Compositions and methods for treating inflammatory bowel disease

Abstract

Some aspects of this disclosure provide compositions and methods for treating subjects suffering from inflammatory bowel disease, the method comprising administering a hemoblastin (HJV) antagonist (e.g., an anti-HJV antibody) to said subject.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 609,585, filed December 13, 2023, entitled “COMPOSITIONS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASE”, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0003] Reference to electronic sequence listing

[0004] The contents of the electronic serial number (D084270013WO00-SEQ-LJG.xml; size: 201,561 bytes; and creation date: December 11, 2024) are incorporated herein by reference in their entirety. Background Technology

[0005] Inflammatory bowel disease (IBD) is characterized by recurrent episodes of inflammation of the gastrointestinal (GI) tract due to an abnormal immune response associated with intestinal barrier dysfunction. IBD encompasses ulcerative colitis (UC) and Crohn's disease (CD), both of which can be classified by severity (mild, moderate, or severe). CD can also be classified by phenotype (inflammatory, stricture, or penetrating). IBD can cause symptoms such as diarrhea, abdominal pain, rectal bleeding, weight loss, anemia, and fatigue, and can be associated with a decline in quality of life (QoL). In some cases, IBD can lead to complications requiring hospitalization and / or surgery. Millions of individuals worldwide are affected by IBD each year. Summary of the Invention

[0006] Certain aspects of this disclosure relate to the understanding that inhibiting hemojuvelin (HJV) in subjects with barrier dysfunction (e.g., intestinal mucosal barrier dysfunction) reduces inflammation in such subjects. In some aspects, this disclosure provides compositions (e.g., anti-HJV antibodies) and methods for treating subjects with inflammatory bowel disease (e.g., ulcerative colitis (UC), Crohn's disease (CD), or unclassified IBD (IBD-U)), the method comprising administering a hemojuvelin antagonist (e.g., the anti-HJV antibody described herein) to the subject. In some embodiments, the methods and related compositions provided herein can be used to suppress inflammation (e.g., intestinal mucosal inflammation) in subjects with IBD. In some embodiments, the compositions and methods provided herein can be used for the purposes of reducing intestinal mucosal inflammation, reducing intestinal bleeding, improving clinical symptoms, inducing remission, and / or maintaining remission in subjects with IBD (e.g., UC, CD, or IBD-U).

[0007] In some aspects, methods for suppressing inflammation in subjects are provided herein, comprising administering an effective amount of anti-hemoblast (HJV) antibody to a subject suffering from inflammation associated with barrier dysfunction. In some embodiments, the barrier dysfunction is intestinal barrier dysfunction. In some embodiments, the intestinal permeability of the subject is increased relative to a subject without intestinal barrier dysfunction. In some embodiments, the subject suffers from intestinal mucosal barrier dysfunction. In some embodiments, the subject has an abnormal immune response to the gastrointestinal (GI) microbiome.

[0008] In some embodiments, the application reduces systemic inflammation in the subject. In some embodiments, the application reduces the number of circulating leukocytes in the subject. In some embodiments, the application reduces the number of circulating neutrophils in the subject. In some embodiments, the application reduces local inflammation at sites of barrier dysfunction. In some embodiments, the application reduces immune cell infiltration at sites of barrier dysfunction. In some embodiments, the application reduces neutrophil infiltration at sites of barrier dysfunction. In some embodiments, the application improves intestinal barrier function.

[0009] In some implementations, the subject suffers from ulcerative colitis.

[0010] In some implementations, the subject suffers from Crohn's disease.

[0011] In some implementations, the subject has unclassified IBD.

[0012] In some respects, methods are provided herein that involve administering an effective amount of anti-HJV antibody to a subject suffering from inflammation associated with inflammatory bowel disease (IBD).

[0013] In some aspects, this document provides a method for treating inflammatory bowel disease (IBD) in a subject, the method comprising administering an effective amount of an anti-HJV antibody to the subject, wherein the subject suffers from inflammation associated with IBD.

[0014] In some respects, this article provides a method for treating a subject with active inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-HJV antibody to the subject.

[0015] In some respects, this article provides a method for treating a subject suffering from chronic inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-HJV antibody to the subject.

[0016] In some respects, this article provides a method for treating inflammation in subjects suffering from inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-HJV antibody to the subject.

[0017] In some implementations, the subject has intestinal mucosal inflammation associated with IBD. In some implementations, the subject has an abnormal immune response to the gastrointestinal (GI) microbiome. In some implementations, the subject has acute-phase IBD. In some implementations, the subject has chronic-phase IBD.

[0018] In some embodiments, the application reduces systemic inflammation in the subject. In some embodiments, the application reduces the number of circulating leukocytes. In some embodiments, the application reduces the number of circulating neutrophils. In some embodiments, the application reduces intestinal mucosal inflammation at sites of barrier dysfunction. In some embodiments, the application reduces immune cell infiltration in the intestine. In some embodiments, the application reduces neutrophil infiltration in the intestine. In some embodiments, the application inhibits the occurrence of intestinal stricture.

[0019] In some implementations, the subject does not respond to or cannot tolerate treatment with one or more of the following: aminosalicylic acid (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators, immunomodulators, Janus kinase (JAK) inhibitors, tumor necrosis factor (TNF) inhibitors, integrin antagonists, interleukin (IL)-23 antagonists, or IL-12 antagonists.

[0020] In some implementations, the subject has ulcerative colitis (UC). In some implementations, the subject has mild to moderate active ulcerative colitis. In some implementations, the subject has moderate to severe active ulcerative colitis. In some implementations, the subject has severe active ulcerative colitis.

[0021] In some implementations, the subject's modified Mayo Disease Activity Index (MMDAI) score was in the range of 3 to 12 prior to administration. In some implementations, administration reduced the MMDAI score by at least 3 points.

[0022] In some implementations, the subject's Mayo endoscopic subscore (MES) was 1 to 3 prior to application. In some implementations, the application improves the subject's endoscopic appearance. In some implementations, the application reduces the MES by at least 1 point.

[0023] In some implementations, administration induces endoscopic remission in the subject. In some implementations, administration maintains endoscopic remission in the subject. In some implementations, administration reduces bowel frequency or defecation. In some implementations, administration reduces rectal bleeding. In some implementations, administration induces clinical remission in the subject. In some implementations, administration maintains clinical remission in the subject. In some implementations, administration reduces the need for hospitalization due to unreactive colitis.

[0024] In some implementations, the medication is used to alleviate extraintestinal symptoms of ulcerative colitis in the recipient. In some implementations, the extraintestinal symptom is fatigue.

[0025] In some embodiments, the subject has Crohn's disease (CD). In some embodiments, the subject's Crohn's Disease Activity Index (CDAI) prior to administration is at least 150. In some embodiments, the subject's CDAI prior to administration is in the range of 150 to 450. In some embodiments, the subject's CDAI prior to administration is greater than 450. In some embodiments, administration reduces the CDAI by at least 70. In some embodiments, the subject has one or more fistulas.

[0026] In some implementations, the application reduces the number of fistulas in the subject relative to the number of fistulas present before application. In some implementations, the application maintains fistula closure in the subject. In some implementations, the application reduces the number of draining enterocutaneous fistulas in the subject. In some implementations, the application improves endoscopic appearance. In some implementations, the application promotes mucosal healing. In some implementations, the application reduces hospitalization in the subject. In some implementations, the application reduces the subject's need for corticosteroids. In some implementations, the application induces clinical remission in the subject. In some implementations, the application maintains clinical remission in the subject. In some implementations, the application reduces fatigue in the subject.

[0027] In some aspects, this document provides a method for treating ulcerative colitis (UC), the method comprising administering an effective amount of anti-HJV antibody to a subject suffering from UC and experiencing mucosal inflammation. In some embodiments, the subject has acute-phase UC. In some embodiments, the subject has chronic-phase UC.

[0028] In some embodiments, the application promotes mucosal healing in the subject. In some embodiments, the application reduces colonic shortening in the subject. In some embodiments, the application reduces weight loss in the subject. In some embodiments, the application reduces bowel frequency in the subject. In some embodiments, the application reduces rectal bleeding in the subject. In some embodiments, the application reduces systemic inflammation in the subject. In some embodiments, the application reduces the number of circulating white blood cells in the subject. In some embodiments, the application reduces the number of circulating neutrophils in the subject. In some embodiments, the application increases the level of circulating red blood cells in the subject. In some embodiments, the application increases hemoglobin in the subject. In some embodiments, the application increases mean corpuscular hemoglobin (MCH) in the subject. In some embodiments, the application increases transferrin saturation (TSAT%) in the subject. In some embodiments, the application increases serum iron in the subject.

[0029] In some embodiments, the anti-HJV antibody is administered in combination with one or more of the following: aminosalicylic acid (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators, immunomodulators, Janus kinase (JAK) inhibitors, tumor necrosis factor (TNF) inhibitors, integrin antagonists, interleukin (IL)-23 antagonists, or IL-12 antagonists. In some embodiments, the anti-HJV antibody is administered intravenously or subcutaneously.

[0030] In some embodiments, the antibody comprises: a heavy chain complementarity-determining region (CDR) 1 (HC CDR1) containing the amino acid of SEQ ID NO: 1, an HC CDR2 containing the amino acid of SEQ ID NO: 2, an HC CDR3 containing the amino acid of SEQ ID NO: 3; a light chain (LC) CDR1 containing the amino acid of SEQ ID NO: 17, an LCCDR2 containing the amino acid of SEQ ID NO: 5, and an LCCDR3 containing the amino acid of SEQ ID NO: 27.

[0031] In some embodiments, the anti-HJV antibody comprises a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 38 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO: 39.

[0032] In some embodiments, the anti-HJV antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 61 and a light chain containing the amino acid sequence of SEQ ID NO: 62.

[0033] In some embodiments, the anti-HJV antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 63 and a light chain containing the amino acid sequence of SEQ ID NO: 62. Attached Figure Description

[0034] The accompanying drawings, which are incorporated in and form part of this specification, illustrate certain embodiments and, together with the written description, serve to provide non-limiting examples of certain aspects of the compositions and methods disclosed herein.

[0035] Figures 1A to 1C This indicates that anti-hemoblast (HJV) antibody treatment reduced the severity of dextran sulfate sodium (DSS)-induced ulcerative colitis. Figure 1A The body weights of mice in groups 1 through 6 during the DSS study are shown. Anti-HJV antibody treatment improved DSS-induced weight loss (compared to 4 DSS cycles). ). Figure 1B Colon lengths of mice in groups 1 through 6 at the defined endpoints in each group are shown (Group 1: Day 0; Group 2: Day 6; Group 3: Day 13; Group 4: Day 20; Group 5: Day 27; Group 6: Day 27). Anti-HJV antibody treatment improved DSS-induced colonic stenosis (compared to 4 DSS cycles). ). Figure 1CThe Disease Activity Index (DAI) scores of mice in groups 1 through 6 during the DSS study are shown. Anti-HJV antibody treatment improved DSS-induced disease severity (compared to 4 DSS cycles). ).

