence having 100% sequence identity with an amino acid sequence according to SEQ ID NO: 3.

[0035] In some embodiments, compositions described herein comprise a heavy chain polypeptide comprising an amino acid sequence that is 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%) identical to SEQ ID NO: 1 or 2, and a light chain polypeptide comprising an amino acid sequence that is 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%) identical to SEQ ID NO: 3. In some embodiments, a ratio of the heavy chain polypeptide and the light chain polypeptide in the compositions described herein is 1: 1.Table 1. Sequences of polypeptidePage 12 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0036] In some embodiments, compositions described herein comprise a heavy chain polypeptide comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptidePage 13 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide comprising an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2; and a light chain polypeptide comprising an amino acid sequence according to SEQ ID NO: 3.

[0037] In some embodiments, compositions described herein comprise a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 90% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 95% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consistingPage 14 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 97% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to SEQ ID NO: 3. In some embodiments, a composition comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1; and a light chain polypeptide comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according SEQ ID NO: 3.Antibodies

[0038] In some embodiments, compositions described herein comprise anti-a4[37 antibodies. Accordingly, in some embodiments, anti-a4[37 antibodies described herein comprise a heavy chain amino acid sequence, wherein the heavy chain amino acid sequence comprises HCDR1, HCDR2, and HCDR3. In some embodiments, anti-a4[37 antibodies described herein further comprise a light chain amino acid sequence, wherein the light chain amino acid sequence comprises LCDR1, LCDR2, and LCDR3. Accordingly, in some embodiments, antigen-binding sites of anti-a4[37 antibodies described herein comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 disclosed in Table 2.Table 2. CDR sequences

[0039] In some embodiments, anti-a4[37 antibodies described herein comprises two heavy chain polypeptides, each independently comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with an amino acid sequence of SEQ ID NO: 1. In some embodiments, anti-a4[37 antibodies described herein comprise two identical heavy chain polypeptides. In some embodiments, anti-a4[37 antibodies described herein comprise two non-identical heavy chain polypeptides.Page 15 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0040] In some embodiments, anti-a4[37 antibodies described herein comprises two light chain polypeptides, each independently comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with an amino acid sequence of SEQ ID NO: 3. In some embodiments, anti-a4[37 antibodies described herein comprise two identical light chain polypeptides. In some embodiments, anti-a4[37 antibodies described herein comprise two non-identical light chain polypeptides.

[0041] In some embodiments, an anti-a4[37 antibody (AbOOl) comprises a heavy chain polypeptide 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.

[0042] In some embodiments, anti-a4[37 antibodies described herein can have properties as described in PCT Application No. PCT / US2024 / 031569, fried May 30, 2024, which is herein incorporate by reference in its entirety for all purposes.

[0043] In some embodiments, anti-a4[37 antibodies described herein can have the properties as provided in Table 3.Table 3. Properties of anti-a4 7 antibody

[0044] Anti-a4[37 antibodies described herein can have the following '-glycan profiling (determined using enzymatically released V-glycans. labeled and monitored by hydrophilic interaction liquid chromatography (HILIC) coupled with a fluorescence detector (FLD)) as provided in Table 4.Table 4. / V-glycan profiling of anti-a4 7 antibodyPage 16 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCTFc Modifications

[0045] Provided herein are anti-a4[37 antibodies comprising modified Fc regions, also referred to as modified a4[37 antibodies. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index.

[0046] In some embodiments, anti-a4[37 antibodies comprise a modified Fc comprising one or more modifications. In some embodiments, the one or more modifications extended half-life of anti-a4[37 antibodies relative to anti-a4[37 antibodies with wildtype Fc regions. In some embodiments, the one or more modifications promote selective binding of Fc-gamma receptors.

[0047] In some embodiments, one or more modifications in the modified Fc is 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 is 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.

[0048] In some embodiments, a 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; and L234A / L235A / G237A; L234A / L235A / P329G.

[0049] In some embodiments, a 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 (SPLE); L234A / L235A (LA);M428L / N434A; L234A / G237A (LAGA); L234A / L235A / G237A; L234A / L235A / P329G;D265 A / 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;Page 17 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCTLAGA / 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; D265A / N434A; LALA / N434A; LAGA / N434A;LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ;LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW; LALAGA / DW; LALAPG / DW; N297A / YD: D265 A / YD: LALA / YD: LAGA / 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, a 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, a modified Fc comprises M428L / N434S (LS) modifications. In some embodiments, a modified Fc comprises M252Y / S254T / T256E (YTE) modifications. In some embodiments, M252Y / S254T / T256E (YTE) modifications in Fc region extends half-life of anti- a4p7 antibodies relative to anti-a4p7 antibodies having wild-type Fc regions. In some embodiments, a modified Fc comprises a modified IgGl Fc region, wherein the modified IgGl Fc region comprises M252Y / S254T / T256E (YTE) modifications relative to a corresponding wild-type IgGl Fc region.

[0050] In some embodiments, an Fc of anti-a4p7 antibodies described herein lacks a C- terminal lysine residue (e.g., AbOOl), the lack of which can decrease pl. In some embodiments, composition comprising an anti-a4p7 antibody, wherein the Fc lacks C-terminal lysine residue (e.g., AbOOl), has a homogeneous charge profile as compared to a composition comprising an anti-a4p7 antibody, wherein the Fc comprises a C-terminal lysine residue. While the lack of C- terminal lysine residue can decrease solubility or decrease recombinant production yield, truncation of C-terminal lysine in an anti-a4p7 antibody yields a highly soluble protein and allows a relatively high production yield of anti-a4p7 antibodies. In particular, AbOOl achieved surprising high yields (greater than 4.5 g / L) and high solubility (greater than 150 g / L).

[0051] In some embodiments, an anti-a4p7 antibody that 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 (e.g., AbOOl) may have increased FcRn binding, while exhibiting satisfactory bioavailability when an anti-a4p7 antibody is administered subcutaneously.

[0052] In some embodiments, the anti-a4p7 antibodies described herein include modifications to improve its ability to mediate effector function. Such modifications are known Page 18 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for antibody-dependent cellular cytotoxicity (ADCC), and towards Clq for complement-dependent cytotoxicity (CDC).

[0053] In some embodiments, an antibody provided herein comprises an IgGl domain with reduced fucose content at position Asn 297 (EU numbering) compared to a naturally occurring IgGl domain. Such Fc domains are known to have improved ADCC. In some embodiments, such antibodies do not comprise any fucose at position Asn 297.

[0054] In some embodiments, an anti-a4[37 antibody provided herein comprises glycan moieties. In some embodiments, an anti-a4[37 antibody provided herein comprises an IgGl domain with high total fucose. The major A-gly can types are G0F and GIF. In some embodiments, an anti-a4[37 antibody of the disclosure has one or more of the following '-glycan profiling: (a) a proportion of G0F can be greater than about 40% (e.g. , from about 40% to about 75%, from about 40% to about 45%, from about 45% to about 50%, from about 50% to about 55%, from about 55% to about 60%, from about 60% to about 65%, from about 65% to about 70%, from about 70% to about 75%); (b) a proportion of GIF can range from about 10% to about 35% (e.g. , from about 10% to about 15%, from about 15% to about 20%, from about 20% to about 25%, from about 25% to about 30%, from about 30% to about 35%); (c) a proportion of Man5 can be less than about 20% (e.g., range from about 1% to about 15%, from about 1% to about 5%, from about 5% to about 10%, from about 10% to about 15%).

[0055] In some embodiments, the anti-a4[37 antibodies described herein comprise an Fc region with one or more amino acid substitutions which improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330.

[0056] In some embodiments, the anti-a4[37 antibodies described herein comprise an Fc region with at least one galactose residue in the oligosaccharide atached to the Fc region. Such antibody variants may have improved CDC function.

[0057] In some embodiments, the anti-a4[37 antibodies described herein comprise one or more alterations that improve or diminish Clq binding and / or CDC.

[0058] In some embodiments, an Fc region, as described herein, comprises one or more amino acid substitutions. In some embodiments, the one or more substitutions can increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity relative to an Fc region without the one or more substitutions. In some embodiments, the one or more amino acid substitutions result in increased antibody half-life at pH 6.0 compared to an antibodyPage 19 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT comprising a wild-type Fc region. In some embodiments, an antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85- fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1-fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region.

[0059] In some embodiments, an Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions can decrease one or more of ADCC activity, ADCP activity, or CDC activity compared with an Fc region without the one or more substitutions.

[0060] In some embodiments, an Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In some embodiments, an Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0061] In some embodiments, the anti-a4[37 antibodies described herein comprise an extended half-life (i.e., serum half-life). In some embodiments, the anti-a4[37 antibodies described herein comprise 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, 100 or more than 100 days in humans. In some embodiments, the anti-a4[37 antibodies described herein comprise an average serum half-life of greater than about 90 days in humans. In some embodiments, the anti-a4[37 antibodies described herein comprise an average serum half-life of greater than about 100 days in humans.

[0062] In some embodiments, the anti-a4[37 antibodies described herein have a half-life that is at least 20% longer than a comparator antibody. In some embodiments, the comparator antibody comprises the same complementarity determining regions and variable regions but different Fc regions. In some embodiments, half-life of the anti-a4[37 antibodies described herein is at least 30% longer, at least 40% longer, at least 50% longer, at least 60% longer, at least 70% longer, at least 80% longer, at least 90% longer, at least 95% longer, at least 100% longer, at least 150% longer, at last 200% longer, at least 250% longer, at least 300% longer or at least 350% longer than half-life of the comparator antibody. In some embodiments, half-life of the anti-a4[37 antibodies described herein is longer than half-life of the comparator antibody by at least 2-fold, at least 3 -fold, at least 4-fold, at least 5 -fold, at least 6-fold, at least 7-fold, at least 8- fold, at least 9-fold, or at least 10-fold. In some embodiments, half-life of the anti-a4[37 antibodies described herein is longer than half-life of the comparator antibody (e.g., vedolizumab) by at least 4-fold. In some embodiments, the comparator antibody comprises aPage 20 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT heavy chain consisting of an amino acid sequence according to SEQ ID NO: 4; and a light chain consisting of an amino acid sequence according to SEQ ID NO: 5.

[0063] In some embodiments, the anti-a4[37 antibodies described herein bind a4[37 with a Koof <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. For example, in some embodiments, a first antigen-binding site binds a4[37 with a KD in a range of about 10 pM - about 1 nM, about 10 pM - about 0.9 nM, about 10 pM - about 0.8 nM, about 10 pM - about 0.7 nM, about 10 pM - about 0.6 nM, about 10 pM - about 0.5 nM, about 10 pM - about 0.4 nM, about 10 pM - about 0.3 nM, about 10 pM - about 0.2 nM, about 10 pM - about 0.1 nM, about 10 pM - about 50 pM, 0.1 nM - about 10 nM, about 0.1 nM - about 9 nM, about 0.1 nM - about 8 nM, about 0. 1 nM - about 7 nM, about 0.1 nM - about 6 nM, about 0.1 nM - about 5 nM, about 0.1 nM - about 4 nM, about 0.1 nM - about 3 nM, about 0.1 nM - about 2 nM, about 0.1 nM - about 1 nM, about 0.1 nM - about 0.5 nM, about 0.5 nM - about 10 nM, about 0.5 nM - about 9 nM, about 0.5 nM - about 8 nM, about 0.5 nM - about 7 nM, about 0.5 nM - about 6 nM, about 0.5 nM - about 5 nM, about 0.5 nM - about 4 nM, about 0.5 nM - about 3 nM, about 0.5 nM - about 2 nM, about 0.5 nM - about 1 nM, about 1 nM - about 10 nM, about 1 nM - about 9 nM, about 1 nM - about 8 nM, about 1 nM - about 7 nM, about 1 nM - about 6 nM, about 1 nM - about 5 nM, about 1 nM - about 4 nM, about 1 nM - about 3 nM, about 1 nM - about 2 nM, about 2 nM - about 10 nM, about 3 nM - about 10 nM, about 4 nM - about 10 nM, about 5 nM - about 10 nM, about 6 nM - about 10 nM, about 7 nM - about 10 nM, about 8 nM - about 10 nM, or about 9 nM - about 10 nM. In some embodiments, affinity of anti-a4[37 antibody to a4[37 is measured by SPR. In some embodiments, affinity of anti-a4[37 antibody to a4[37 is measured by BLI. In some embodiments, affinity of anti-a4[37 antibody to a4[37 is measured by KinExA.METHODS OF TREATMENT AND DOSAGE REGIMENS

[0064] Described herein, in some embodiments, are methods of treating a disease or disorder in a human subject in need thereof, the method comprising subcutaneously or intravenously administering to the human subject an effective amount of an anti-a4[37 antibody disclosed herein.

[0065] Provided herein are methods of treating a disease or disorder in a human subject in need thereof comprising administering to the human subject one or more initial doses comprising an effective amount of an anti-a4[37 antibody (also referred to herein as “induction dose”,Page 21 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT“induction regimen” or “induction therapy”) and one or more subsequent doses comprising an effective amount of the anti-a4p7 antibody (also referred to herein as “maintenance dose”).

[0066] In some embodiments, a single or more than one induction dose is administered, followed by maintenance doses. The disclosure contemplates one, two, three, or more induction doses. In some embodiments, divided induction doses are administered one week apart, two weeks apart, three weeks apart, or four weeks apart. For example, in some embodiments, a second induction dose is administered four weeks from when the first induction dose was administered. In some embodiments, maintenance dose is administered every 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26 or more weeks. The induction dosing can involve administration of a higher dose than a maintenance dose. Alternatively, the induction dosing amount is the same as the maintenance dosing amount.

[0067] In some embodiments, methods described herein comprise administering a total induction dose of at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 800 mg, at least 900 mg or at least 1000 mg of an anti-a4[37 antibody in a single / divided dose to a human subject in need thereof. In some embodiments, methods described herein comprise administering a total induction dose of at least 100 mg of an anti-a4[37 antibody in a single or divided dose to a human subject in need thereof. In some embodiments, methods described herein comprise administering a total induction dose of at least 300 mg of an anti-a4[37 antibody in a single / divided dose to a human subject in need thereof. In some embodiments, methods described herein comprise administering a total induction dose of at least 600 mg of an anti-a4[37 antibody in a single / divided dose to a human subject in need thereof. In some embodiments, methods described herein comprise administering a total induction dose of at least 1000 mg of an anti-a4[37 antibody in a single / divided dose to a human subject in need thereof. In some embodiments, an induction dose can be administered intravenously or subcutaneously. In some embodiments, at least one of divided induction doses can be administered intravenously or subcutaneously.

[0068] In some embodiments, the average plasma or serum concentration of at least about 35 pg / mL is achieved in human subjects for at least 2 weeks or more upon the administration of the one or more induction doses(s) of an anti-a4[37 antibody. In some embodiments, the plasma or serum concentration 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, 70, 80, 90 or more than 90 pg / mL is achieved in human subjects for at least 2 weeks or more upon the administration of the one or more induction doses(s) of an anti-a4[37 antibody. In some embodiments, the average plasma or serum concentration of at least about 35 pg / mL (e.g., from 35 to 40 pg / mL, from 40 to 45 pg / mL, from Page 22 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT45 to 50 pg / mL, from 50 to 55 pg / mL, from 55 to 60 pg / mL, e.g., 36 pg / mL, 40 pg / mL, 46 pg / mL, 51 pg / mL, 56 pg / mL, 60 pg / mL, 70 pg / mL, 80 pg / mL, 90 pg / mL or more) is achieved in the human subject over the course of the induction period. In some embodiments, the average plasma or serum concentration of at least about 45 pg / mL is achieved in the human subject over the course of the induction period. In some embodiments, the average plasma or serum concentration of at least about 60 pg / mL is achieved in the human subject over the course of the induction period.

[0069] In some embodiments, administration of the induction doses can result in plasma or serum Cavg, wo-we of at least about 65 pg / mL, e.g., from about 65 pg / mL to about 75 pg / mL or greater, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL or more. In some embodiments, administration of the induction doses can result in plasma or serum Cavg, wo-we of about 70 pg / mL. In some embodiments, administration of the induction doses can result in plasma or serum Cavg, wo-wi2 of at least about 60 pg / mL, e.g., from about 60 pg / mL to about 70 pg / mL or greater, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 80 pg / mL about 90 pg / mL, about 100 pg / mL, about 110 pg / mL, about 120 pg / mL, about 130 pg / mL or more. In some embodiments, administration of the induction doses can result in plasma or serum Cavg, wo-wi2 of about 123 pg / mL. In some embodiments, administration of the induction doses can result in plasma or serum Cavg, wo-wi2 of about 65 pg / mL. In some embodiments, the plasma or serum concentration of at least about 35 pg / mL (e.g., from 35 to 40 pg / mL, from 40 to 45 pg / mL, from 45 to 50 pg / mL, from 50 to 55 pg / mL, from 55 to 60 pg / mL, e.g., 36 pg / mL, 40 pg / mL, 46 pg / mL, 51 pg / mL, 56 pg / mL, 60 pg / mL or more) is achieved in human subjects for at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 26 weeks or more (e.g., from 4 weeks to 6 weeks, from 6 weeks to 8 weeks, from 8 weeks to 10 weeks, from 10 weeks to 12 weeks, from 12 weeks to 14 weeks, from 14 weeks to 16 weeks, from 16 weeks to 18 weeks, from 18 weeks to 20 weeks, from 20 weeks to 22 weeks, from 22 weeks to 24 weeks, from 24 weeks to 26 weeks or more) upon administration of an effective amount of anti-a4[37 antibody during the induction phase.

[0070] In some embodiments, methods described herein comprise administering a maintenance dose of anti-a4[37 antibody at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26 weeks or more (e.g., from 4 weeks to 6 weeks, from 6 weeks to 8 weeks, from 8 weeks to 10 weeks, from 10 weeks to 12 weeks, from 12 weeks to 14 weeks, from 14 weeks to 16 weeks, from 16 weeks to 18 weeks, from 18 weeks to 20 weeks, from 20 weeks to 22 weeks, from 22 weeks to 24 weeks, from 24 weeks to 26 weeks or more) after the administration of the Page 23 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT final induction dose. In some embodiments, the maintenance dose is lower than the induction dose (e.g., twice, three times or more lower than the induction dose). In some embodiments, the maintenance dose is the same as the induction dose. A maintenance dose can be administered intravenously or subcutaneously.

[0071] In some embodiments, methods described herein comprise administering a maintenance dose of at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 800 mg, at least 900 mg or at least 1000 mg of an anti-a4[37 antibody in a single dose to a human subject in need thereof following administration of the final induction dose. In some embodiments, methods described herein comprise administering a maintenance dose of at least 100 mg of an anti-a4[37 antibody in a single dose to a human subject in need thereof following administration of the final induction dose. In some embodiments, methods described herein comprise administering a maintenance dose of at least 300 mg of an anti-a4[37 antibody in a single dose to a human subject in need thereof following administration of the final induction dose. In some embodiments, methods described herein comprise administering a maintenance dose of at least 600 mg of an anti-a4[37 antibody in a single dose to a human subject in need thereof following administration of the final induction dose. In some embodiments, methods described herein comprise administering a maintenance dose of at least 1000 mg of an anti-a4[37 antibody in a single dose to a human subject in need thereof following administration of the final induction dose.

[0072] In some embodiments, the plasma or serum concentration of at least about 6 pg / mL (e.g. from about 6 pg / mL to about 10 pg / mL, from about 6 pg / mL to about 20 pg / mL, from about 6 pg / mL to about 30 pg / mL e.g., 6 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, 30 pg / mL or more) is achieved in a human subject for at least 4, at least 8, at least 12, at least 16, at least 20, at least 24, at least 26 weeks or more (e.g., from 4 weeks to 6 weeks, from 6 weeks to 8 weeks, from 8 weeks to 10 weeks, from 10 weeks to 12 weeks, from 12 weeks to 14 weeks, from 14 weeks to 16 weeks, from 16 weeks to 18 weeks, from 18 weeks to 20 weeks, from 20 weeks to 22 weeks, from 22 weeks to 24 weeks, from 24 weeks to 26 weeks or more) upon the administration of the a4[37 binding antibody. In some embodiments, the plasma or serum concentration does not fall below 6 pg / mL between maintenance dosing intervals. In some embodiments, the plasma or serum concentration does not fall below 10 pg / mL between maintenance dosing intervals. In some embodiments, the plasma or serum concentration does not fall below 20 pg / mL between maintenance dosing intervals. In some embodiments, the plasma or serum concentration does not fall below 30 pg / mL between maintenance dosing intervals.Page 24 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0073] In some embodiments, a first induction dose, a second induction dose, a first maintenance dose and a second maintenance dose are administered at week 0, week 4, week 12 and week 24, respectively. In some embodiments, each subsequent maintenance dose is administered every three months or Q12W. In some embodiments, each subsequent maintenance dose is administered every six months or Q24W.

[0074] In some embodiments, a first induction dose, a second induction dose, a first maintenance dose and a second maintenance dose are administered at week 0, week 4, week 14 and week 26, respectively. In some embodiments, each subsequent maintenance dose is administered every three months or Q12W. In some embodiments, each subsequent maintenance dose is administered every six months or Q24W.

[0075] In some embodiments, the plasma or serum concentration of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 100, 150, or more than 150 pg / mL is achieved in human subject for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks or more upon administration of the one or more induction dose(s) and / or one or more of the maintenance dose(s) of the a4[37 binding antibody.