[0036] Figures 2A to 2H This indicates that the administration of anti-HJV antibodies improved blood cell counts and inflammation in DSS-induced colitis. Figures 2A to 2C The figure shows red blood cell parameters, including red blood cell (RBC) count, in mice treated with DSS when treated with anti-HJV. Figure 2A ), hemoglobin (HGB) Figure 2B ) and mean corpuscular hemoglobin (MCH) Figure 2C The condition was improved. Anti-HJV improved anemia in a DSS-induced colitis mouse model (compared to 4 DSS cycles). ). Figures 2D to 2E It was shown that anti-HJV treatment increased serum iron levels in DSS-treated mice. Figure 2D ) and transferrin saturation (TSAT%) Figure 2E Anti-HJV treatment restored serum iron levels and TSAT% to normal (compared to 4 DSS cycles). ). Figures 2F to 2H This study demonstrates that anti-HJV antibody treatment attenuated systemic inflammation in a DSS-induced colitis mouse model. A comparison between group 5 and group 6 showed that in mice treated with anti-HJV antibodies, white blood cells (WBCs)... Figure 2F ) and neutrophils ( Figure 2G The cycle level decreased (compared to 4 DSS cycles). Additionally, there was a trend toward lower lymphocyte counts in the anti-HJV treatment group (Group 6) (p = 0.11 compared to Group 5). Surprisingly, these data suggest that HJV antagonism suppresses the inflammatory response by reducing systemic WBC and neutrophil counts. Detailed Implementation

[0037] According to some aspects, this disclosure provides compositions and methods for treating subjects with IBD, the method comprising administering a hemoblastin (HJV) antagonist (e.g., an anti-HJV antibody) to the subject. In some embodiments, this disclosure provides compositions and methods for treating subjects with ulcerative colitis (UC), the method comprising administering a hemoblastin (HJV) antagonist (e.g., an anti-HJV antibody) to the subject. In some embodiments, this disclosure provides compositions and methods for treating subjects with Crohn's disease (CD), the method comprising administering a hemoblastin (HJV) antagonist (e.g., an anti-HJV antibody) to the subject. In some embodiments, this disclosure provides compositions and methods for treating subjects with unclassified IBD (IBD-U), the method comprising administering a hemoblastin (HJV) antagonist (e.g., an anti-HJV antibody) to the subject.

[0038] Other aspects of this disclosure are provided below, including a description of the qualified terminology.

[0039] I. Definition

[0040] Application: As used herein, the term “application” or variations thereof means the delivery of a complex to a subject in a physiologically and / or pharmacologically available manner (e.g., to treat a condition in the subject).

[0041] Antibody: As used herein, the term "antibody" refers to a polypeptide comprising at least one immunoglobulin variable domain or at least one antigenic determinant (e.g., a complementary site that specifically binds to an antigen). In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, an F(ab')2 fragment, an Fv fragment, or a scFv fragment. In some embodiments, the antibody is a nanobody derived from a camel antibody or a shark antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody comprises a framework having a human germline sequence. In another embodiment, the antibody comprises a heavy chain constant domain selected from IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. In some embodiments, the antibody comprises a heavy (H) chain variable region (hereinafter referred to as VH) and / or a light (L) chain variable region (hereinafter referred to as VL). In some embodiments, the antibody comprises a constant domain, such as an Fc region. An immunoglobulin constant domain refers to a heavy chain constant domain or a light chain constant domain. The amino acid sequences and functional variations of the heavy and light chain constant domains of human IgG are known. Regarding the heavy chain, in some embodiments, the heavy chain of the antibody described herein may be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (µ) heavy chain. In some embodiments, the heavy chain of the antibody described herein may comprise a human alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (µ) heavy chain. In one specific embodiment, the antibody described herein comprises human γ1 CH1, CH2, and / or CH3 domains. In some embodiments, V... H The amino acid sequence of the domain comprises the amino acid sequence of the human gamma (γ) heavy chain constant region, such as any known in the art. Some non-limiting examples of human constant region sequences have been described in the art, see, for example, U.S. Patent No. 5,693,780 above and Kabat EA et al., (1991). In some embodiments, V HThe domain contains an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identity with any variable chain constant region provided herein. In some embodiments, the antibody is modified, for example, by glycosylation, phosphorylation, SUMOylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody conjugated to one or more sugar or carbohydrate molecules. In some embodiments, one or more sugar or carbohydrate molecules are conjugated to the antibody by N-glycosylation, O-glycosylation, C-glycosylation, glycosylphosphatidylinositol (GPI-anchored attachment), and / or phosphorylated glycosylation. In some embodiments, one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, one or more sugar or carbohydrate molecules include mannose units, glucose units, N-acetylglucosamine units, or phospholipid units. In some embodiments, the antibody is a construct comprising a polypeptide containing one or more antigen-binding fragments of this disclosure linked to a linker polypeptide or an immunoglobulin constant domain. The linker polypeptide comprises two or more amino acid residues linked by peptide bonds and is used to link one or more antigen-binding moieties. Examples of linker polypeptides have been reported (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-1123). Alternatively, the antibody may be part of a larger immunoadhesion molecule formed by covalent or non-covalent association of the antibody or antibody moieties with one or more other proteins or peptides. Some examples of such immunoadhesion molecules include the preparation of tetrameric scFv molecules using the streptavidin core region (Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6:93-101) and the preparation of divalent and biotinylated scFv molecules using cysteine ​​residues, biomarker peptides, and C-terminal multihistidine tags (Kipriyanov, SM, et al. (1994) Mol. Immunol. 31:1047-1058).

[0042] Affinity-matured antibodies: "Affinity-matured antibody" as used herein refers to an antibody having one or more alterations in one or more CDRs, which result in an improved affinity (i.e., KD, kd, or ka) for the target antigen compared to a parent antibody without the alterations. Exemplary affinity-matured antibodies will have nanomolar or even picomolar affinity for the target antigen. Various procedures for generating affinity-matured antibodies are known in the art, including screening combinatorial antibody libraries prepared using biodisplay. For example, Marks et al., BioTechnology, 10: 779-783 (1992) describe affinity maturation via VH and VL domain shuffling. Random mutagenesis of CDRs and / or framework residues is described in the following: Barbas et al., Proc. Nat. Acad. Sci. USA, 91: 3809-3813 (1994); Schier et al., Gene, 169: 147-155 (1995); Yelton et al., J. Immunol., 155: 1994-2004 (1995); Jackson et al., J. Immunol., 154(7): 3310-3319 (1995); and Hawkins et al., J. Mol. Biol., 226: 889-896 (1992). Selective mutagenesis at selective mutagenesis sites and at contact or hypermutation sites with activity-enhancing amino acid residues is described in U.S. Patent No. 6,914,128 B1.

[0043] Approximately: As used herein, the term “approximately” or “about” when applied to one or more target values ​​refers to a value similar to the reference value. In some embodiments, the term “approximately” or “about” refers to a range of values ​​falling within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in any direction (greater than or less than the reference value), unless otherwise stated or otherwise apparent from the context (unless such a number exceeds 100% of the possible value).

[0044] Baseline Level: As used herein, the term "baseline level" refers to a value representing an initial level (including normal or disease-prone levels) of a measurable trait, used for comparison with a value representing a response to an intervention (e.g., a drug, medical procedure, or control). In some embodiments, the baseline reflects the health status of an individual or group of individuals at the start of the process—disease severity, confounding conditions, biomarkers (e.g., hematological biomarkers). In some embodiments, the process is a medical treatment program. In some embodiments, the process is a prospective study (e.g., a clinical trial). In some embodiments, the baseline value is the last non-missing value before the subject begins the process (e.g., a treatment program or clinical trial). In some embodiments, the baseline value is the value before the subject suffers from a condition associated with barrier dysfunction as described herein (e.g., IBD, UC, or CD). In some embodiments, the subject experiences a change in the value compared to the baseline value before receiving the drug, and treatment with the drug brings the value back to the baseline level. In some embodiments, treatment with the drug brings the value back to the baseline level more quickly compared to subjects who did not receive the drug.

[0045] Comorbidity: As used in this article, “comorbidity” refers to one or more conditions or disorders that co-occur (or occur simultaneously) with an individual’s primary condition (e.g., a disease associated with barrier dysfunction (e.g., IBD, UC, or CD)).

[0046] Control subjects: Subjects with comparable characteristics and traits (e.g., age, species, health status, and other similar parameters) to the subjects described herein. In some embodiments, control subjects may be a group of subjects with similar conditions (e.g., IBD) but who are receiving or are expected to receive treatment different from the treatments described herein (e.g., treatment using a hemoblastoid antagonist). In some embodiments, in experimental or clinical trials, control subjects may be a group of participants with characteristics similar to those of the treatment group, but who do not receive the treatment being studied. In some embodiments, control subjects receive a substance or treatment designed to have no therapeutic value (i.e., a placebo).

[0047] CDR: As used herein, the term "CDR" refers to the complementarity determining region within the variable sequence of an antibody. A typical antibody molecule contains a heavy chain variable region (VH) and a light chain variable region (VL), which are typically involved in antigen binding. The VH and VL regions can be further subdivided into hypervariable regions, also known as "complementarity determining regions" (CDRs), within which are interspersed more conserved regions called "framework regions" (FRs). Each VH and VL typically consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the frame region and CDR can be precisely determined using methods known in the art, such as the Kabat definition, IMGT definition, Chothia definition, AbM definition, and / or contact definition, all of which are well-known in the art.See, for example, Kabat, EA, et al., (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242; IMGT®, the international ImMunoGeneTics informationsystem® http: / / www.imgt.org; Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999); Ruiz, M. et al., Nucleic Acids Res., 28:219-221 (2000); Lefranc, M.-P., Nucleic Acids Res., 29:207-209 (2001); Lefranc, M.-P., Nucleic Acids Res., 31:307-310 (2003); Lefranc, M.-P. Lefranc, et al., In Silico Biol., 5, 0006 (2004) [Epub], 5:45-60 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 33:D593-597 (2005); Lefranc, M.-P. et al., Nucleic Acids Res., 37:D1006-1012 (2009); Lefranc, M.-P. et al., Nucleic Acids Res., 43:D413-422 (2015); Chothia et al., (1989) Nature 342:877; Chothia, C. et al., (1987) J. Mol. Biol. 196:901-917; Al-lazikani et al., (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. The CDR used herein may refer to a CDR defined by any method known in the art. Two antibodies having the same CDR means that the amino acid sequences of the CDRs of the two antibodies, determined by the same method (e.g., the IMGT definition), are identical.

[0048] Generally, each variable region of the heavy and light chains contains three CDRs, referred to as CDR1, CDR2, and CDR3 for each variable region. The term "CDR group" used in this paper refers to a group of three CDRs capable of binding the antigen that appear within a single variable region. The exact boundaries of these CDRs have been defined differently depending on the system. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides a definitive residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining three CDRs. These CDRs may be referred to as Kabat CDRs. Sub-regions of a CDR may be designated as L1, L2, and L3 or H1, H2, and H3, where “L” and “H” designate the light chain and heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Padlan (FASEBJ. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)) have described other boundaries defining CDRs that overlap with Kabat CDRs. Other CDR boundaries may not strictly follow one of the systems described above, but still overlap with Kabat CDRs. CDR overlap, although they can be shortened or lengthened based on predictions or experimental findings that a particular residue or group of residues or even the entire CDR does not significantly affect antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, but exemplary embodiments use CDRs defined by Kabat or Chothia.