[0076] Further described herein, in some embodiments, are methods of increasing C-C chemokine receptor type 9 (CCR9) gene expressing blood cells in a human subject. Blood cells (e.g., T cells, B cells, dendritic cells) express CCR9 gene. CCL25 is a chemokine that attracts blood cells that express CCR9 gene. The CCR9 gene expressing blood cells are attracted to tissues comprising CCR9 chemokines (e.g., CCL25). T cells that express a4[37 integrin binds / adheres to MAdCAM-1 (Mucosal addressin cell adhesion molecule 1) expressing cells / tissues. MAdCAM-1 is a trafficking molecule that allows infiltration and localization of blood cells in MAdCAM-1 expressing tissues. Thus, MAdCAM-1 helps / facilitates T cells to infiltrate / localize in MAdCAM-1 expressing tissues. When a4[37 integrin on blood cells (e.g, memory T cells) is bound by anti-a4[37 antibody, the blood cells cannot bind to MAdCAM- 1 (Mucosal addressin cell adhesion molecule 1). Therefore, in some embodiments, administering of an effective amount of an anti-a4[37 antibody to a human subject does not allow CCR9 gene expressing blood cells to infiltrate / localize in tissues comprising CCR9 chemokines resulting in increase in proportion of CCR9 gene expressing blood cells in the blood of the human subject relative to a baseline proportion of CCR9 gene expressing blood cells prior to administering. In some embodiments, the method comprises the administering increases the proportion of the CCR9 gene expressing blood cells in the blood of the human subject for at least twelve days, at least twenty-six days, at least fifty-four days, or at least eighty-one days as compared to a baseline proportion of the CCR9 gene expressing blood cells prior to the administering. In some embodiments, the method comprises administering to the human subject an effective dose of aPage 25 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT composition comprising an anti-a4[37 antibody, wherein the effective dose, when administered to the human subject, increases the CCR9 gene expression in whole blood for at least twelve days, at least twenty-six days, at least fifty-four days, or at least eighty-one days as compared to the CCR9 gene expression prior to the administering. In some embodiments, CCR9 gene expression can be determined by RT-qPCR. In some embodiments, the blood cells are whole blood cells. In some embodiments, administration of an effective dose of anti-a4[37 antibodies described herein increases the CCR9 gene expression by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 100%, at least 120%, at least 150%, at least 200%, as compared to the CCR9 gene expression prior to the administering. In some embodiments, administration of an effective dose of anti-a4p7 antibodies described herein increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering. In some embodiments, an administration of an effective dose of an anti-a4p7 antibody can modulate trafficking and distribution of dendritic cells in intestinal mucosa. In some embodiments, an effective dose of an anti-a4p7 antibody can be at least one dose of the anti-a4p7 antibody.

[0077] Further described herein, in some embodiments, are methods of occupying a4p7 receptors of memory T cells circulating in blood of a human subject. An effective dose of anti- a4p7 antibodies described herein, when binds a4p7 integrin on blood cells (e.g., memory T cells), prevents interaction between the blood cells and MAdCAM-1 (Mucosal addressin cell adhesion molecule 1). MAdCAM-1 is a trafficking molecule that allows infiltration and localization of blood cells in MAdCAM-1 expressing tissues. Accordingly, in some embodiments, an effective dose of anti-a4p7 antibodies described herein prevents / reduces infiltration and / or localization of blood cells in MAdCAM-1 expressing tissues. In some embodiments, the method comprises administering to the human subject an effective dose of a composition comprising an anti-a4p7 antibody, wherein the effective dose, when administered to the human subject, saturates the a4p7 receptors for at least twelve days, at least twenty-six days, at least fifty-four days, at least eighty-one days, or at least 24 weeks, as compared to a baseline occupancy of the a4p7 receptors prior to the administering. In some embodiments, a4p7 receptor occupancy saturation was observed at drug concentrations >2 pg / mL. In some embodiments, a4p7 receptor occupancy saturation was observed at drug concentrations >6.5 pg / mL. In some embodiments, receptor occupancy appeared to decrease when drug concentrations decreased below 1 pg / mL, e.g., at week 32 in a subset of participants. In some embodiments, occupancy of a4[37 receptors of memory T cells can be determined by flow cytometry assay. In some embodiments, memory T cells comprise CD8+memory T cells, CD4+memory T cells or both. In some embodiments, administration of an effective dose of the anti-a4[37 antibody can modulatePage 26 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT trafficking and distribution of dendritic cells in intestinal mucosa. In some embodiments, an effective dose of an anti-a4p7 antibody can be at least one dose of the anti-a4p7 antibody. In some embodiments, an effective dose of an anti-a4p7 antibody can be a single dose of the anti- a4p7 antibody.

[0078] Further described herein, in some embodiments, are methods of treating a disease or disorder in a human subject in need thereof comprising subcutaneously administering to a human subject about >300 mg of an anti-a4p7 antibody, wherein the anti-a4p7 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; and wherein a plasma or serum concentration of the anti-a4p7 antibody remains at least about 10 pg / mL for 6 weeks or more following the administration. In some embodiments, methods of treating a disease or disorder in a human subject in need thereof comprising subcutaneously administering to a human subject about >300 mg of an anti-a4p7 antibody, wherein the anti-a4p7 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; and wherein a plasma or serum concentration of the anti-a4p7 antibody remains at least about 10 pg / mL for 84 days or more following the administration. Further described herein, in some embodiments, are methods of treating a disease or disorder in a human subject in need thereof comprising subcutaneously administering to the human subject about 600 mg of an anti-a4p7 antibody, wherein the anti-a4p7 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; and wherein a plasma or serum concentration of the anti-a4p7 antibody remains at least about 40 pg / mL for 6 weeks or more following the administration.

[0079] In some embodiments, methods described herein comprise administering intravenously or subcutaneously of at least one dose of an anti-a4p7 antibody. Accordingly, in some embodiments, methods described herein comprise administering of an effective amount of the anti-a4p7 antibody every three months. In some embodiments, methods described herein comprise administering of an effective amount of the anti-a4p7 antibody every six months. In some embodiments, methods described herein comprise administering of at least one dose of the anti-a4p7 antibody every three months. In some embodiments, administering of at least one dose of an anti-a4p7 antibody can be administering of at least one dose of the anti-a4p7 antibody every six months. In some embodiments, administering of at least one dose of an anti-a4p7 antibody can be administering of one dose of the anti-a4p7 antibody every three months. InPage 27 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT some embodiments, administering of at least one dose of an anti-a4[37 antibody can be administering of one dose of the anti-a4[37 antibody every six months.

[0080] In some embodiments, the injectable dosage form is an injectable liquid formulation. In some embodiments, the injectable liquid formulation does not comprise citrate. In some embodiments, the injectable liquid formulation comprises one or more of: histidine; arginine or a salt thereof; ethylenediaminetetraacetic acid (EDTA); and polysorbate 80 or poloxamer 188.

[0081] In some embodiments, the administration of the anti-a4p7 antibody follows a biphasic decline in serum concentration. In some embodiments, repeated dosing of anti-a4p7 antibody does not have a significant influence on clearance (CL) and steady-state volume of distribution (Vss). In some embodiments, pharmacokinetic is not impacted by disease state of a human subject.

[0082] Bioavailability is also an important factor determining the SC maintenance dose level. In some embodiments, SC administration results in absolute bioavailability of 50% or higher. In some embodiments, modeling reveals a bioavailability >70% following SC injection.

[0083] Described herein, in certain embodiments, are methods of treating a gastrointestinal inflammatory disease in a human subject in need thereof. As used herein, the term “gastrointestinal inflammatory disease” refers to a disease of the gastrointestinal tract that involves inflammatory pathways. For example, the gastrointestinal inflammatory disease includes, but is not limited to, inflammatory bowel disease, ulcerative colitis (with or without exposure to anti-tumor necrosis factor (anti-TNF)), Crohn’s disease (including fistulizing Crohn's Disease), chronic pouchitis, collagenous gastritis, microscopic or collagenous colitis, colitis (including immune mediated colitis), sclerosing cholangitis (including in human subjects with underlying inflammatory bowel disease, celiac enteritis, ileitis. In other aspects of the disclosure, provided herein are methods of treating Intestinal Acute Graft Versus Host Disease (aGVHD) (e.g., in human subjects undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT)), steroid-refractory acute intestinal graft-versus-host disease (GvHD) (e.g., in human subjects who have undergone Allo-HSCT), Type 1 diabetes (T1D) (e.g., with or without anti-TNF pre-treatment), immune checkpoint inhibitor-related colitis in human subjects with genitourinary cancer or melanoma, microscopic colitis (e.g., lymphocytic colitis and collagenous colitis), autoimmune enteropathy, eosinophilic gastroenteritis (e.g. eosinophilic esophagitis), and chronic granulomatous disease.

[0084] In some embodiments, the disease is a gastrointestinal inflammatory disease. In some embodiments, the disease is an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is Crohn’s disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis.Page 28 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT

[0085] In some embodiments, the human subject in need thereof has moderately to severely active ulcerative colitis. The Mayo score is a commonly used disease activity index in UC. The complete Mayo score is composed of four parts: rectal bleeding, stool frequency, physician assessment, and endoscopy appearance, each part being rated from 0 to 3, giving a total score of 0 to 12. In some embodiments, the human subject in need thereof has a Mayo score 6 to 12 with endoscopic sub score >2. In some embodiments, administration of the anti-a4[37 antibody results in clinical response defined as a reduction in complete Mayo score of 3 or more points and 30% from baseline, (or a partial Mayo score reduction of 2 or more points and 25% or greater from baseline, if the complete Mayo score was not performed at the visit) with an accompanying decrease in rectal bleeding subscore of 1 or 0. In some embodiments, administration of the anti-a4[37 antibody results in clinical remission, for example results in a complete Mayo score of 2 or less points and no individual subscore greater than 1 point. Alternatively, a modified or adapted Mayo score can be used for inclusion and for the clinical remission endpoint for UC. Clinical remission by the modified or adapted Mayo score is: stool frequency subscore 0 or 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore 0 or 1 without friability.

[0086] In some embodiments, the human subject in need thereof has moderately to severely 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. Crohn's disease “clinical remission” refers to a CDAI score of 150 points or less, as defined by U.S. Food and Drug Administration. The American College of Gastroenterology and the European Crohn's 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 the anti-a4[37 antibody results in clinical response defined as a >100-point decrease in the CDAI score from baseline. In some embodiments, administration of the anti-a4[37 antibody results in clinical remission defined as a CDAI score of 150 points or less.

[0087] Described herein, in certain embodiments, are methods of treating an inflammatory bowel disease in a human subject in need thereof, the method comprising subcutaneously or intravenously administering to the human subject an effective amount of an anti-a4[37 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.

[0088] In some embodiments, the inflammatory bowel disease is Crohn’s disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis.Page 29 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0089] Described herein, in certain embodiments, are methods of treating an inflammatory bowel disease in a human subject in need thereof, the method comprising subcutaneously or intravenously administering to the human subject an effective amount of an anti-a4[37 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 anti-a4[37 antibody is a long acting engineered anti-a4[37 antibody, consisting of 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.

[0090] In some embodiments, the anti-a4[37 antibody is administered at a dose in a range of about 75 mg to about 1100 mg, about 75 mg to about 750 mg, about 75 mg to about 350 mg, about 75 mg to about 150 mg, about 150 mg to about 1100 mg, about 150 mg to about 750 mg, about 150 mg to about 350 mg, about 350 mg to about 1100 mg, about 350 mg to about 750 mg, or about 750 mg to about 1100 mg. In some embodiments, the anti-a4[37 antibody is administered at a dose of about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg or about 1200 mg. In some embodiments, the anti-a4[37 antibody is administered at a dose of about 100 mg. In some embodiments, the anti- a4[37 antibody is administered at a dose of about 300 mg. In some embodiments, the anti-a4[37 antibody is administered at a dose of about 600 mg. In some embodiments, the anti-a4[37 antibody is administered at a dose of about 1000 mg.

[0091] In some embodiments, administration of the anti-a4[37 antibody is intravenous, intratumoral, intramuscular, subcutaneous, intralesional, intraintestinal, intracolonic, intrarectal, intrapouch, or intraperitoneal. In some embodiments, administration of the anti-a4[37 antibody is through a parenteral route such as intravenous, intramuscular, subcutaneous, intraarterial, or intraperitoneal administration. In some embodiments, administration of the anti-a4[37 antibody is intravenous or subcutaneous. In some embodiments, administration of the anti-a4[37 antibody is intravenous. In some embodiments, administration of the anti-a4[37 antibody is subcutaneous.PHARMACEUTICAL COMPOSITIONS

[0092] The present disclosure also features pharmaceutical compositions that contain a therapeutically effective amount of the anti-a4[37 antibodies described herein. The pharmaceutical composition can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation.Page 30 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0093] 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 a colorless to brown; in some embodiments, the liquid composition is clear to opalescent. 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 an anti-a4[37 antibody. In some embodiments, the liquid composition contains from about 150 mg / mL to about 200 mg / mL. In some embodiments, the liquid composition contains from about 150 mg / mL to about 160 mg / mL, from about 160 mg / mL to about 170 mg / mL, from about 170 mg / mL to about 180 mg / mL, from about 180 mg / mL to about 190 mg / mL, from about 190 mg / mL to about 200 mg / mL or more of an anti-a4[37 antibody.

[0094] In some embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids or salt thereof (such as glycine, glutamine, asparagine, arginine (e.g., arginine-HCl), histidine, or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA), pentetic acid (DTP A)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl- beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; 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 glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants.Page 31 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0095] In some embodiments, a pharmaceutical composition is citrate-free. In some embodiments, a pharmaceutical composition may contain nanoparticles, e.g., polymeric nanoparticles, liposomes, or micelles.

[0096] In some embodiments, a pharmaceutical composition may contain a sustained- or controlled-delivery formulation. Techniques for formulating sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Sustained-release preparations may include, e.g., porous polymeric microparticles or semipermeable polymer matrices in the form of shaped articles, e.g., fdms, or microcapsules. Sustained release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly (2- hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained release compositions may also include liposomes that can be prepared by any of several methods known in the art.

[0097] Pharmaceutical compositions containing an anti-a4[37 antibody disclosed herein can be presented in a dosage unit form and can be prepared by any suitable method. A 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 anti-a4[37 antibody disclosed herein is administered by intravenously. In some embodiments, the anti-a4[37 antibody disclosed herein is administered intravenously or subcutaneously. In specific embodiments, the anti-a4[37 antibody disclosed herein is administered subcutaneously.

[0098] Aspects of the disclosure relate to injectable dosage forms of anti-a4[37 antibody. In some embodiments, the anti-a4[37 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 anti-a4[37 antibody consists of 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 injectable dosage form is a liquid formulation. In some embodiments, the liquid formulation comprises one or more of histidine, arginine or a salt thereof, EDTA and polysorbate 80. In some embodiments, the injectable liquid formulation does not comprise citrate.

[0099] In some embodiments, the injectable dosage form 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 the anti-a4[37 antibody. For example, the injectable dosage form comprises from at least about 100 mg / mL to at least 110 mg / mL, from at least about 110 mg / mL to at least 120 mg / mL, from at Page 32 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT least about 120 mg / mL to at least 130 mg / mL, from at least about 130 mg / mL to at least 140 mg / mL, from at least about 140 mg / mL to at least 150 mg / mL, from at least about 150 mg / mL to at least 160 mg / mL, from at least about 160 mg / mL to at least 170 mg / mL, from at least about 170 mg / mL to at least 180 mg / mL, from at least about 180 mg / mL to at least 190 mg / mL, from at least about 190 mg / mL to at least 200 mg / mL, from at least about 200 mg / mL to at least 210 mg / mL or more of the anti-a4[37 antibody.

[0100] In some embodiments, the injectable dosage form comprises from about 100 mg to about 1200 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises from about 100 mg to about 300 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises from about 300 mg to about 600 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises from about 600 mg to about 1000 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises from about 600 mg to about 1200 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises about 100 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises about 300 mg of the anti-a4[37 antibody. In some embodiments, the injectable dosage form comprises about 600 mg of the anti- a4[37 antibody. In other embodiments, the injectable dosage form comprises about 1000 mg of the anti-a4[37 antibody. In other embodiments, the injectable dosage form comprises about 1200 mg of the anti-a4[37 antibody.

[0101] Useful formulations can be prepared by methods known in the pharmaceutical art. Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. In some embodiments, the formulation is citrate-free.

[0102] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic 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 preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0103] An intravenous or subcutaneous drug delivery formulation may be contained in a syringe, pen, or bag. In some embodiments, the bag is connected to a channel comprising a tube and / or a needle. In some embodiments, the formulation is a lyophilized formulation or a liquid Page 33 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT formulation. In some embodiments, the formulation is a liquid formulation. Various devices can be used to deliver liquid formulations by subcutaneous route of administration, including on- body infusion devices, autoinjector devices, prefdled syringes, and syringes. Generally, administration time depends on volume and device, and can range from seconds to minutes.

[0104] These compositions may be sterilized by conventional sterilization techniques, or may be sterile fdtered. The resulting aqueous solutions may be packaged for use as-is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0105] A polyol, which acts as a tonicifier and may stabilize the anti-a4[37 antibody, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol which is used in the formulation as a tonicity agent is mannitol.

[0106] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g, polysorbates 20, 80 etc.) or poloxamers (e.g., poloxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated antibody and / or minimizes the formation of particulates in the formulation and / or reduces adsorption. In some embodiments, the formulation may include 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 (80) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0107] In embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at stabilizing levels. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, a stabilizer is added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is disaccharides, e.g., sucrose. In some embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.

[0108] In some embodiments, the pH of the liquid formulation is set by addition of 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 from about to 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.Page 34 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0109] The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.

[0110] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation.[oni] The anti-a4[37 antibody may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0112] The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1:2 protein to sucrose or maltose. In some embodiments, the protein to sucrose or maltose weight ratio is of from 1:2 to 1:5. In some embodiments, the pH of the formulation, prior to lyophilization, is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0113] The specific dose can be a uniform dose for each human subject of about 100 mg, about 150 mg, of about 200 mg, of about 250 mg, 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, about 1000 mg, about 1100 mg, about 1200 mg or more of anti-a4[37 antibody. Alternatively, a human subject’s dose can be tailored to the approximate body weight or surface area of the human subject. Other factors in determining the appropriate dosage can include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the age, sex and medical condition of the human subject. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those skilled in the art, especially in light of the dosage information and assays disclosed herein. The dosage can also be determined through the use of known assays for determining dosages used in conjunction with appropriate doseresponse data. An individual human subject's dosage can be adjusted as the progress of the disease is monitored. Blood levels of the targetable construct or complex in a human subject can be measured to see if the dosage needs to be adjusted to reach or maintain an effectivePage 35 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT concentration. Pharmacogenomics may be used to determine which targetable constructs and / or complexes, and dosages thereof, are most likely to be effective for a given individual.KITS

[0114] Provided herein is a kit for treating a disease in a human subject in need thereof by (i) upregulating CCR9 gene expression as set forth and exemplified herein; and / or (ii) occupying a4[37 receptors on memory T cells as set forth and exemplified herein; and / or (iii) providing exposures of at least 60 days as set forth and exemplified herein, which kit comprises: (a) an injectable liquid formulation comprising an anti-a4[37 antibody, wherein the anti-a4[37 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 to administer from about 100 mg to about 1200 mg of the anti-a4[37 antibody. In some embodiments, the anti-a4[37 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 injectable liquid formulation is a subcutaneous formulation. In some embodiments, the injectable liquid formulation is an intravenous formulation.

[0115] Provided herein is a kit for treating a disease in a human subject in need thereof by (i) upregulating CCR9 gene expression as set forth and exemplified herein; and / or (ii) occupying a4[37 receptors on memory T cells as set forth and exemplified herein; and / or (iii) providing exposures of at least 60 days as set forth and exemplified herein, which kit comprises: (a) an injectable liquid formulation comprising an anti-a4[37 antibody, wherein the anti-a4[37 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 to administer at least 100 mg of the anti-a4[37 antibody. In some embodiments, the anti-a4[37 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 injectable liquid formulation is a subcutaneous formulation. In some embodiments, the injectable liquid formulation is an intravenous formulation.

[0116] Provided herein is a kit for treating a disease in a human subject in need thereof by (i) upregulating CCR9 gene expression as set forth and exemplified herein; and / or (ii) occupying a4[37 receptors on memory T cells as set forth and exemplified herein; and / or (iii) providing exposures of at least 60 days as set forth and exemplified herein, which kit comprises: (a) an injectable liquid formulation comprising an anti-a4[37 antibody, wherein the anti-a4[37 antibodyPage 36 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT 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 to administer at least 300 mg of the anti-a4[37 antibody. In some embodiments, the anti-a4[37 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 injectable liquid formulation is a subcutaneous formulation. In some embodiments, the injectable liquid formulation is an intravenous formulation.

[0117] Provided herein is a kit for treating a disease in a human subject in need thereof by (i) upregulating CCR9 gene expression as set forth and exemplified herein; and / or (ii) occupying a4p7 receptors on memory T cells as set forth and exemplified herein; and / or (iii) providing exposures of at least 60 days as set forth and exemplified herein, which kit comprises: (a) an injectable liquid formulation comprising an anti-a4p7 antibody, wherein the anti-a4p7 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 to administer at least 600 mg of the anti-a4p7 antibody. In some embodiments, the anti-a4p7 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 injectable liquid formulation is a subcutaneous formulation. In some embodiments, the injectable liquid formulation is an intravenous formulation.

[0118] Provided herein is a kit for treating a disease in a human subject in need thereof by (i) upregulating CCR9 gene expression as set forth and exemplified herein; and / or (ii) occupying a4p7 receptors on memory T cells as set forth and exemplified herein; and / or (iii) providing exposures of at least 60 days as set forth and exemplified herein, which kit comprises: (a) an injectable liquid formulation comprising an anti-a4[37 antibody, wherein the anti-a4[37 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 to administer at least 1000 mg of the anti-a4[37 antibody. In some embodiments, the anti-a4[37 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 injectable liquid formulation is a subcutaneous formulation. In some embodiments, the injectable liquid formulation is an intravenous formulation.METHODS OF PREPARATION

[0119] The anti-a4[37 antibodies described above can be made using recombinant DNA technology well known to a skilled person in the art. For example, one or more isolatedPage 37 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT polynucleotides encoding the anti-a4[37 antibody can be ligated to other appropriate nucleotide sequences, including, for example, constant region coding sequences, and expression control sequences, to produce conventional gene expression constructs (i.e., expression vectors) encoding the desired anti-a4[37 antibodies. Production of defined gene constructs is within routine skill in the art.