[0049] CDR-grafted antibody: The term "CDR-grafted antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species, but in which one or more CDR regions of VH and / or VL are replaced by CDR sequences from another species, such as an antibody with mouse heavy and light chain variable regions and in which one or more mouse CDRs (e.g., CDR3) have been replaced by human CDR sequences.

[0050] Chimeric antibody: The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species and constant region sequences from another species, such as a mouse heavy and light chain variable region linked to a human constant region.

[0051] Complementarity: As used herein, the term “complementarity” refers to the ability to precisely pair between two nucleotides or groups of nucleotides. Specifically, complementarity is a term characterizing the degree of hydrogen bond pairing that causes the binding between two nucleotides or groups of nucleotides. For example, if a base at a position of an oligonucleotide is able to hydrogen bond with a base at a corresponding position of a target nucleic acid (e.g., mRNA), the bases at that position are considered complementary to each other. Base pairing can include both canonical Watson-Crick base pairing and non-Watson-Crick base pairing (e.g., Wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairing, an adenosine base (A) is complementary to a thymidine base (T) or a uracil base (U), a cytosine base (C) is complementary to a guanosine base (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize with any A, C, U, or T and are considered complementary to them. Inosine (I) is also considered a universal base in the art and is believed to be complementary to any A, C, U or T.

[0052] Conservative amino acid substitution: As used herein, “conservative amino acid substitution” refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein to which the substitution is made. Variants can be prepared according to methods known to those skilled in the art for altering polypeptide sequences, methods described, for example, in compilations of such methods, such as *Molecular Cloning: A Laboratory Manual*, J. Sambrook, et al., eds., 4th ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or *Current Protocols in Molecular Biology*, FM Ausubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions between amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0053] Cross-reactivity: As used herein and in the case of a targeted substance (e.g., an antibody), the term "cross-reactivity" refers to the property of a substance to specifically bind with more than one antigen of similar type or class (e.g., multiple homologs, paralogs, or orthologs) with similar affinity or co-affinity. For example, in some embodiments, antibodies that are cross-reactive to similar types or classes of human and non-human primate antigens (e.g., human hemoblastin and non-human primate hemoblastin) are capable of binding to human and non-human primate antigens with similar affinity or co-affinity. In some embodiments, antibodies are cross-reactive to similar types or classes of human and rodent antigens. In some embodiments, antibodies are cross-reactive to similar types or classes of rodent and non-human primate antigens. In some embodiments, antibodies are cross-reactive to similar types or classes of human, non-human primate, and rodent antigens.

[0054] Effective amount: As used herein, “effective amount” or “effective amount” means the amount of each active agent (e.g., hemoblastoid antagonists, including anti-HJV antibodies) required, alone or in combination with one or more other active agents, to impart a therapeutic effect to a subject (e.g., to treat a condition associated with barrier dysfunction (e.g., IBD)).

[0055] Erythropoiesis: As used herein, the term "erythropoiesis" refers to the process of producing red blood cells (RBCs or erythrocytes). In some embodiments, erythropoiesis includes the development from hematopoietic stem cells into mature red blood cells. For example, during red blood cell maturation, cells typically undergo a series of differentiation steps, which may include, in the bone marrow, differentiation of hematopoietic cells (pluripotent hematopoietic stem cells) along pathways comprising one or more of the following: common myeloid progenitor cells, pluripotent stem cells, proerythroids, erythroblasts, polychromatophilic cells, and orthochromatic cells. In some embodiments, at the end of the orthochromatic phase, the nucleus is expelled through asymmetric division of orthochromatic erythroblasts, becoming reticulocytes (which are immature red blood cells). Reticulocytes are typically released from the bone marrow into circulation and eventually become "erythrocytes" or mature red blood cells after one or two days. Therefore, reticulocytes are primarily present in circulating blood. In some embodiments, by the reticulocyte stage, the cell has expelled its nucleus but is still able to produce hemoglobin. In other embodiments, the normal RBC count in the subject is 4.7 × 10⁻⁶. 12 Up to 6.1×10 12 1 cell / L (in males) or 4.2 × 10⁻⁶ cells / L 12Up to 5.4×10 12 Cells / L

[0056] Ferritin: As used in this article, the term "ferritin" refers to a protein that stores and releases iron in a controlled manner. Ferritin is the primary intracellular iron storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, ferritin acts as a buffer against iron deficiency and iron overload. Circulating ferritin is also an indirect marker of total iron stored in the body; therefore, serum ferritin is used as a diagnostic test for iron deficiency anemia.

[0057] Frame: As used herein, the term “frame” or “frame sequence” refers to the sequence remaining after subtracting the CDR from the variable region. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a frame sequence can be interpreted accordingly. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 for the light chain and CDR-H1, CDR-H2, and CDR-H3 for the heavy chain) also divide the frames on the light and heavy chains into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, where CDR1 is located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Where no specific sub-region is designated as FR1, FR2, FR3, or FR4, other references to frame regions refer to combinations of FRs within the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR represents one of the four sub-regions, and plural FRs represent two or more of the four sub-regions constituting a frame region. Human heavy and light chain receptor sequences are known in the art. In one embodiment, an acceptor sequence known in the art can be used in the antibody disclosed herein.

[0058] Hemojuglin (HJV): As used herein, the term "hemojuglin (HJV)" (also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2)) refers to a membrane-bound and soluble protein that regulates hepcidin production via the bone morphogenic protein (BMP) / SMAD signaling pathway (Xiao et al., "Bone morphogenic proteins in iron homeostasis." Bone. 2020; 138:115495). The HFE2 gene encodes two known classes of glycosylphosphatidylinositol (GPI)-anchored and glycosylated HJV molecules that target membranes and undergo different fates. HJV exists in multiple isoforms, including two soluble isoforms and two membrane-associated isoforms. In some embodiments, the dominant membrane-associated isoform is a disulfide-linked double-stranded form consisting of N-terminal and C-terminal segments. In some embodiments, the full-length single-stranded isoform associates with the membrane but is released from the cell surface and accumulates in the extracellular fluid. In some embodiments, HJV can be of human (NCBI Gene ID 148738), non-human primate (e.g., NCBI Gene ID 698805), or rodent (e.g., NCBI Gene ID 69585 or NCBI Gene ID 310681) origin. In addition to HJV (RGMc), the family of rejection-directing molecules also includes rejection-directing molecule A (RGMa) and rejection-directing molecule B (RGMb). RGMa and RGMb are expressed in the central nervous system during development and are thought to be involved in controlling axonal pattern formation and neuronal survival, while HJV is produced in the liver, as well as in the cardiac muscle and skeletal muscle.

[0059] Hepcidin: As used herein, "hepcidin" refers to an iron-regulating peptide hormone encoded by the HAMP gene, primarily produced in the liver. In some embodiments, hepcidin controls the delivery of iron from iron-absorbing enterocytes, from circulating erythrocyte macrophages, and from iron-storing hepatocytes into the plasma. Normal hepcidin levels vary depending on the measurement technique, sex, the tissue or fluid present, and / or menopausal status. In some embodiments, hepcidin inhibits iron transport by binding to iron transporters located on the basolateral surface of enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). In some embodiments, inhibition of iron transporters prevents iron export and chelation within the cells. In some embodiments, by inhibiting iron transporters, hepcidin prevents enterocytes from the portal venous system, thereby reducing dietary iron absorption. Hepcidin expression involves multiple aspects, including, for example, the transcription of the HAMP gene, the translation of the transcribed mRNA, and the post-translational processing of hepcidin precursors into the biologically active hepcidin-25 peptide. (SEQ ID NO: 129). In some embodiments, hepcidin expression is regulated via the hemoblastin-induced BMP signaling pathway. In some embodiments, hepcidin expression is regulated via the IL-6-JAK-STAT signaling pathway.

[0060] Hepcidin antagonists: As used herein, "hepcidin antagonists" refers to substances that (directly or indirectly) reduce hepcidin expression and / or hepcidin activity. In some embodiments, hepcidin antagonists inhibit hepcidin-induced ferrotransferase degradation. Thus, in some embodiments, hepcidin antagonists indirectly target hepcidin function via the hepcidin-stimulated pathway to reduce hepcidin expression. In some embodiments, hepcidin antagonists directly target hepcidin function, for example, by binding hepcidin peptides to chelate free hepcidin, or by binding ferrotransferases to inhibit hepcidin-ferrotransferase binding interactions, thereby reducing hepcidin-induced ferrotransferase degradation. In some implementations, hepcidin antagonists are hepcidin inhibitors that disrupt the hepcidin-ferroportin interaction, for example, as disclosed in Ross SL, et al., Identification of Antibody and Small Molecule Antagonists of Ferroportin-Hepcidin Interaction. Front Pharmacol. 2017 Nov 21;8:838; Fung E., et al., High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists. Molecular Pharmacology, March 2013, 83 (3) 681-690; and Angeliki Katsarou and Kostas Pantopoulos, Hepcidin Therapeutics. Pharmaceuticals (Basel). 2018 Dec; 11(4):127, the relevant contents of which are incorporated herein by reference.

[0061] Hematologic recovery: As used herein, the term "hematologic recovery" refers to the process of bringing the oxygen-carrying capacity of a subject's blood to a state comparable to (e.g., equal to or within) the baseline values ​​of a normal healthy subject (e.g., a normal healthy control subject). A "typical" range for baseline oxygen levels in the blood of a normal healthy subject is 95% to 100% oxygen saturation. In some embodiments, hematologic recovery can be assessed by evaluating one or more of the following levels: erythropoiesis, circulating hemoglobin levels, reticulocyte hemoglobin (CHr), and mean corpuscular hemoglobin (MCH), which indicate whether the subject has achieved steady-state oxygen-carrying capacity.

[0062] Hemoglobin: As used herein, the term "hemoglobin (Hgb)" refers to an iron-containing oxygen-transporting metalloprotein found in red blood cells (erythrocytes). Hemoglobin in the blood carries oxygen from respiratory organs (e.g., lungs or gills) to other parts of the body (e.g., tissues). There, it releases oxygen to allow aerobic respiration, thus providing energy to power the organism's functions in what is known as metabolism. The blood of a healthy individual contains approximately 12 to 20 g / dL of hemoglobin. Hemoglobin (Hgb) is synthesized through a complex series of steps. The heme portion is synthesized in the mitochondria and cytosol of immature red blood cells through a series of steps, while the globin portion is synthesized by ribosomes in the cytosol. Iron is an essential element for hemoglobin synthesis, particularly heme synthesis. The final step in heme synthesis involves the addition of iron ions to protoporphyrin IX (PPIX, a precursor of heme) by ferrous chelate enzymes, thereby producing the heme molecule. The production of globin chains occurs in the cytosol of red blood cells and is carried out through genetic transcription and translation. Numerous studies have shown that the presence of heme induces globin production. Heme combines with globin to form hemoglobin.