[0120] Nucleic acids encoding desired anti-a4p7 antibodies can be incorporated (ligated) into expression vectors, which can be introduced into host cells through conventional transfection or transformation techniques. Exemplary host cells are E. coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells that do not otherwise produce IgG protein. Transformed host cells can be grown under conditions that permit the host cells to express the genes that encode anti- a4p7 antibodies. In some embodiments, the nucleic acid comprises a sequence as set forth in SEQ ID NOs: 12-17.

[0121] Specific expression and purification conditions will vary depending upon the expression system employed. 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 from a suitable bacterial promoter, e.g., Trp or Tac, and a prokaryotic signal sequence. The expressed protein may be secreted. The expressed protein may accumulate in refractile or inclusion bodies, which can be harvested after disruption of the cells by French press or sonication. The refractile bodies then are solubilized, and the protein may be refolded and / or cleaved by methods known in the art.

[0122] If the engineered gene is to be expressed in eukaryotic host cells, e.g., CHO cells, it is first inserted into an expression vector containing a suitable eukaryotic promoter, a secretion signal, a poly A sequence, and a stop codon. Optionally, the vector or gene construct may contain enhancers and introns. In embodiments involving fusion proteins comprising an anti- a4[37 antibody or portion thereof, the expression vector optionally contains sequences encoding all or part of a constant region, enabling an entire, or a part of, a heavy or light chain to be expressed. The gene construct can be introduced into eukaryotic host cells using conventional techniques.

[0123] In some embodiments, in order to express an anti-a4[37 antibody, an N-terminal signal sequence is included in the protein construct. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgG kappa light chain, trypsinogen, serum albumin, and prolactin.Page 38 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0124] After transfection, single clones can be isolated for cell bank generation using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or Clonepix. Clones can be cultured under conditions suitable for bio-reactor scale-up and maintained expression of the anti-a4[37 antibodies.

[0125] The anti-a4[37 antibodies can be isolated and purified using methods known in the art including centrifugation, depth filtration, cell lysis, homogenization, freeze-thawing, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography.

[0126] While the present disclosure provides for subcutaneous administration of the anti- a4[37 antibody, it is also possible to administer the anti-a4[37 antibody by the intravenous route, i.e., by infusion. It is further contemplated that induction or loading dose or doses may be administered by the subcutaneous (SC) or intravenous (IV) route of administration.EXEMPLARY EMBODIMENTS

[0127] Embodiment 1: A method of upregulating C-C chemokine receptor type 9 (CCR9) gene expression in a human subject, the method comprising administering to the human subject at least one dose of a composition comprising an effective amount of an anti-a4[37 antibody having a modified Fc and having an extended half-life compared to an antibody comprising a wild-type Fc, wherein the at least one dose, when administered to the human subject, increases the CCR9 gene expression in blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering.

[0128] Embodiment 2 : The method of Embodiment 1, wherein the modified Fc comprisesM252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

[0129] Embodiment 3: The method of Embodiment 1, wherein the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

[0130] Embodiment 4 : The method of Embodiment 1, wherein the CCR9 gene expression is determined by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR).

[0131] Embodiment 5: The method of Embodiment 1, wherein the blood cells are whole blood cells.Page 39 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0132] Embodiment 6: The method of Embodiment 1, wherein the administering of the at least one dose increases the CCR9 gene expression for at least twenty-six days.

[0133] Embodiment 7: The method of Embodiment 1, wherein the administering of the at least one dose increases the CCR9 gene expression for at least fifty-four days.

[0134] Embodiment 8: The method of Embodiment 1, wherein the administering of the at least one dose increases the CCR9 gene expression for at least eighty-one days.

[0135] Embodiment 9: The method of any one of Embodiments 1-8, wherein the administering of the at least one dose increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.

[0136] Embodiment 10: The method of any one of Embodiments 1-9, wherein the at least one dose, when administered to the human subject, saturates a4[37 receptors of memory T cells circulating in blood for at least twelve days as compared to a baseline occupancy of the a4[37 receptors of memory T cells prior to the administering.

[0137] Embodiment 11: The method of Embodiment 10, wherein the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least fifty-four days.

[0138] Embodiment 12: The method of Embodiment 10, wherein the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least eighty-one days.

[0139] Embodiment 13: The method of Embodiment 10, wherein the administering of the at least one dose saturates the a4[37 receptors of memory T cells for at least 24 weeks.

[0140] Embodiment 14: The method of any one of Embodiments 10-13, wherein the memory T cells are CD8+memory T cells.

[0141] Embodiment 15: The method of any one of Embodiments 10-13, wherein the memory T cells are CD4+memory T cells.

[0142] Embodiment 16: A method of occupying a4[37 receptors of memory T cells circulating in the blood of a human subject in need thereof, the method comprising administering to the human subject at least one dose of a composition comprising an effective amount of anti- a4[37 antibody having a modified Fc and having an extended half-life compared to an anti-a4[37 antibody comprising a wild-type Fc, and wherein the at least one dose, when administered to the human subject, saturates the a4[37 receptors for at least twelve days as compared to a baseline occupancy of the a4[37 receptors prior to the administering.Page 40 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0143] Embodiment 17: The method of Embodiment 16, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

[0144] Embodiment 18: The method of Embodiment 16, wherein the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

[0145] Embodiment 19: The method of Embodiment 16, wherein the administering of the at least one dose saturates the a4[37 receptors for at least fifty-four days.

[0146] Embodiment 20: The method of Embodiment 16, wherein the administering of the at least one dose saturates the a4[37 receptors for at least eighty-one days.

[0147] Embodiment 21: The method of Embodiment 16, wherein the administering of the at least one dose saturates the a4[37 receptors for at least 24 weeks.

[0148] Embodiment 22: The method of any one of Embodiments 16-21, wherein the memory T cells are CD8+memory T cells.

[0149] Embodiment 23: The method of any one of Embodiments 16-21, wherein the memory T cells are CD4+memory T cells.

[0150] Embodiment 24: The method of any one of Embodiments 1-23, wherein the human subject has an inflammatory bowel disease.

[0151] Embodiment 25: The method of Embodiment 24, wherein the inflammatory bowel disease is Crohn’s disease.

[0152] Embodiment 26: The method of Embodiment 24, wherein the inflammatory bowel disease is ulcerative colitis.

[0153] Embodiment 27: The method of any one of Embodiments 1-26 comprising administering the composition subcutaneously.

[0154] Embodiment 28: The method of any one of Embodiments 1-26 comprising administering the composition intravenously.

[0155] Embodiment 29: The method of any one of Embodiments 1-28, wherein the effective amount comprises at least 100 mg of the antibody.

[0156] Embodiment 30: The method of any one of Embodiments 1-28, wherein the effective amount comprises at least 300 mg of the antibody.Page 41 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0157] Embodiment 31: The method of any one of Embodiments 1-28, wherein the effective amount comprises at least 600 mg of the antibody.

[0158] Embodiment 32: The method of any one of Embodiments 1-28, wherein the effective amount comprises at least 1000 mg of the antibody.

[0159] Embodiment 33: The method of any one of Embodiments 1-32, wherein the antibody has an average serum half-life greater than about 60 days in humans.

[0160] Embodiment 34: The method of any one of Embodiments 1-32, wherein the antibody has an average serum half-life of about 70 days in humans.

[0161] Embodiment 35: The method of any one of Embodiments 1-32, wherein the antibody has an average serum half-life of about 80 days in humans.

[0162] Embodiment 36: The method of any one of Embodiments 1-32, wherein the antibody has an average serum half-life is about 90 days or greater in humans.

[0163] Embodiment 37: The method of any one of Embodiments 10-36, wherein receptor occupancy is determined by a flow cytometry assay.

[0164] Embodiment 38: A composition for use in upregulating C-C chemokine receptor type 9 (CCR9) gene expression in a human subject in need thereof, the composition comprising an effective amount of anti-a4[37 antibody having a modified Fc and an extended half-life compared to an anti-a4[37 antibody having a wild-type Fc, wherein the composition, when administered to the human subject in at least one dose, increases the CCR9 gene expression in blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering.

[0165] Embodiment 39: The composition of Embodiment 38, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

[0166] Embodiment 40: The composition of Embodiment 38, wherein the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

[0167] Embodiment 41: The composition of Embodiment 38, wherein the blood cells are whole blood cells.Page 42 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0168] Embodiment 42: The composition according to Embodiment 38, wherein the effective amount increases the CCR9 gene expression for at least twenty-six days.

[0169] Embodiment 43: The composition according to Embodiment 38, wherein the effective amount increases the CCR9 gene expression for at least fifty-four days.

[0170] Embodiment 44: The composition according to Embodiment 38, wherein the effective amount increases the CCR9 gene expression for at least eighty-one days.

[0171] Embodiment 45: The composition according to any one of Embodiments 38-44, wherein the effective amount increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.

[0172] Embodiment 46: The composition according to any one of Embodiments 38-45, wherein the effective amount, when administered to the human subject, saturates a4[37 receptors of memory T cells circulating in blood for at least twelve days as compared to a baseline occupancy of the a4[37 receptors of memory T cells prior to the administering as determined by flow cytometry assay.

[0173] Embodiment 47: The composition according to Embodiment 46, wherein the effective amount saturates the a4[37 receptors of memory T cells for at least fifty-four days.

[0174] Embodiment 48: The composition according to Embodiment 46, wherein the effective amount saturates the a4[37 receptors of memory T cells for at least eighty-one days.

[0175] Embodiment 49: The composition according to Embodiment 46, wherein the effective amount saturates the a4[37 receptors of memory T cells for at least 24 weeks.

[0176] Embodiment 50: The composition according any one of Embodiments 46-49, wherein the memory T cells are CD8+memory T cells.

[0177] Embodiment 51: The composition according any one of Embodiments 46-49, wherein the memory T cells are CD4+memory T cells.

[0178] Embodiment 52: A composition for use in saturating a4[37 receptors of memory T cells circulating in blood of a human subject comprising an effective amount of anti-a4[37 antibody having a modified Fc and having an extended half-life compared to an antibody comprising a wild-type Fc, wherein an effective amount of the composition, when administered to the human subject in at least one dose, saturates the a4[37 receptors of memory T cells for at least twelve days as compared to a baseline occupancy of a4[37 receptors of memory T cells prior to the administering.Page 43 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0179] Embodiment 53: The composition of Embodiment 52, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

[0180] Embodiment 54: The composition of Embodiment 52, wherein the anti-a4[37 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

[0181] Embodiment 55: The composition according to Embodiment 52, wherein the effective amount, when administered to the human subject, saturates the a4[37 receptors for at least fifty-four days.

[0182] Embodiment 56: The composition according to Embodiment 52, wherein the effective amount, when administered to the human subject, saturates the a4[37 receptors for at least eighty-one days.

[0183] Embodiment 57: The composition according to Embodiment 52, wherein the effective amount, when administered to the human subject, saturates the a4[37 receptors for at least eighty-one days.

[0184] Embodiment 58: The composition according to any one of Embodiments 52-57, wherein the memory T cells are CD8+memory T cells.

[0185] Embodiment 59: The composition according any one of Embodiments 52-57, wherein the memory T cells are CD4+memory T cells.

[0186] Embodiment 60: The composition according to any one of Embodiments 52-59, wherein the effective amount, when administered to the human subject, increases C-C chemokine receptor type 9 (CCR9) gene expression in blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering.

[0187] Embodiment 61: The composition according to Embodiment 60, wherein the effective amount increases the CCR9 gene expression for at least twenty-six days.

[0188] Embodiment 62: The composition according to Embodiment 60, wherein the effective amount increases the CCR9 gene expression for at least fifty-four days.

[0189] Embodiment 63: The composition according to Embodiment 60, wherein the effective amount increases the CCR9 gene expression for at least eighty-one days.Page 44 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0190] Embodiment 64: The composition according to any one of Embodiments 60-63, wherein the effective amount increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.

[0191] Embodiment 65: The composition according to any one of Embodiments 38-64, wherein the human subject has an inflammatory bowel disease.

[0192] Embodiment 66: The composition according to Embodiment 65, wherein the inflammatory bowel disease is Crohn’s disease.

[0193] Embodiment 67: The composition according to Embodiment 65, wherein the inflammatory bowel disease is ulcerative colitis.

[0194] Embodiment 68: The composition according to any one of Embodiments 38-67 is formulated for subcutaneous administration.

[0195] Embodiment 69: The composition according to any one of Embodiments 38-67 is formulated for intravenous administration.

[0196] Embodiment 70: The composition according to Embodiment 38-69, wherein the effective amount comprises at least 100 mg of the anti-a4[37 antibody.

[0197] Embodiment 71: The composition according to Embodiment 38-69, wherein the effective amount comprises at least 300 mg of the anti-a4[37 antibody.

[0198] Embodiment 72: The composition according to Embodiment 38-69, wherein the effective amount comprises at least 600 mg of the anti-a4[37 antibody.

[0199] Embodiment 73: The composition according to Embodiment 38-69, wherein the effective amount comprises at least 1000 mg of the anti-a4[37 antibody.

[0200] Embodiment 74: The composition according to any one of Embodiments 38-73, wherein the anti-a4[37 antibody has an average serum half-life greater than about 60 days in humans.

[0201] Embodiment 75: The composition according to any one of Embodiments 38-73, wherein the anti-a4[37 antibody has an average serum half-life of about 70 days in humans.

[0202] Embodiment 76: The composition according to any one of Embodiments 38-73, wherein the anti-a4[37 antibody has an average serum half-life of about 80 days in humans.

[0203] Embodiment 77: The composition according to any one of Embodiments 38-73, wherein the anti-a4[37 antibody has an average serum half-life of about 90 days or greater in humans.Page 45 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0204] Embodiment 78: The method of any one of Embodiments 1-37 or the composition of any one of Embodiments 38-77, wherein the at least one dose comprises a single dose.

[0205] Embodiment 79: The method of any one of Embodiments 1-37 comprising administering the effective amount of the anti-a4[37 antibody every three months.

[0206] Embodiment 80: The method of any one of Embodiments 1-37 comprising administering the effective amount of the anti-a4[37 antibody every six months.

[0207] Embodiment 81: The method of any one of Embodiments 1-37, wherein the administering of the at least one dose results in a plasma or serum concentration of the anti-a4[37 antibody of at least about 40 pg / mL for 6 weeks or more.

[0208] Embodiment 82: A method for increasing a proportion of C-C chemokine receptor type 9 (CCR9) gene expressing blood cells in the blood of a human subject in need thereof, the method comprising administering to the human subject at least one dose of a composition comprising at least 100 mg of an anti-a4[37 antibody, wherein the anti-a4[37 antibody has a modified Fc and an extended half-life compared to an anti-a4[37 antibody comprising a wild-type Fc, wherein the administering increases the proportion of CCR9 gene expressing blood cells in the blood for at least twelve days relative to a baseline proportion of the CCR9 gene expressing blood cells prior to the administering, and wherein the administering reduces infiltration of CCR9 gene expressing blood cells in a tissue of the human subject that comprises CCR9 ligand, thereby protecting the tissue from an immune response induced by the CCR9 gene expressing blood cells.

[0209] Embodiment 83: A method of occupying a4[37 receptors of memory T cells circulating in the blood of a human subject in need thereof, the method comprising administering to the human subject at least one dose of a composition comprising at least 100 mg of anti-a4[37 antibody having a modified Fc and having an extended half-life compared to an anti-a4[37 antibody comprising a wild-type Fc, and wherein the at least one dose, when administered to the human subject, saturates the a4[37 receptors for at least twelve days as compared to a baseline occupancy of the a4[37 receptors prior to the administering.

[0210] Embodiment 83: The method of Embodiment 83, wherein the anti-a4[37 antibody reduces a level of infiltration of CCR9 gene expressing memory T cells in a tissue of the human subject that comprises CCR9 ligand, thereby protects the tissue from an immune response induced by the CCR9 gene expressing memory T cells.

[0211] Embodiment 84: A composition for use in increasing a proportion of C-C chemokine receptor type 9 (CCR9) gene expressing blood cells in the blood of a human subject, Page 46 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT the composition comprising an effective amount of anti-a4[37 antibody having a modified Fc and an extended half-life compared to an anti-a4[37 antibody having a wild-type Fc, wherein the composition, when administered to the human subject in at least one dose of >100 mg: increases the proportion of CCR9 gene expressing blood cells in the blood for at least twelve days as compared to a baseline proportion of the CCR9 gene expressing blood cells prior to the administering; reduces infiltration of CCR9 gene expressing blood cells in a tissue of the human subject that comprises CCR9 ligand; and the tissue from an immune response induced by the CCR9 gene expressing blood cells.

[0212] Embodiment 85: The composition according to Embodiment 84, wherein the effective amount, when administered to the human subject, increases C-C chemokine receptor type 9 (CCR9) gene expression in blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering.

[0213] Embodiment 86: The composition according to Embodiment 85, wherein the anti- a4[37 antibody reduces a level of infiltration of CCR9 gene expressing memory T cells in a tissue of the human subject that comprises CCR9 ligand, thereby protects the tissue from an immune response induced by the CCR9 gene expressing memory T cells.EXAMPLES

[0214] The disclosure now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and is not intended to limit the disclosure.EXAMPLE 1: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of AbOOl in Healthy Human Subjects

[0215] AbOOl is a high-affinity immunoglobulin G1 (IgGl) humanized monoclonal antibody that binds a4[37. AbOOl (150 mg / mL formulation) was administered via SC injection with the exception of the single -ascending dose (SAD) cohorts and multiple-ascending dose (MAD) cohorts that were designated for IV infusion. Normal saline (0.9% NaCl) was administered via SC injection with the exception of the SAD and MAD cohorts (planned and optional) that are designated for IV infusion.

[0216] In the SAD part of the study, the starting dose was 300 mg, as determine in the nonclinical pharmacokinetic (PK), pharmacodynamics (PD), and toxicology data, with > 10-foldPage 47 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT margin (for a human subject of at least 60 kg) based on the human equivalent dose of the no observed adverse effect level (NOAEL) in a Good Laboratory Practices (GLP) 28-day multipledose toxicity study in cynomolgus monkeys. Beyond the starting dose in the SAD study, dose levels, route of administration, and regimens were determined based on emerging safety data review by the scientific review committee (SRC) and included a dose of 100 mg SC in one cohort. Dose escalation did not exceed a 2-fold increase between each cohort and the subsequent cohort. The primary objective of this study was to evaluate the safety and tolerability of single and multiple doses of AbOOl. Specifically, the study evaluated the incidence of treatment- emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to study drug discontinuation, and the incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade >3 laboratory abnormalities.

[0217] Secondary objectives included characterizing the single-dose and multiple-dose PK properties of AbOOl in healthy human subjects. For single dose, noncompartmental PK analysis was performed to provide PK parameters appropriate for either the IV or SC route. PK parameters include: AUCo-<», Cmax, Tmax, CL (CL / F), F, and ti / 2. For multiple doses, noncompartmental PK analysis was performed to provide PK parameters appropriate to a multiple dose regimen. PK parameters included: AUCo <», Cmax, Tmax, and ti / 2. Another secondary endpoint evaluated the presence of anti-drug antibody (ADA) in healthy human subjects given AbOOl. These included the number and proportion of human subjects with positive ADA and PK parameters (e.g., Cmax, AUC) in human subjects with and without ADA.

[0218] The study also examined the impact of AbOO 1 on biomarkers in healthy human subjects. These included changes over time in a4[37 receptor occupancy on circulating T lymphocytes, changes over time in b7+ circulating lymphocytes, and changes overtime in CCR9 gene expression in whole blood.Abbreviations:

[0219] ADA = anti-drug antibody; AE = adverse event; AUCo-oo = area under the concentration-time curve from time zero extrapolated to infinity; AUCo-iast = area under the concentration-time curve from time zero to the last quantifiable time point; CL= Clearance (IV route only), CL / F = apparent clearance of an extravascular dose (SC route only); Cmax = maximum observed concentration; ECG = electrocardiogram; PK = pharmacokinetic(s); Tmax = time to maximum concentration; ti / 2 = terminal elimination half-life; Vss = steady-state volume of distribution (IV route only); Vz = terminal phase volume of distribution (IV route only); Vz / F = apparent terminal phase volume of distribution (SC route only).Methodology:Page 48 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0220] This was a Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose, first-in-human (FIH) safety, tolerability, and PK study of AbOOl in healthy human subjects. AbOOl or placebo was administered subcutaneously (SC) in single-ascending and multiple ascending doses (SAD and MAD, respectively).

[0221] AbOO 1 or placebo was administered intravenously (IV) in up to 6 SAD cohorts and 3 MAD cohorts. Each cohort consisted of 8 healthy human subjects, randomized 6:2 to AbOOl or placebo.SAD Cohorts

[0222] A maximum of 6 SAD cohorts (4 planned; 2 optional) were enrolled. The starting AbOOl SC dose was 300 mg for Cohort 1, based on the nonclinical PK, PD, and toxicology data, with > 10-fold margin (for a human subject of at least 60 kg) based on the human equivalent dose of the NOAEL in a GLP 28-day multiple dose toxicity study in cynomolgus monkeys. Three additional ascending dose levels, 600 mg (cohort 2), 1000 mg (cohort 3) and 100 mg (cohort 4), were administered subcutaneously on Day 1. One additional cohort received a single IV dose of 1000 mg of AbOOl (cohort 4) on Day 1.