[0063] Human Antibody: As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of this disclosure may comprise amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced through random or site-specific mutagenesis in vitro or through somatic mutations in vivo), such as in CDRs, and particularly in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which a CDR sequence derived from another mammalian species (e.g., a mouse) has been grafted onto a human frame sequence (e.g., a CDR grafted into a heterologous frame).

[0064] Humanized antibody: The term "humanized antibody" refers to an antibody that contains variable region sequences of both heavy and light chains derived from a non-human species (e.g., mouse), but in which V... H and / or V L At least a portion of the sequence has been altered to be more "human-like" (i.e., more similar to human germline variable sequences) antibodies. One type of humanized antibody is a CDR-grafted antibody, in which a human CDR sequence is introduced into a non-human antibody. H and V LThe corresponding non-human CDR sequence is replaced in the sequence. In one embodiment, a humanized anti-erythroblast antibody and an antigen-binding moiety are provided. Such an antibody can be produced by obtaining a mouse anti-erythroblast monoclonal antibody using conventional hybridoma techniques, followed by humanization using in vitro genetic modification, such as those disclosed in PCT Publication No. WO2005 / 123126 A2 by Kasaian et al.

[0065] Isolated Antibodies: As used herein, “isolated antibodies” are intended to refer to antibodies that are substantially free of other antibodies with different antigen specificities (e.g., isolated antibodies that specifically bind hemoblastin are substantially free of antibodies that specifically bind antigens other than hemoblastin). However, isolated antibodies that specifically bind hemoblastin may be cross-reactive with other antigens, such as other repulsive guidance molecule (RGM) proteins (e.g., RGMa and / or RGMb). Furthermore, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0066] Kabat Numbering: The terms “Kabat numbering,” “Kabat definition,” and “Kabat labeling” are used interchangeably herein. These terms, as accepted in the art, refer to a system for numbering amino acid residues in the variable regions of the heavy and light chains of antibodies or their antigen-binding moieties that are more variable (i.e., hypervariable) than other amino acid residues (Kabat, et al. (1971) Ann. NY Acad, Sci. 190:382-391 and Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable regions, the hypervariable region of CDR1 is amino acids 31 to 35, the hypervariable region of CDR2 is amino acids 50 to 65, and the hypervariable region of CDR3 is amino acids 95 to 102. For the light chain variable regions, the hypervariable region of CDR1 is amino acids 24 to 34, the hypervariable region of CDR2 is amino acids 50 to 56, and the hypervariable region of CDR3 is amino acids 89 to 97.

[0067] Mean corpuscular hemoglobin content (MCH): As used in this article, “mean corpuscular hemoglobin content” refers to the average mass of hemoglobin (Hgb) per red blood cell (RBC) in a blood sample. It is calculated by dividing the total mass of hemoglobin in a given volume of blood by the number of red blood cells: MCH = (Hgb) / (RBC ... 10) / RBC.

[0068] In some implementations, the normal MCH value for humans is 27 to 31 picograms (pg) per cell. The amount of hemoglobin per red blood cell (RBC) depends on hemoglobin synthesis and RBC size. The mass of a red blood cell is determined by iron (which is part of the hemoglobin molecule), so MCH in picograms is approximately the mass of one red blood cell. In some implementations, in iron deficiency anemia, cell mass is lighter, and an MCH below 27 pg is an indication of iron deficiency.

[0069] Recombinant Antibody: As used herein, the term “recombinant human antibody” is intended to include all human antibodies prepared, expressed, generated, or isolated in a recombinant manner, such as antibodies expressed using a recombinant expression vector transfected into host cells (described in more detail in this disclosure), antibodies isolated from recombinant, combinatorial human antibody libraries (Hoogenboom HR, (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35:425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378), and antibodies isolated from animals (e.g., mice) that are transgenic to the human immunoglobulin gene (see, for example, Taylor, LD, et al. (1992) Nucl. Acids Res.). 20:6287-6295; Kellermann SA., and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al. (2000) Immunology Today 21:364-370), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are mutagenized in vitro (or, when using transgenic animals for human Ig sequences, in vivo somatic cell mutagenization), and thus the V of the recombinant antibody is determined. H and V L The amino acid sequence of the region is as follows: although it originates from human lineage V H and V LThe sequence is associated with, but may not be naturally present in the in vivo human antibody germline library. One embodiment of this disclosure provides a fully human antibody capable of binding human leukocytes, which can be generated using techniques known in the art, such as, but not limited to, using human Ig phage libraries, such as those disclosed in Jermutus et al., PCT Publication No. WO 2005 / 007699 A2.

[0070] Reticulocyte hemoglobin content (CHr): As used herein, “reticulocyte hemoglobin content (CHr)” refers to the level of hemoglobin in reticulocytes (immature red blood cells in circulation). Reticulocyte hemoglobin content reflects the amount of iron available for hemoglobin production in the bone marrow. Reticulocyte hemoglobin content provides an indirect measure of the functional iron available for the production of new red blood cells over the preceding days (e.g., 3 to 4 days). In some embodiments, reticulocyte hemoglobin equivalent (Ret-He) is used instead of CHr (Toki et al., “Usefulness of Reticulocyte Hemoglobin Equivalent for Diagnosis of Iron Deficiency.” Blood. 2016; 128(22):3621).

[0071] Selectivity: As used herein, the term “selectivity” or variations thereof refers to the ability of a molecule to produce an effect related to its target molecule compared to a reference molecule. For example, a molecule that selectively inhibits its target molecule means that the molecule is able to inhibit its target molecule to a degree that distinguishes it from a reference molecule in an inhibition assay or other inhibition conditions. For example, with respect to inhibitors, the term “selective inhibition” refers to the ability of an inhibitor to inhibit its target molecule to a degree that distinguishes it from a reference molecule that is substantially uninhibited in an inhibition assay, such as to the extent that selective inhibition of the target molecule is permitted, as described herein. For example, the half-maximal inhibitory concentration (IC50) for the target molecule and / or the reference molecule can be tested in a kinase potency assay, as described in Asshoff, M. et al., Momelotinib inhibits ACVR1 / ALK2, decreases hepcidinproduction, and ameliorates anemia of chronic disease in rodents. Blood. 2017 Mar 30; 129(13): 1823-1830 (e.g., by a kinase potency assay from Carna Biosciences). In this assay, an inhibitor solution (e.g., a solution containing the selective inhibitor to be tested) / kinase substrate is mixed with a target molecule solution (e.g., ALK2) or a reference molecule solution (e.g., JAK1 or JAK2) and incubated at room temperature for 1 hour. Once the reaction is terminated, the signal generated by enzyme activity on the substrate can be measured. The half-maximum inhibitor concentrations of the target and reference molecules can be calculated. In some embodiments, the molecules described herein selectively bind to the target molecule. In some embodiments, the molecules described herein selectively inhibit the target molecule. In some embodiments, the molecules described herein selectively antagonize the target molecule. In some embodiments, the molecules described herein selectively neutralize the target molecule.

[0072] Specific binding: As used herein, the term "specific binding" refers to the ability of a molecule to bind with a binding partner with a degree of affinity or affinity that enables the molecule to be used to distinguish the binding partner from a suitable control in a binding assay or other binding scenario. Regarding antibodies, the term "specific binding" refers to the ability of an antibody to bind with a specific antigen with a degree of affinity or affinity compared to one or more suitable reference antigens that enables the antibody to be used to distinguish the specific antigen from other antigens, for example, to the extent that it allows preferential targeting of certain cells (e.g., myocytes) by binding to antigens as described herein. In some embodiments, if the antibody binds to the K of the target… D For at least about 10 -4 M, 10 -5 M, 10-6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 If M is smaller, the antibody binds specifically to the target. In some implementations, the antibody binds specifically to hemoblastin.

[0073] Object: As used herein, the term "object" refers to a mammal. In some embodiments, the object is a non-human primate or rodent. In some embodiments, the object is a human. In some embodiments, the object is a patient, such as a person who has or is suspected of having a disease. In some embodiments, the object is a person who has or is suspected of having a condition associated with barrier dysfunction. In some embodiments, the object is a person who has or is suspected of having IBD and / or one or more related conditions, including ulcerative colitis (UC), Crohn's disease (CD), or unclassified IBD (IBD-U).

[0074] Transferrin saturation (TSAT%): As used in this article, “transferrin saturation (TSAT%)” refers to the percentage of serum iron divided by the total iron-binding capacity of available transferrin (the main protein that binds iron in the blood). This value indicates how much serum iron is bound to transferrin. For example, a value of 15% means that 15% of the iron-binding sites of transferrin are occupied by iron. Low transferrin saturation is a common marker of iron deficiency; however, high transferrin saturation can indicate iron overload or hemochromatosis. Transferrin saturation is also known as the transferrin saturation index (TSI) or the percentage of transferrin saturation (TS%).

[0075] Treatment: As used herein, the term "treatment" or variations thereof means the application or administration of a composition comprising one or more active substances to a subject suffering from a target disease or condition, having symptoms of that disease / condition, or being predisposed to that disease / condition, with the aim of curing, treating, alleviating, relieving, altering, remedying, improving, or influencing the condition, its symptoms, or the predisposition to that disease or condition. Alleviating a target disease / condition includes delaying or preventing the onset or progression of the disease, or reducing its severity.

[0076] II. Methods for treating inflammatory bowel disease

[0077] Certain aspects of this disclosure relate to the understanding that inhibiting hemolymphocytes alleviates inflammation in subjects with barrier dysfunction (e.g., intestinal mucosal barrier dysfunction). Generally, the term "barrier dysfunction" refers to the abnormal function of the epithelial barrier lining organ systems or other body structures (e.g., the gastrointestinal system, skin, and trachea), and particularly to the disruption of barrier integrity, such as sufficient to increase permeability across the barrier or otherwise allow molecular transport across the barrier to exceed physiologically normal levels. Under normal conditions, epithelial tissue acts as a barrier by forming a continuous layer, protecting the body from a variety of factors such as environmental stress, physical and chemical injury, infection, and allergens (see, for example, Sozener et al., Environmental factors in epithelial barrierdysfunction, Clinical Reviews in Allergy and Immunology, Vol. 145, No. 6, pp. 1517-1528, June 2020). In some embodiments, the barrier dysfunction is intestinal barrier dysfunction. In some embodiments, the barrier dysfunction is skin barrier dysfunction. In some implementations, barrier dysfunction is airway barrier dysfunction.

[0078] In some embodiments, the methods and related compositions provided herein can be used to suppress inflammation (e.g., intestinal mucosal inflammation) in subjects with IBD (e.g., UC, CD, IBD-U). In some embodiments, the compositions and methods provided herein can be used to reduce intestinal mucosal inflammation, reduce intestinal bleeding, improve clinical symptoms, induce remission, and / or maintain remission in subjects with IBD (e.g., UC, CD, IBD-U).

[0079] In some embodiments, this disclosure provides compositions (e.g., anti-HJV antibodies) and methods for treating subjects with intestinal barrier dysfunction.