[0223] Human subjects were randomized in a blinded fashion 6:2 to AbOOl or placebo. In SAD cohorts, where dose escalation is implemented, the first 2 human subjects in each SAD cohort (sentinel human subjects) were randomized 1 to 1 (active to placebo) in blinded fashion and followed for at least 24 hours post-dose before the remainder of the cohort is randomized. The remaining 6 human subjects were randomized 5 to 1 (active to placebo).

[0224] Dose escalation in subsequent cohorts did not exceed a 2-fold increase relative to the previous cohort for the remaining cohorts.

[0225] For all cohorts, assessments included vital signs, ECGs, evaluation of AEs / SAEs, and concomitant medications. Blood draws for PK, ADA, PD, and safety laboratory tests were obtained.MAD Cohorts

[0226] Human subjects were enrolled in two multiple-dose cohorts. The starting AbOOl MAD SC dose was 300 mg on Day 1 and 300 mg on Day 15. Human subjects were enrolled in MAD Cohort 1 after the SRC reviewed a minimum of 14 days of safety data from at least 2 SAD cohorts, one of which was at an equal or higher total dose (e.g, 300 mg MAD Cohort 1 was initiated after at least 14 days of safety data from the 600 mg SAD Cohort 2 were available for review).Page 49 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0227] In each subsequent MAD cohort, human subjects were enrolled after the SRC reviewed a minimum of 14 days (i.e., Day 29) of safety data after the prior dose of the study drug was given to human subjects, who received A001 at the previous dose level in MAD.

[0228] Dose escalation did not exceed a 2-fold increase in dose relative to the previous cohort. The study population, dose, and route of administration for the optional MAD cohort 3 was determined based on emerging data but did not exceed the highest dose level examined in SAD.

[0229] Each MAD cohort enrolled 8 human subjects. Human subjects were randomized in a blinded fashion 6:2 to AbOOl or placebo. Human subjects received an SC or IV dose of AbOOl on Day 1 and a second dose SC or IV dose on Day 15. The study day of SC / IV dose 2 may have been altered based on a review of any available PK data from prior SAD cohorts. Assessments included vital signs, ECGs, evaluation of AEs, and blood draws for PK, ADA, PD, and safety laboratory tests will be obtained.Criteria for evaluation:Safety:

[0230] Safety included assessments of TEAEs, clinical laboratory tests (hematology, chemistry, and urinalysis), vital signs, ECGs, and physical examinations.Pharmacokine tics :

[0231] For single doses, noncompartmental PK analysis was performed to provide PK parameters appropriate to either the IV or SC route. PK parameters included but were not limited to: AUCo-co. AUCo-iast, CL, CL / F, Cmax, F, Tmax, ti / 2, Vss, Vz, and Vz / F.

[0232] For multiple doses, noncompartmental PK analysis was performed to provide PK parameters appropriate to a multiple dose regimen. PK parameters included but were not limited to: AUCo-co, AUCo-iast, Cmax, Tmax and tl / 2.Anti-drug Antibodies:

[0233] Presence of ADAs and impact of ADAs on the PK of AbOO 1.Pharmacodynamics :

[0234] Include but not limited to: Changes over time in a4[37 receptor occupancy on circulating T lymphocytes, proportions of [37-positive T and B cell subtypes, and whole blood CCR9 gene expression.EXAMPLE 2: Single ascending dose study anti-a4 7 antibodyPage 50 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT

[0235] Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose, FIH study of AbOOl in healthy human subjects was conducted. AbOOl or placebo was administered subcutaneously (SC) in single-ascending dose cohort. Briefly, each cohort consisted of 8 healthy human subjects, randomized 6:2 to AbOOl or placebo. Human subjects were administered with a subcutaneous dose of 100 mg, 300 mg, 600 mg or 1000 mg. Whole blood from each human subject was collected and processed to isolate peripheral blood mononuclear cells (PBMC) at various timepoints pre- and post-administration.

[0236] Next, half-life of AbOOl in human subject was determined. Multiple blood samples were collected for each dosage regimen at regular intervals for 100 days. Mean AbOOl serum concentration was determined and plotted against time in weeks (FIG. 1A). An analysis of FIG. 1A indicates that AbOOl showed dose dependent PK profde between 100 mg and 1000 mg dosage regimen. Interim elimination half-life was initially determined for just the 300 mg and 600 mg dosage regimen, which were found to be 91 days and more than 100 days, respectively. Analysis of more complete data (summarized in Table 5a and 5b) yielded a population PK (pop PK) half-life value of 78.5 days, in humans. Initial PK data from the MAD cohorts were consistent with the SAD cohort PK (FIG. IB).Table 5a. AbOOl Mean (SD) PK Parameters Following SC SAD AdministrationPage 51 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCTTable 5b. AbOOl Mean (SD) PK Parameters Following Single IV Administration

[0237] Next, receptor occupancy assay was performed to determine bound a4[37 receptor on CD4+and CD8+memory T-cells. A commercially available PE-labeled ACT-1 (mouse monoclonal antibody to a4[37 integrin) or biotinylated MAdCAM-1 was used in a qualified flow cytometry to measure the receptor occupancy. The assay relied on competitive inhibition of ACT-1 PE or MAdCAM-1 binding to a4[37 integrin on cells, such that if AbOOl was already bound to a4[37, there would be a decrease in fluorescently labeled ACT-1 or MAdCAM-1 signal relative to pre-dose samples. Leukocyte subsets were identified in PBMC samples using fluorescently conjugated antibodies directed toward the following receptors: CD4, CD8, and CD45RO. A cell-impermeant viability dye was also used to exclude dead cells. For biotinylated MAdCAM-1, detection was enabled by Streptavidin-PE. The addition of 1 mM manganese chloride (MnCh) during the incubation of biotinylated MAdCAM-1 with PBMC samples was required for sufficient binding to a4[37. Additionally, PBMCs were stained with a cell- impermeant viability dye that penetrates the damaged membrane of dead cells and fluoresces upon reaction with amine groups. Cells were acquired by a flow cytometer and the percentage of ACT-1 or MAdCAM-1 bound was determined. For analysis, full saturation was defined as percentage bound >6.7% which is the 5thpercentile of % bound values for all pooled drug-naive samples (i.e placebo values at all timepoints and pre-treatment values of all AbOOl treated participants). Results were plotted using ggplot in R.

[0238] FIGS. 2A, 2C (SAD cohorts) and 2D (MAD cohorts), show results of a4[37 receptor occupancy assay on CD4+memory T-cells and FIGS. 2B and 2E (SAD cohorts) showPage 52 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT results of a4[37 receptor occupancy assay on CD8+memory T-cells, respectively. FIGS. 2A, 2B, 2C and 2E show that a single subcutaneous dose comprising 100 mg, 300 mg, 600 mg or 1000 mg of AbOOl saturates a4[37 receptors on CD4+and CD8+memory T-cells circulating in blood in healthy volunteers. A 100 mg SC dose saturated CD4+memory T-cells for up to 225 days, a 300 mg SC dose saturated for up to 281 days, a 600 mg SC dose saturated for up to 281 days, 1000 mg SC dose saturated CD4+memory T-cells for up to 225 days, and a 1000 mg IV dose saturated CD4+memory T-cells for up to 225 days (FIG. 2C). Multiple doses of 300 mg and 600 mg of AbOOl saturated CD4+memory T-cells for up to 24 weeks (FIG. 2D). Full saturation of a4p7 receptors on CD4+ memory T cells was observed in all participants across all cohorts where AbOOl serum drug concentration was maintained above 6.5 micrograms / mL.

[0239] RT-qPCR was performed to measure expression of CC motif chemokine receptor 9 gene (CCR9) in human whole blood samples. RNA (Ribonucleic Acid) was purified from whole blood samples using the PAXgene Whole Blood RNA Kit. Samples were lysed, homogenized, and loaded onto a silica membrane that binds RNA, allowing contaminants to flow through. RNA was washed and then eluted with buffer. RNA purification was followed by a 2-step RT- qPCR reaction. First, RNA was converted to cDNA by reverse transcription (RT) using random primers. Then, the synthesized cDNA was used as the nucleic acid input to the qPCR. TaqMan real-time qPCR was utilized to specifically amplify the CCR9 target. Gene expression was normalized to housekeeping (HK) gene, TATA-box binding protein (TBP), and results were reported as Ct values, ACt values relative to TBP, AACt values relative to reference sample, and relative expression of CCR9 (RQ). Relative expression was defined as expression of CCR9 gene relative to baseline (predose), which was normalized to 1. Results were ploted using ggplot in R. FIGS. 3A and 3B show effect of AbOOl in healthy human subjects on relative gene expression level of CCR9. An analysis of FIGS. 3A and 3B indicates that CCR9 expression in whole blood is increased over time in human subjects treated with single subcutaneous dose of 300 mg, 600 mg and 1000 mg of AbOOl.

[0240] As additional data from subject treated with AbOOl become available, there may be changes to the calculated values. For example, antibody clearance rates in patients may be different from those rates in healthy volunteers. Nevertheless, the data demonstrates significant pharmacodynamic and pharmacokinetic properties of AbOOl compared to vedolizimab.EXAMPLE 3. Modelling Higher Efficacy Exposure with a Half-life Extended anti-a4 7 Antibody

[0241] Previous studies showed a significant increase in efficacy with greater exposure to the comparator antibody (vedolizumab), summarized in Table 6.Page 53 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCTTable 6. Precent remission at week 14 after treatment with comparator antibody

[0242] Based on the remarkable serum half-life of antibody AbOOl in humans, comparative PK simulations were generated for induction phase of AbOOl and vedolizumab (FIG. 4A). These simulations were based on administration of 300 mg of vedolizumab intravenous on Week 0 and 2, and 108 mg subcutaneous starting on Week 6 and repeat every 2 weeks, and 600 mg and 300 mg of antibody AbOOl intravenous on Week 0 and 4. At Week 6, induction dosing with the halflife extended antibody AbOOl would provide for 95% of human subjects to have exposures equal or greater than the 4thquartile of the exposures in the vedolizumab study discussed above (FIGS. 4A and 4B). Similarly, administration of maintenance doses of antibody AbOOl every 3 months would be expected to result in greater exposure than vedolizumab dose bi-weekly, and even a 6- month dosing schedule would provide exposure comparable to that of vedolizumab dosed biweekly (FIG. 4C).