[0080] Generally, the term "intestinal barrier dysfunction" refers to the impairment of the barrier function of the epithelial barrier lining the gastrointestinal tract. The intestinal barrier is selectively permeable due to its protein-protein network and is designed to absorb and exchange nutrients, water, and electrolytes while providing effective defense against microorganisms and toxins. The intestinal barrier comprises multiple layers, including a mucus layer (i.e., the mucosal barrier) and an epithelial layer. The epithelial layer consists of a single layer of columnar epithelial cells, including absorptive intestinal cells, secretory goblet cells, Paneth cells, and enteroendocrine cells. The mucus layer in the intestine is thick and adheres to the intestinal epithelium. It is crucial for the selective permeability of the intestinal barrier. The mucus layer consists of two layers: an inner layer firmly attached to the epithelial cells and a thicker but looser outer layer with less adhesion. The inner mucosal layer does not allow bacterial penetration, keeping the epithelial cell surface from direct contact with bacteria. Conversely, the outer mucosal layer contains symbiotic bacteria that prevent pathogens from entering the outer mucus layer and the inner mucus layer. The mucus layer prevents large particles and microorganisms from directly contacting epithelial cells, while allowing small molecules to pass through and protecting epithelial cells from digestive enzymes. In addition to its protective function, the intestinal epithelium also controls the absorption and exchange of nutrients, water, and electrolytes. Furthermore, the intestinal barrier includes various factors, such as intestinal alkaline phosphatase and antibacterial peptides, whose additional functions include maintaining pH, nutrient absorption, and providing antimicrobial defense. In some embodiments, subjects with IBD have increased intestinal permeability compared to subjects without intestinal barrier dysfunction. In some embodiments, subjects with IBD have mucosal barrier dysfunction.

[0081] In some embodiments, intestinal barrier function is essential for normal intestinal homeostasis. In some embodiments, intestinal barrier dysfunction is intestinal mucosal barrier dysfunction. In some embodiments, intestinal epithelial cell damage leads to intestinal barrier dysfunction. In some embodiments, intestinal epithelial cell damage and / or cell death leads to intestinal barrier dysfunction. In some embodiments, loss of tight junctions between intestinal epithelial cells leads to intestinal barrier dysfunction. In some embodiments, loss of intestinal mucus leads to intestinal barrier dysfunction. In some embodiments, intestinal barrier dysfunction leads to increased intestinal permeability. In some embodiments, disruption or dysfunction of the intestinal barrier is associated with local and systemic consequences, primarily related to direct contact between bacteria / bacterial products and epithelial cells and their translocation into systemic circulation. Direct contact with bacteria / bacterial products induces immune cell activation, leading to the secretion of pro-inflammatory mediators that perpetuate local inflammation. In some implementations, localized intestinal inflammation is the basis for the development of many gastrointestinal diseases, such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis (see, for example, Ghosh et al., Intestinal Barrier Dysfunction, LPS Translocation, and Disease Development, J Endocr Soc. 2020 Feb 1; 4(2):bvz039). In some implementations, subjects with IBD have mucosal barrier dysfunction.

[0082] In some aspects, this disclosure provides compositions (e.g., anti-HJV antibodies) and methods for treating subjects with inflammatory bowel disease (e.g., ulcerative colitis (UC), Crohn's disease (CD), or unclassified IBD (IBD-U)), the method comprising administering a hemoblastoid antagonist (e.g., the anti-HJV antibody described herein) to the subject. In some embodiments, methods and related compositions are provided herein for suppressing inflammation (e.g., intestinal mucosal inflammation) in subjects with IBD. In some embodiments, the compositions and methods provided herein can be used for the purposes of reducing intestinal mucosal inflammation, reducing intestinal bleeding, improving clinical symptoms, inducing and maintaining remission in subjects with IBD (e.g., UC, CD, or IBD-U).

[0083] Generally, the term "inflammatory bowel disease" ("IBD") refers to a group of diseases characterized by recurrent episodes of gastrointestinal inflammation caused by an abnormal immune response. In some embodiments, IBD encompasses two types of idiopathic bowel diseases, such as UC or CD, distinguished by the location and depth of their involvement in the intestinal wall. In some embodiments, IBD-U encompasses IBD-U, which is an inflammatory bowel disease exhibiting symptoms of one or more of both Crohn's disease (CD) and ulcerative colitis (UC). In some embodiments, individuals with IBD (e.g., UC, CD, IBD-U) have a genetic predisposition to IBD. In some implementations, the subject may have a genetic variant associated with IBD in one or more of the following genes: NOD2, ATG16L1, IRGM, IL23R, CARD9, CLEC7A, RNF186, HLA, TNF, TNFSF15 / TL1A, LR4, IL-6, IL-1, IL-10, IL-12, IL-23, IL17, TLR2, TLR9, Fas-L, CASP9, and ATG16L1 or PRDM1. In some implementations, the subject with IBD may be at risk of developing colorectal cancer or may have already developed colorectal cancer.

[0084] In some embodiments, IBD is ulcerative colitis (UC). UC involves diffuse inflammation of the colonic mucosa. In some embodiments, UC affects the rectum and the subject has proctitis. In some embodiments, the area affected by UC may extend to the sigmoid colon, and the subject has proctosigmoid colitis. In some embodiments, UC may affect the gastrointestinal tract outside the sigmoid colon, and the subject has distal ulcerative colitis. In some embodiments, UC may affect the entire colon down to the cecum, and the subject has pancolitis. In some embodiments, a subject with UC has one or more symptoms, including abdominal pain, hematochezia and / or pus in the stool, diarrhea, fever, weight loss, or tenesmus. In some embodiments, a subject with UC has atypical expression of perinuclear anti-neutrophil cytoplasmic antibody (P-ANCA) relative to a healthy subject. In some implementations, subjects with UC have similar expression of anti-Saccharomyces cerevisiae antibodies (ASCA) compared to healthy subjects.

[0085] In some embodiments, IBD is Crohn's disease (CD). CD causes transmural ulceration of any part of the gastrointestinal (GI) tract. In some embodiments, CD affects the terminal ileum and colon. In some embodiments, CD affects any part of the GI tract, including the oral cavity and esophagus. In some embodiments, a subject with CD is at risk of developing or already has a fistula (i.e., the subject has fistulous Crohn's disease) (see Scharl et al., Fistulizing Crohn's Disease, ClinTransl Gastroenterol. 2017 Jul; 8(7): e106). In some embodiments, a subject with CD is at risk of developing or already has a stricture (see, for example, Lin et al., Therap Adv Gastroenterol. 2022; 15: 17562848221104951). In some embodiments, a subject with CD has one or more symptoms, including diarrhea, fever, fatigue, abdominal pain, abdominal cramps, bloody stools, oral ulcers, decreased appetite, weight loss, and / or fistula. In some implementations, subjects with CD have similar p-ANCA expression compared to healthy subjects. In some implementations, subjects with UC have atypical ASCA expression compared to healthy subjects.

[0086] In some implementations, IBD is unclassified (IBD-U). IBD-U, also known as indeterminate colitis, refers to colitis that cannot be correctly identified as CD or UC (see: Zhou, N., et al. (2011). Inflammatory boweldisease unclassified. Journal of Zhejiang University Science B, 12, 280-286.; Shao, Y. et al. (2024) Clinical features of inflammatory bowel disease unclassified: a case-control study. BMC Gastroenterol 24, 105). In some implementations, IBD-U includes one or more symptoms or histopathological features of UC and / or one or more symptoms or histopathological features of CD. In some implementations, IBD-U includes transmural inflammation or crypt abscesses. In some implementations, IBD-U lacks transmural lymphoid aggregates or fissuring ulcers. In some embodiments, IBD-U includes the presence of mild, typically focal, basal lymphoplasmacytosis in a sample from the subject. In some embodiments, IBD-U includes minute structural abnormalities in a sample from the subject. In some embodiments, the subject with IBD-U has a history of inflammatory diarrhea. In some embodiments, the subject with IBD-U has liver disease. In some embodiments, the subject with IBD-U and intestinal bleeding develops UC. In some embodiments, the subject with IBD-U and hypoalbuminemia develops UC. It should be understood that the compositions and methods described herein (e.g., administration of anti-HJV antibodies) are suitable for the treatment of IBD-U.

[0087] In some implementations, in addition to the GI pathway, subjects with IBD (e.g., UC, CD, IBD-U) also have extraintestinal manifestations (EIM) (see, for example, Levine et al., Extraintestinal Manifestations of Inflammatory Bowel Disease, Gastroenterol Hepatol (NY). 2011 Apr; 7(4): 235–241; Malik et al., Extraintestinal Manifestations of Inflammatory Bowel Disease, In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. 2023 Mar 6). In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) have one or more EIMs, including but not limited to musculoskeletal manifestations such as axial spondyloarthritis (SpA) (e.g., ankylosing spondylitis (AS) and sacroiliitis) and / or peripheral spondyloarthritis (SpA) (e.g., oligoarticular (type 1) peripheral arthritis and polyarticular (type 2) peripheral arthritis); skin manifestations such as erythema nodosum (EN), pyoderma gangrenosa, Sweet syndrome, and / or oral aphthous lesions; ocular manifestations such as episcleritis, scleritis, and / or uveitis; and hepatobiliary manifestations such as primary sclerosing cholangitis. Cholangitis (PSC), autoimmune / granulomatous hepatitis, fatty liver disease, cholestasis, gallstone formation, and autoimmune pancreatitis; other manifestations include anemia, urinary manifestations (e.g., kidney stones with possible urinary outflow obstruction or interstitial nephritis), thromboembolic diseases (deep vein thrombosis or pulmonary embolism), heart disease, stroke, fatigue, interstitial pneumonia, or metabolic bone disease.

[0088] IBD is a condition characterized by alternating periods of active disease (flare-up) and minimal or no disease activity (remission). In some embodiments, a subject with IBD (e.g., UC, CD, IBD-U) may be in an active state of IBD. In some embodiments, the active state of IBD and active IBD refer to a period of symptom flare-up or exacerbation in the subject. In some embodiments, a subject with IBD may be in a remission period, during which the subject may experience minimal to no symptoms for a period of time (e.g., weeks to months). In some embodiments, a subject with IBD (e.g., UC, CD, IBD-U) may be in an active phase of IBD, during which symptoms recur after a period of remission (i.e., relapse). In some embodiments, a subject in an active phase of IBD may also have one or more extraintestinal manifestations of IBD. In some embodiments, a subject with active IBD (e.g., active US, active CD, active IBD-U) is in the acute phase of IBD. In some embodiments, subjects with active IBD (e.g., active UC, active CD, active IBD-U) have one or more symptoms associated with IBD (e.g., UC, CD, IBD-U). In some embodiments, subjects with active IBD (e.g., active UC, active CD, active IBD-U) have increased inflammation (e.g., systemic and / or local inflammation) compared to subjects during remission. In some embodiments, subjects with active IBD (e.g., active UC, active CD, active IBD-U) have one or more endoscopic findings associated with IBD. In some embodiments, subjects enter remission after the active phase of IBD.

[0089] In some implementations, subjects with IBD are in clinical remission. In some implementations, subjects with IBD are in endoscopic remission. In some implementations, subjects with IBD are in biochemical remission. In some implementations, subjects with IBD are in histological remission. In some implementations, subjects with IBD are in surgical remission.

[0090] In some implementations, the subject is in the chronic phase of IBD (e.g., including the remission phase and the period after an acute episode during active IBD).

[0091] In some implementations, the subject suffers from inflammation associated with intestinal barrier dysfunction. In some implementations, the subject has increased intestinal permeability compared to subjects without intestinal barrier dysfunction. In some implementations, the subject has an abnormal immune response to the gastrointestinal microbiome. In some implementations, inflammation in the intestine further damages the intestinal epithelial cells. In some implementations, damage to the epithelial cells further exacerbates the inflammation.

[0092] In some embodiments, the subject has reduced liver function. Reduced liver function typically occurs in subjects with IBD; for example, subjects with IBD may also have chronic liver disease, abnormal liver function, cirrhosis, hepatitis, primary sclerosing cholangitis, autoimmune hepatitis, primary biliary cholangitis, or drug-induced liver injury (e.g., as a result of IBD treatment). Liver function can be assessed by any suitable assay. In some embodiments, the subject's liver function is assessed by determining the levels of one or more liver enzymes (e.g., AST, ALT). In some embodiments, the subject's baseline aspartate aminotransferase (AST) level is below 3.0x of the upper limit of normal (ULN). In some embodiments, the subject's baseline alanine transaminase (ALT) level is < 3.0x ULN.

[0093] In some implementations, the subject has systemic inflammation. Systemic inflammation can be measured using any suitable method, such as the levels of total white blood cell (WBC) count, neutrophil count, lymphocyte count, and / or pro-inflammatory biomarkers (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP), etc.). In some implementations, the subject has regional intestinal inflammation. Regional intestinal inflammation can be measured using any suitable method, such as endoscopy, immune cell infiltration in biopsy tissue, fecal biomarkers, etc.

[0094] In some implementations, the subject has inflammatory bowel disease (IBD). In some implementations, the subject has one or more gene variants that make the subject susceptible to IBD. In some implementations, the subject has one or more gene variants of the following genes: NOD2, ATG16L1, IRGM, IL23R, CARD9, CLEC7A, RNF186, HLA, TNF, TNFSF15 / TL1A, LR4, IL-6, IL-1, IL-10, IL-12, IL-23, IL-17, TLR2, TLR9, Fas-L, CASP9, and ATG16L1 or PRDM1 genes (see, for example, Hadad et al., The Genetics of Inflammatory Bowel Disease, MolDiagn Ther (2023); Venema et al., The genetic background of inflammatory bowel disease: from correlation to causality, J Pathol. 2017 Jan;241(2):146-158; Jarmakiewicz-Czaja et al., Genetic and Epigenetic Etiology of Inflammatory Bowel Disease: An Update, Genes 2022, 13(12), 2388). IBD (e.g., UC, CD, IBD-U) can be classified by severity (mild, moderate or severe) and / or location.

[0095] In some embodiments, the subject has IBD associated with intestinal barrier dysfunction. In some embodiments, the subject has increased intestinal mucosal barrier dysfunction associated with IBD. In some embodiments, the mucus layer in the intestine of the subject with IBD is defective. In some embodiments, the subject with IBD has altered pattern recognition receptors on intestinal epithelial cells and immune cells. In some embodiments, the intestinal permeability of the subject with IBD is increased. In some embodiments, the subject with IBD has increased contact between the gut microbiome and epithelial cells. In some embodiments, the subject with IBD has an aberrant immune response to the gut microbiome and / or intestinal contents. In some embodiments, the subject with IBD (e.g., UC, CD, IBD-U) has infiltration of immune cells (e.g., neutrophils, macrophages, dendritic cells, and / or natural killer T cells) into the intestinal wall mucus layer, compared to, for example, subjects without IBD.

[0096] IBD is a condition characterized by alternating periods of active disease (attacks) and periods of little or no disease activity (remission). In some implementations, a subject with IBD (e.g., UC, CD, IBD-U) may be in an active state of IBD. UC and CD are classified according to severity (mild, moderate, or severe). In some implementations, "active state of IBD" and "active IBD" refer to a period in which a subject experiences an attack or exacerbation of symptoms. In some implementations, a subject with IBD may be in a remission period of IBD. A "remission period" refers to a period of time (e.g., weeks to months) in which a subject experiences very few symptoms to be asymptomatic.

[0097] In some embodiments, a subject with IBD (e.g., UC, CD, IBD-U) may be in the active phase of IBD, during which symptoms recur after a period of remission (i.e., relapse). In some embodiments, a subject in the active phase of IBD may also have one or more extraintestinal manifestations of IBD. In some embodiments, a subject with active IBD (e.g., active UC, CD, or IBD-U) is in the acute phase of IBD. In some embodiments, a subject with active IBD (e.g., active UC, CD, or IBD-U) has one or more symptoms associated with IBD (e.g., active UC, CD, or IBD-U). In some embodiments, a subject with active IBD (e.g., active UC, CD, or IBD-U) has increased inflammation (e.g., systemic and / or local inflammation) compared to a subject in remission. In some embodiments, a subject with active IBD (e.g., active UC, CD, or IBD-U) has one or more endoscopic findings associated with IBD.

[0098] In some implementations, subjects enter remission after the active phase of IBD. In some implementations, subjects with IBD are in clinical remission. In some implementations, subjects are in clinical remission of IBD when IBD symptoms have lessened to the point where symptoms are largely absent or have disappeared. In some implementations, subjects in clinical remission have a disease index score within the remission range. In some implementations, subjects with IBD are in endoscopic remission. In some implementations, subjects are in endoscopic remission when no inflammation is observed during an endoscopy (e.g., colonoscopy or sigmoidoscopy). In some implementations, subjects in endoscopic remission have an endoscopic score for IBD (e.g., UC, CD, IBD-U) within the remission range. In some implementations, subjects with IBD are in biochemical remission. In some implementations, subjects with IBD are in biochemical remission when laboratory tests on blood or stool do not show any hallmarks of IBD (e.g., inflammatory markers including C-reactive protein (CRP) and / or fecal calprotectin values ​​are not elevated). In some implementations, subjects with IBD are in histological remission. In some embodiments, a subject with IBD is in histological remission when no inflammation is observed in the biopsy tissue. In some embodiments, a subject with IBD is in surgical remission. In some embodiments, a subject with IBD is in surgical remission when there is no active disease after surgical removal of the affected bowel segment (e.g., removal of the affected bowel segment reduces inflammation and / or symptoms). In some embodiments, the subject is in the chronic phase of IBD (e.g., including remission periods and periods following acute exacerbations during active IBD).

[0099] In some embodiments, this disclosure provides a method comprising administering a predetermined amount of anti-HJV antibody to a subject. In some embodiments, the predetermined amount is an effective amount. In some embodiments, the effective amount is an amount that effectively induces one or more desired effects. In some embodiments, the effective amount is an amount of anti-HJV antibody that confers reduced intestinal inflammation, reduced intestinal bleeding, reduced weight loss, reduced fatigue, improved endoscopic appearance, induction of remission, and / or prolongation of remission. In some embodiments, the methods provided herein suppress inflammation in subjects suffering from inflammation associated with barrier dysfunction. In some embodiments, the effective amount is a therapeutic amount, e.g., an amount sufficient to confer a therapeutic effect (e.g., treatment of intestinal barrier dysfunction, IBD) on the subject. In some embodiments, this disclosure provides a method for treating barrier dysfunction in a subject, the method comprising administering an effective amount of the anti-HJV antibody described herein to the subject.

[0100] In some embodiments, this disclosure provides a method for inducing remission in subjects with active IBD (e.g., active UC or active CD), the method comprising administering an effective amount of anti-HJV antibody to the subject. In some embodiments, administration induces remission in subjects with active IBD (e.g., active UC or active CD). In some embodiments, administration induces clinical remission in subjects with active IBD (e.g., active UC or active CD). In some embodiments, administration induces endoscopic remission in subjects with active IBD (e.g., active UC or active CD). In some embodiments, administration induces histological remission in subjects with active IBD (e.g., active UC or active CD). In some embodiments, administration induces biochemical remission in subjects with active IBD (e.g., active UC or active CD). In some embodiments, administration maintains postoperative remission in subjects with active IBD (e.g., UC, CD, IBD-U).

[0101] In some embodiments, this disclosure provides a method for maintaining remission (e.g., prolonging the remission period between two episodes) in subjects with IBD (e.g., active UC or active CD), the method comprising administering an effective amount of anti-HJV antibody to the subject. In some implementations, the application prolongs the remission period of subjects with IBD (e.g., UC, CD, IBD-U) by at least 1 day, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 15 months, at least 18 months, at least 24 months, at least 28 months, at least 30 months, at least 32 months, at least 36 months, at least 38 months, at least 40 months, at least 45 months, at least 48 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or longer, relative to subjects before application or relative to subjects with IBD who have not received the application.