[0243] AbOOl showed exposure-dependent target engagement (FIG. 5). Indeed, AbOOl fully saturated a4[37 at concentration below 2 mg / mL, which is well below expected clinical trough concentrations.INCORPORATION BY REFERENCE

[0244] All publications and patents cited throughout the text of this specification (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety for all purposes. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.EQUIVALENTS

[0245] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.Page 54 of 62ACTIVE 716380663v1

Claims

Attorney Docket No. 220703-011103 / PCTCLAIMSWe claim:

1. A method for increasing a proportion of C-C chemokine receptor type 9 (CCR9) gene expressing blood cells in the blood of a human subject in need thereof, the method comprising administering to the human subject at least one dose of a composition comprising at least 100 mg of an anti-a4p7 antibody, wherein the anti-a4p7 antibody has a modified Fc and an extended halflife compared to an anti-a4p7 antibody comprising a wild-type Fc, wherein the administering increases the proportion of CCR9 gene expressing blood cells in the blood for at least twelve days relative to a baseline proportion of the CCR9 gene expressing blood cells prior to the administering, and wherein the administering reduces infiltration of CCR9 gene expressing blood cells in a tissue of the human subject that comprises CCR9 ligand, thereby protecting the tissue from an immune response induced by the CCR9 gene expressing blood cells.

2. The method of claim 1, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

3. The method of claim 1, wherein the anti-a4p7 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

4. The method of claim 1, wherein the CCR9 gene expression is determined by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR).

5. The method of claim 1, wherein the blood cells are whole blood cells.

6. The method of claim 1, wherein the administering of the at least one dose increases the CCR9 gene expression for at least twenty-six days.

7. The method of claim 1, wherein the administering of the at least one dose increases the CCR9 gene expression for at least fifty-four days.

8. The method of claim 1, wherein the administering of the at least one dose increases the CCR9 gene expression for at least eighty-one days.

9. The method of any one of claims 1-8, wherein the administering of the at least one dose increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.Page 55 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT10. The method of any one of claims 1-9, wherein the at least one dose, when administered to the human subject, saturates a4p7 receptors of memory T cells circulating in blood for at least twelve days as compared to a baseline occupancy of the a4p7 receptors of memory T cells prior to the administering.

11. The method of claim 10, wherein the administering of the at least one dose saturates the a4p7 receptors of memory T cells for at least fifty-four days.

12. The method of claim 10, wherein the administering of the at least one dose saturates the a4p7 receptors of memory T cells for at least eighty-one days.

13. The method of claim 10, wherein the administering of the at least one dose saturates the a4p7 receptors of memory T cells for at least 24 weeks.

14. The method of any one of claims 10-13, wherein the memory T cells are CD8+memory T cells.

15. The method of any one of claims 10-13, wherein the memory T cells are CD4+memory T cells.

16. A method of occupying a4p7 receptors of memory T cells circulating in the blood of a human subject in need thereof, the method comprising administering to the human subject at least one dose of a composition comprising at least 100 mg of anti-a4p7 antibody having a modified Fc and having an extended half-life compared to an anti- a4p7 antibody comprising a wild-type Fc, and wherein the at least one dose, when administered to the human subject, saturates the a4p7 receptors for at least twelve days as compared to a baseline occupancy of the a4p7 receptors prior to the administering.

17. The method of claim 16, wherein the anti-a4p7 antibody reduces a level of infiltration of CCR9 gene expressing memory T cells in a tissue of the human subject that comprises CCR9 ligand, thereby protects the tissue from an immune response induced by the CCR9 gene expressing memory T cells.

18. The method of claim 16, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

19. The method of claim 16, wherein the anti-a4p7 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

20. The method of claim 16, wherein the administering of the at least one dose saturates the a4p7 receptors for at least fifty-four days.

21. The method of claim 16, wherein the administering of the at least one dose saturates the a4p7 receptors for at least eighty-one days.Page 56 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT22. The method of claim 16, wherein the administering of the at least one dose saturates the a4p7 receptors for at least 24 weeks.

23. The method of any one of claims 16-22, wherein the memory T cells are CD8+memory T cells.

24. The method of any one of claims 16-22, wherein the memory T cells are CD4+memory T cells.

25. The method of any one of claims 1-24 comprising administering the composition subcutaneously.

26. The method of any one of claims 1-24 comprising administering the composition intravenously.

27. The method of any one of claims 1-26, wherein the at least one dose comprises at least 100 mg of the anti-a4p7 antibody.

28. The method of any one of claims 1-26, wherein the at least one dose comprises at least 300 mg of the anti-a4p7 antibody.

29. The method of any one of claims 1-26, wherein the at least one dose comprises at least 600 mg of the anti-a4p7 antibody.

30. The method of any one of claims 1-26, wherein the at least one dose comprises at least 1000 mg of the anti-a4p7 antibody.

31. The method of any one of claims 1-30, wherein the anti-a4p7 antibody has an average serum half-life greater than about 60 days in humans.

32. The method of any one of claims 1-30, wherein the anti-a4p7 antibody has an average serum half-life of about 70 days in humans.

33. The method of any one of claims 1-30, wherein the anti-a4p7 antibody has an average serum half-life of about 80 days in humans.

34. The method of any one of claims 1-31, wherein the anti-a4p7 antibody has an average serum half-life is about 90 days or greater in humans.

35. The method of any one of claims 10-34, wherein receptor occupancy is determined by a flow cytometry assay.

36. A composition for use in increasing a proportion of C-C chemokine receptor type 9 (CCR9) gene expressing blood cells in the blood of a human subject, the composition comprising an effective amount of anti-a4p7 antibody having a modified Fc and an extended half-life compared to an anti-a4p7 antibody having a wild-type Fc, wherein the composition, when administered to the human subject in at least one dose of >100 mg:Page 57 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT increases the proportion of CCR9 gene expressing blood cells in the blood for at least twelve days as compared to a baseline proportion of the CCR9 gene expressing blood cells prior to the administering, reduces infiltration of CCR9 gene expressing blood cells in a tissue of the human subject that comprises CCR9 ligand, and the tissue from an immune response induced by the CCR9 gene expressing blood cells.

37. The composition of claim 36, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

38. The composition of claim 36, wherein the anti-a4p7 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

39. The composition of claim 36, wherein the blood cells are whole blood cells.

40. The composition according to claim 36, wherein the effective amount increases the CCR9 gene expression for at least twenty-six days.

41. The composition according to claim 36, wherein the effective amount increases the CCR9 gene expression for at least fifty-four days.

42. The composition according to claim 36, wherein the effective amount increases the CCR9 gene expression for at least eighty-one days.

43. The composition according to any one of claims 36-42, wherein the effective amount increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.

44. The composition according to any one of claims 36-43, wherein the effective amount, when administered to the human subject, saturates a4p7 receptors of memory T cells circulating in blood for at least twelve days as compared to a baseline occupancy of the a4p7 receptors of memory T cells prior to the administering as determined by flow cytometry assay.

45. The composition according to claim 44, wherein the effective amount saturates the a4p7 receptors of memory T cells for at least fifty-four days.

46. The composition according to claim 44, wherein the effective amount saturates the a4p7 receptors of memory T cells for at least eighty-one days.

47. The composition according to claim 44, wherein the effective amount saturates the a4p7 receptors of memory T cells for at least 24 weeks.

48. The composition according any one of claims 44-47, wherein the memory T cells are CD8+memory T cells.Page 58 of 62ACTIVE 716380663v1Attorney Docket No. 220703-011103 / PCT49. The composition according any one of claims 44-47, wherein the memory T cells are CD4+memory T cells.

50. A composition for use in saturating a4p7 receptors of memory T cells circulating in the blood of a human subject in need thereof comprising an effective amount of anti-a4p7 antibody having a modified Fc and having an extended half-life compared to an anti- a4p7 antibody comprising a wild-type Fc, wherein an effective amount of the composition, when administered to the human subject in at least one dose of >100 mg, saturates the a4p7 receptors of memory T cells for at least twelve days as compared to a baseline occupancy of a4p7 receptors of memory T cells prior to the administering51. The composition of claim 50, wherein the modified Fc comprises M252Y, S254T, and T256E (YTE) modifications, numbering according to EU numbering system.

52. The composition of claim 50, wherein the anti-a4p7 antibody comprises a heavy chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 1 and a light chain polypeptide consisting of an amino acid sequence according to SEQ ID NO: 3.

53. The composition according to claim 50, wherein the effective amount, when administered to the human subject, saturates the a4p7 receptors for at least fifty-four days.

54. The composition according to claim 50, wherein the effective amount, when administered to the human subject, saturates the a4p7 receptors for at least eighty-one days.

55. The composition according to claim 50, wherein the effective amount, when administered to the human subject, saturates the a4p7 receptors for at least eighty-one days.

56. The composition according to any one of claims 50-55, wherein the memory T cells are CD8+memory T cells.

57. The composition according any one of claims 50-55, wherein the memory T cells are CD4+memory T cells.

58. The composition according to any one of claims 50-57, wherein the effective amount, when administered to the human subject, increases C-C chemokine receptor type 9 (CCR9) gene expression in blood cells for at least twelve days as compared to the CCR9 gene expression prior to the administering.

59. The composition according to claim 58, wherein the anti-a4p7 antibody reduces a level of infiltration of CCR9 gene expressing memory T cells in a tissue of the human subject that comprises CCR9 ligand, thereby protects the tissue from an immune response induced by the CCR9 gene expressing memory T cells.Page 59 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT60. The composition according to claim 58 or 59, wherein the effective amount increases the CCR9 gene expression for at least twenty-six days.

61. The composition according to claim 58 or 59, wherein the effective amount increases the CCR9 gene expression for at least fifty-four days.

62. The composition according to claim 58 or 59, wherein the effective amount increases the CCR9 gene expression for at least eighty-one days.

63. The composition according to any one of claims 58 or 59-63, wherein the effective amount increases the CCR9 gene expression by at least 20% as compared to the CCR9 gene expression prior to the administering.

64. The composition according to any one of claims 36-63 is formulated for subcutaneous administration.

65. The composition according to any one of claims 36-63 is formulated for intravenous administration.

66. The composition according to claim 36-65, wherein the effective amount comprises at least 300 mg of the anti-a4p7 antibody.

67. The composition according to claim 36-65, wherein the effective amount comprises at least 600 mg of the anti-a4p7 antibody.

68. The composition according to claim 36-65, wherein the effective amount comprises at least 1000 mg of the anti-a4p7 antibody.

69. The composition according to any one of claims 36-68, wherein the anti-a4p7 antibody has an average serum half-life greater than about 60 days in humans.

70. The composition according to any one of claims 36-68, wherein the anti-a4p7 antibody has an average serum half-life of about 70 days in humans.

71. The composition according to any one of claims 36-68, wherein the anti-a4p7 antibody has an average serum half-life of about 80 days in humans.

72. The composition according to any one of claims 36-68, wherein the anti-a4p7 antibody has an average serum half-life of about 90 days or greater in humans.

73. The method of any one of claims 1-35 or the composition of any one of claims 36-72, wherein the at least one dose comprises a single dose.

74. The method of any one of claims 1-35 comprising administering the composition every three months.

75. The method of any one of claims 1-35 comprising administering the composition every six months.Page 60 of 62ACTIVE 716380663v1Atorney Docket No. 220703-011103 / PCT76. The method of any one of claims 1-35, wherein the administering of the at least one dose results in a plasma or serum concentration of the anti-a4p7 antibody of at least about 40 pg / mL for 6 weeks or more.Page 61 of 62ACTIVE 716380663v1

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