[0102] In some implementations, compared to subjects before administration or to subjects with IBD who have not received administration, administration prolongs the remission period for subjects with IBD (e.g., UC, CD, IBD-U) within the following ranges: 1-500 days, 1-450 days, 1-400 days, 1-300 days, 1-200 days, 1-100 days, 1-90 days, 1-80 days, 1-70 days, 1-60 days, 1-50 days, 1-40 days, 1-30 days, 1-20 days, 1-10 days, 1-5 days, 1-100 weeks, 1-90 weeks, 1-80 weeks, 1-70 weeks, 1-60 weeks, 1-50 weeks, 1-40 weeks, 1-30 weeks, 1-20 weeks, 1-10 weeks, 1-5 weeks, 1-4 weeks. 1-3 weeks, 1-2 weeks, 2-3 weeks, 2-4 weeks, 2-5 weeks, 2-6 weeks, 2-8 weeks, 2-10 weeks, 5-100 weeks, 5-90 weeks, 5-80 weeks, 5-70 weeks, 5-60 weeks, 5-50 weeks, 5-40 weeks, 5-30 weeks, 5-20 weeks, 5-10 weeks, 8-100 weeks, 8-90 weeks, 8-80 weeks, 8-7 0 weeks, 8-60 weeks, 8-50 weeks, 8-40 weeks, 8-30 weeks, 8-20 weeks, 8-10 weeks, 10-100 weeks, 10-90 weeks, 10-80 weeks, 10-70 weeks, 10-60 weeks, 10-50 weeks, 10-40 weeks, 10-30 weeks, 10-20 weeks, 15-100 weeks, 15-90 weeks, 15-80 weeks 15-70 weeks, 15-60 weeks, 15-50 weeks, 15-40 weeks, 15-30 weeks, 15-20 weeks, 20-100 weeks, 20-90 weeks, 20-80 weeks, 10-70 weeks, 20-60 weeks, 20-50 weeks, 20-40 weeks, 20-30 weeks, 30-100 weeks, 30-90 weeks, 30-80 weeks, 30- 70 weeks, 30-60 weeks, 30-50 weeks, 30-40 weeks, 40-100 weeks, 40-90 weeks, 40-80 weeks, 40-70 weeks, 40-60 weeks, 40-50 weeks, 50-100 weeks, 50-90 weeks, 50-80 weeks, 50-70 weeks, 50-60 weeks, 60-100 weeks, 60-90 weeks, 60-80 weeks 60-70 weeks, 70-100 weeks, 70-90 weeks, 70-80 weeks, 80-100 weeks, 80-90 weeks, 90-100 weeks, 1-100 months, 1-90 months, 1-80 months, 1-70 months, 1-60 months, 1-50 months, 1-40 months, 1-30 months, 1-20 months, 1-10 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, 2-3 months, 2-4 months, 2-5 months, 2-6 months, 2-8 months, 2-10 months, 5-100 months, 5-90 months, 5-80 months, 5-70 months, 5-60 months, 5-50 months, 5-40 months, 5-30 months, 5-20 months5-10 months, 8-100 months, 8-90 months, 8-80 months, 8-70 months, 8-60 months, 8-50 months, 8-40 months, 8-30 months, 8-20 months, 8-10 months, 10-100 months, 10-90 months, 10-80 months, 10-70 months, 10-60 months, 10-50 months, 10-40 months, 10-30 months, 10-20 months, 15-100 months, 15-90 months, 15-80 months, 15-70 months, 15-6 0 months, 15-50 months, 15-40 months, 15-30 months, 15-20 months, 20-100 months, 20-90 months, 20-80 months, 10-70 months, 20-60 months, 20-50 months, 20-40 months, 20-30 months, 30-100 months, 30-90 months, 30-80 months, 30-70 months, 30-60 months, 30-50 months, 30-40 months, 40-100 months, 40-90 months, 40-80 months, 40-70 months Months, 40-60 months, 40-50 months, 50-100 months, 50-90 months, 50-80 months, 50-70 months, 50-60 months, 60-100 months, 60-90 months, 60-80 months, 60-70 months, 70-100 months, 70-90 months, 70-80 months, 80-100 months, 80-90 months, 90-100 months, 1-10 years, 1-9 years, 1-8 years, 1-7 years, 1-6 years, 1-5 years, 1-4 years, 1-3 years, 1-2 years 2-10 years, 2-9 years, 2-8 years, 2-7 years, 2-6 years, 2-5 years, 2-4 years, 2-3 years, 3-10 years, 3-9 years, 3-8 years, 3-7 years, 3-6 years, 3-5 years, 3-4 years, 4-10 years, 4-9 years, 4-8 years, 4-7 years, 4-6 years, 4-5 years, 5-10 years, 5-9 years, 5-8 years, 5-7 years, 5-6 years, 6-10 years, 6-9 years, 6-8 years, 6-7 years, 7-10 years, 7-9 years, 7-8 years, 8-10 years, 8-9 years, or 9-10 years.

[0103] In some implementations, a subject with IBD (e.g., UC, CD, IBD-U) is receiving or has previously received one or more treatments for IBD. These treatments include, but are not limited to, aminosalicylic acids (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators (e.g., estrasasimod, ozanimod), immunomodulators (e.g., azathioprine, 6-mercaptopurine, cyclosporine, or tacrolimus), Janus kinase (JAK) inhibitors (e.g., upadacitinib, tofacitinib), and tumor necrosis factor (TNF) inhibitors (e.g., adalimumab, certolizumab). pegol, infliximab, golimumab, integrin antagonists (e.g., natalizumab, vedolizumab), interleukin (IL)-23 antagonists (e.g., Risankizumab-rzaa, or IL-12 / IL23 antagonists (e.g., Ustekinumab), nicotine, sulfasalazine (e.g., Azulfidine, Salazopyrin, Sulazine), mesalazine, olsalazine, balsalazine, or azathioprine. In some embodiments, subjects with CD are resistant to existing treatments for IBD (e.g., the IBD-specific agents described herein).

[0104] In some embodiments, the disclosure herein provides a method for treating subjects with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments such as 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors, the method comprising administering an effective amount of an anti-HJV antibody to the subject. In some embodiments, the administration is effective in alleviating one or more symptoms in subjects with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors). In some embodiments, the administration is effective in reducing the CDAI score in subjects with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors). In some implementations, the administration is effective in reducing the disease severity (e.g., disease severity based on a disease index as described herein) in subjects with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators and / or TNF inhibitors).

[0105] In some embodiments, the administration is effective in improving the endoscopic appearance of patients with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors). In some embodiments, the administration is effective in improving the endoscopic appearance of patients with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors). In some embodiments, the administration is effective in inducing remission in patients with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors). In some embodiments, the administration is effective in prolonging remission in patients with IBD (e.g., UC, CD, IBD-U) who are resistant to other existing treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or TNF inhibitors). In some embodiments, the anti-HJV described herein may be combined with any existing IBD therapeutic agent for treating IBD (e.g., any therapeutic agent described herein). In some embodiments, subjects with IBD (UC, CD, IBD-U) have extraintestinal manifestations (EIM) in addition to the GI tract (see, for example, Levine et al., Extraintestinal Manifestations of Inflammatory Bowel Disease, Gastroenterol Hepatol (NY). 2011 Apr; 7(4): 235–241; Malik et al., Extraintestinal Manifestations of Inflammatory Bowel Disease, In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. 2023 Mar 6).

[0106] In some implementations, subjects with IBD (UC, CD, IBD-U) have one or more EIMs, including but not limited to musculoskeletal manifestations such as axial spondyloarthritis (SpA) (e.g., ankylosing spondylitis (AS) and sacroiliitis) and / or peripheral spondyloarthritis (SpA) (e.g., oligoarticular (type 1) peripheral arthritis and polyarticular (type 2) peripheral arthritis); skin manifestations such as erythema nodosum (EN), pyoderma gangrenosa, Sweet syndrome, and / or oral cavity. Aphthous lesions; ocular manifestations, such as episcleritis, scleritis, and / or uveitis; hepatobiliary manifestations, such as primary sclerosing cholangitis (PSC), autoimmune / granulomatous hepatitis, fatty liver disease, cholestasis, gallstone formation, and autoimmune pancreatitis; other manifestations include anemia, urinary manifestations (e.g., kidney stones with possible urinary outflow obstruction or interstitial nephritis), thromboembolic diseases (deep vein thrombosis or pulmonary embolism), heart disease, stroke, fatigue, interstitial pneumonia, or metabolic bone disease.

[0107] In some embodiments, this disclosure provides a method for reducing one or more parenteral manifestations in subjects with IBD, the method comprising administering an effective amount of anti-HJV antibody to the subject. In some embodiments, the administration reduces the occurrence of one or more parenteral manifestations by the following ranges relative to the subject before administration or relative to the subject who did not receive administration: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%. -50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%.

[0108] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have increased levels of circulating immune cells (e.g., neutrophils, macrophages, dendritic cells, and / or natural killer T cells) compared to subjects without IBD. In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have increased levels of circulating pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP), etc.).

[0109] In some embodiments, this disclosure provides a method for reducing inflammation in a subject with IBD (e.g., UC, CD, IBD-U) by administering an effective amount of the anti-HJV antibody described herein. In some embodiments, administration of the anti-HJV antibody described herein reduces systemic inflammation in a subject with IBD (e.g., UC, CD, IBD-U). Systemic inflammation can be measured by any suitable method, such as total white blood cell count, neutrophil count, lymphocyte count, levels of pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP)), etc.

[0110] In some embodiments, administration of the anti-HJV antibody described herein reduces systemic inflammation (e.g., total white blood cell count, neutrophil count, lymphocyte count, and levels of pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP)) in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100% of a subject with IBD (e.g., UC, CD, IBD-U) compared to a subject prior to administration or compared to a subject with IBD who has not received administration. In some embodiments, administration of the anti-HJV antibody described herein reduces systemic inflammation (e.g., total white blood cell count, neutrophil count, lymphocyte count, and levels of pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP)) in subjects with IBD (e.g., UC, CD, IBD-U) by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, and 10% to 40% of the antibody, relative to the subject before administration or relative to a subject with IBD who has not received administration. 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90% 0%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0111] In some implementations, administration of the anti-HJV antibody described herein reduces the total white blood cell count in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to subjects prior to administration or subjects with IBD who have not received administration. In some implementations, relative to subjects who had IBD prior to administration or those who had not received administration, administration of the anti-HJV antibody described herein reduced the total white blood cell count in subjects by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70 ...90%, 20% to 80%, 20% to 70%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 10% to 90%, 20% to 80%, 20% to 70%, 20% to 10% to 90%, 20% to 80%, 20% to 70%, 20% to 90%, 20% to 90%, 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Total circulating white blood cell count can be measured by any suitable method, such as blood smear, flow cytometry, etc.

[0112] In some embodiments, administration of the anti-HJV antibody described herein reduces the total circulating neutrophil count in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to subjects prior to administration or subjects with IBD who have not received administration. In some implementations, relative to subjects prior to administration or relative to subjects with IBD who have not received administration, administration of the anti-HJV antibody described herein reduces circulating neutrophils in subjects by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 100%, 20% to 70%, 20% to 100%, 20% to 70%, 20% to 100%, 20% to 90%, 20% to 8 ... % to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Total circulating neutrophil count can be measured by any suitable method, such as blood smear, flow cytometry, etc.

[0113] In some implementations, administration of the anti-HJV antibody described herein reduces the circulating lymphocyte count in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to subjects prior to administration or subjects with IBD who have not received administration. In some implementations, relative to subjects prior to administration or relative to subjects with IBD who have not received administration, administration of the anti-HJV antibody described herein reduces the circulating lymphocyte count in subjects by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 10 ... % to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Total circulating lymphocyte count can be measured by any suitable method, such as blood smear, flow cytometry, etc.

[0114] In some embodiments, administration of the anti-HJV antibody described herein reduces one or more circulating pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP), etc.) in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100% of the subject with IBD (e.g., UC, CD, IBD-U). In some embodiments, administration of the anti-HJV antibody described herein reduces one or more circulating pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP), etc.) in the subject by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, and 10% to 15% relative to the subject before administration or relative to the subject with IBD who has not received administration. 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 4 0% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Circulating pro-inflammatory cytokine levels can be measured by any suitable method, such as ELISA, Western blot, RT-PCR, etc.

[0115] In some embodiments, administration of the anti-HJV antibody described herein reduces local inflammation in subjects with IBD (e.g., UC, CD, IBD-U). In some embodiments, administration of the anti-HJV antibody described herein reduces local inflammation (e.g., white blood cell count, neutrophil count, lymphocyte count, levels of pro-inflammatory cytokines from biopsy tissue, endoscopic findings) in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100% compared to subjects prior to administration or subjects with IBD who have not received administration. In some implementations, relative to a subject prior to administration or relative to a subject with IBD who has not received administration, administration of the anti-HJV antibody described herein reduces local inflammation (e.g., white blood cell count, neutrophil count, lymphocyte count, levels of pro-inflammatory cytokines from biopsy tissue, endoscopic findings) in the subject by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, respectively. 0%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%. 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Local inflammation can be measured by any suitable method, such as by white blood cell count, neutrophil count, lymphocyte count, levels of pro-inflammatory cytokines from biopsy tissue, endoscopic findings, etc.

[0116] In some embodiments, administration of the anti-HJV antibody described herein reduces leukocyte infiltration in the affected intestinal site of a subject with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to a subject prior to administration or a subject with IBD who has not received administration. In some implementations, relative to subjects before administration or relative to subjects with IBD who have not received administration, administration of the anti-HJV antibody described herein reduces leukocyte infiltration in the affected intestinal site of the subject by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, and 20% to 70%. 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0117] In some embodiments, administration of the anti-HJV antibody described herein reduces neutrophil infiltration in the affected intestinal site of a subject with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to a subject prior to administration or a subject with IBD who has not received administration. In some implementations, compared to subjects before administration or to subjects with IBD who did not receive administration, administration of the anti-HJV antibody described herein reduced neutrophil infiltration in the affected intestinal site of the subject by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, and 20% to 70%. 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0118] In some embodiments, administration of the anti-HJV antibody described herein reduces lymphocyte infiltration in the affected intestinal site of a subject with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to a subject prior to administration or a subject with IBD who has not received administration. In some implementations, relative to subjects before administration or relative to subjects with IBD who have not received administration, administration of the anti-HJV antibody described herein reduces lymphocyte infiltration in the affected intestinal site of the subject by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, and 20% to 70%. 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0119] In some embodiments, administration of the anti-HJV antibody described herein reduces one or more pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP), etc.) in the affected intestinal tissue or feces of subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100% compared to subjects prior to administration or subjects with IBD who have not received administration. In some embodiments, relative to the subject prior to administration or relative to a subject with IBD who has not received administration, administration of the anti-HJV antibody described herein reduces one or more pro-inflammatory cytokines (e.g., TNF-α, interferon-γ, IL-1, IL-6, IL-8, IL-17, IL-12, IL-23, IL-25, C-reactive protein (CRP), etc.) by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, and 10% to 15%. 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 4 0% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0120] In some implementations, administration of the anti-HJV antibody described herein improves intestinal barrier function in subjects with IBD (e.g., UC, CD, IBD-U) by at least 1%, at least 5%, 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 90%, or 100%, relative to subjects prior to administration or subjects with IBD who have not received administration. In some implementations, administration of the anti-HJV antibody described herein improves intestinal barrier function by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to ...100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 10% to 100%, 20% to 70%, 20% to 10% to 100%, 20% to 70%, 20% to 10% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 10% to 10% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 20% to 70%, 20% 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Intestinal barrier function can be measured using any suitable method, such as an intestinal permeability test.

[0121] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have elevated levels of C-reactive protein (CRP) in their blood or stool, where the severity of IBD increases with increasing CRP levels. Generally, normal CRP levels range from about 1 mg / L to about 10 mg / L. In some embodiments, the subject's CRP level is determined (e.g., before treatment with anti-HJV antibodies) and compared to the subject's post-treatment CRP level. In some implementations, compared to before administration, after administration of anti-HJV antibodies, the subjects' CRP levels decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, subjects with active IBD (e.g., active UC, active CD, or active IBD-U) have C-reactive protein (CRP) levels ≥5 mg / dL.

[0122] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have reduced serum albumin levels, wherein the severity of IBD (e.g., UC, CD, IBD-U) increases as serum albumin concentration decreases. Generally, normal serum albumin concentrations range from about 3.5 g / dL to about 5.0 g / dL. In some embodiments, the subject's serum albumin (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment serum albumin. In some implementations, compared to before administration, after treatment with anti-HJV antibodies, the serum albumin concentration of the subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. %, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0123] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have an elevated erythrocyte sedimentation rate (ESR), where the severity of IBD increases with increasing ESR. Generally, a normal ESR ranges from approximately 0 mm / h to approximately 15 mm / h for adult males and from approximately 0 mm / h to approximately 20 mm / h for adult females. In some embodiments, the subject's ESR is determined (e.g., prior to treatment with an anti-HJV antibody) and compared to the subject's post-treatment ESR. In some implementations, compared to before administration, the erythrocyte sedimentation rate (ESR) of subjects decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50% after administration of anti-HJV antibodies. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0124] In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) have elevated erythropoietin levels compared to healthy subjects. Normal erythropoietin levels for adults are typically in the range of approximately 10 to 30 mU / mL, but this value can be elevated in individuals with severe anemia (e.g., IBD with anemia). In some implementations, subjects with IBD have erythropoietin levels higher than 30 mU / mL prior to treatment with anti-HJV antibodies. In some implementations, the subject's erythropoietin level (e.g., prior to treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment erythropoietin level.In some implementations, compared to before administration, after administration of anti-HJV antibodies, the subjects' erythropoietin levels decreased by 1% to 1000%, 100% to 1000%, 200% to 1000%, 300% to 1000%, 400% to 1000%, 500% to 1000%, 600% to 1000%, 700% to 1000%, 800% to 1000%, 900% to 1000%, 100% to 900%, 200% to 900%, 300% to 900%, 400% to 900%, 500% to 900%, 600% to 900%, 700% to 900%, 800% to 900%, 100% to 800%, 2 00% to 800%, 300% to 800%, 400% to 800%, 500% to 800%, 600% to 800%, 700% to 800%, 100% to 700%, 200% to 700%, 300% to 700%, 400% to 700%, 500% to 700%, 600% to 700%, 100% to 600%, 200% to 600%, 300% to 600%, 400% to 600%, 500% to 600%, 100% to 500%, 200% to 500%, 300% to 500%, 400% to 500%, 100% to 400%, 200% to 400%, 300% to 4 ... 1% to 300%, 200% to 300%, 100% to 200%, 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40% %, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0125] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have elevated fecal calprotectin (FCP) levels, where the severity of IBD increases with increasing fecal calprotectin levels. Generally, normal fecal calprotectin levels are below approximately 50 μg / g. In some embodiments, the subject's fecal calprotectin level (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment fecal calprotectin level. In some implementations, compared with before administration, after administration of anti-HJV antibodies, the fecal calprotectin level of the subjects decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. %, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, subjects with active IBD (e.g., active UC, CD, or IBD-U) have fecal calprotectin (FCP) levels > 150 mg / kg.

[0126] In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) experience anemia. In some implementations, the therapeutic effect includes treating the subject's anemia (e.g., anemia associated with IBD (e.g., UC, CD, IBD-U)). Anemia can be assessed using any scale or metric known in the art, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale (Cella, D. (1997). The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: anew tool for the assessment of outcomes in cancer anemia and fatigue. In Seminars in Hematology (Vol. 34, Supplement 2, No. 3, pp. 13-19)). In some implementations, the administration of hematological parameters that modulate iron status and anemia includes, but is not limited to, increasing hemoglobin (Hgb), increasing erythrocyte levels, increasing hematocrit levels, decreasing soluble transferrin receptor levels, decreasing the sTfR / log ferritin index, increasing transferrin saturation (TSAT%), increasing serum iron levels, decreasing ferritin, decreasing hepcidin levels or activity, increasing circulating hemoglobin levels, increasing reticulocyte hemoglobin (CHr), decreasing total iron binding capacity (TIBC), and decreasing zinc protoporphyrin (ZPP) levels. In some implementations, the administration of other markers that improve hematological recovery (e.g., restoration of erythropoiesis, mean corpuscular hemoglobin (MCH), etc.) is also included.

[0127] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have reduced hemoglobin (Hgb) levels (e.g., < 12 g / dL for female subjects, < 13 g / dL for male subjects) compared to healthy subjects. In some embodiments, subjects with IBD and reduced hemoglobin levels have IBD-related anemia. In some embodiments, the severity of IBD increases with decreasing Hgb levels. Generally, normal hemoglobin levels are from about 12 g / dL to about 18 g / dL. In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have HGB levels below 12 g / dL. In some embodiments, a subject's hemoglobin level (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment Hgb level. In some implementations, compared to before administration, after administration of anti-HJV antibodies, the Hgb level of the subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the Hgb level of the subject increased by more than 100% after administration of the anti-HJV antibody compared to before administration. In some implementations, the Hgb level of the subject increased by at least 1 g / dL after administration of the anti-HJV antibody.In some implementations, after administration of the anti-HJV antibody, the subject's HGB level increased by at least 1.0 g / dL, at least 1.1 g / dL, at least 1.2 g / dL, at least 1.3 g / dL, at least 1.4 g / dL, at least 1.5 g / dL, at least 1.6 g / dL, at least 1.7 g / dL, at least 1.8 g / dL, at least 1.9 g / dL, 2.0 g / dL, at least 2.1 g / dL, at least 2.2 g / dL, at least 2.3 g / dL, at least 2.4 g / dL, at least 2.5 g / dL, at least 2.6 g / dL, at least 2.7 g / dL, at least 2.8 g / dL, at least 2.9 g / dL, at least 3.0 g / dL, or more.

[0128] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have reduced red blood cell levels. In some embodiments, IBD subjects with reduced red blood cell levels have IBD-related anemia. In some embodiments, the severity of IBD increases with the decrease in red blood cell count. Generally, a normal red blood cell count is approximately 4 million cells / µL to approximately 550 million cells / µL. In some embodiments, the subject's red blood cell count is determined (e.g., before treatment with anti-HJV antibodies) and compared to the subject's red blood cell count after treatment. In some implementations, compared to before administration, after administration of anti-HJV antibodies, the red blood cell count of the subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the red blood cell levels of the subjects increased by more than 100% after administration of the anti-HJV antibody compared to before administration.

[0129] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have a decreased hematocrit (i.e., HCT; the proportion of cells in the blood). In some embodiments, subjects with IBD have a decreased HCT. In some embodiments, IBD subjects with decreased HCT have IBD-related anemia. In some embodiments, the severity of IBD increases as hematocrit levels decrease. Generally, normal hematocrit levels are from about 37% to about 52%. In some embodiments, the subject's hematocrit level (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment hematocrit level. In some implementations, compared to before administration, after administration of anti-HJV antibodies, the hematocrit level of the subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the HCT level of the subject is increased by more than 100% (e.g., at least 2, at least 3, at least 5, at least 10, at least 20, at least 50, at least 100, at least 500, at least 1000 or more) after administration of the anti-HJV antibody compared to before administration.

[0130] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have elevated soluble transferrin receptor (sTfR) levels. Soluble transferrin receptor (sTfR) is a peptide cleaved from transferrin receptor 1, the receptor required for iron entry into cells; sTfR levels are commonly used as an indicator of transferrin receptor 1 and functional iron status. In some embodiments, IBD subjects with high sTfR levels have IBD-associated anemia. In some embodiments, the severity of IBD increases with increasing sTfR levels. Generally, healthy subjects have sTfR levels ranging from 1.15 mg / L to 2.75 mg / L. In some embodiments, a subject's sTfR level (e.g., before treatment with an anti-HJV antibody) is determined and compared to the subject's post-treatment sTfR level. In some implementations, compared to before administration, after administration of the anti-HJV antibody, the subject's sTfR level decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0131] In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) have an elevated sTfR / log ferritin index (tfR-F index). The TfR-F index has been shown to be useful in differentiating anemia caused by confounding factors (e.g., elevated sTfR due to inflammation rather than reduced iron stores; see: Mücke, V., et al. (2016). Diagnosis and treatment of anemia in patients with inflammatory bowel disease. Annals of gastroenterology: quarterly publication of the Hellenic Society of Gastroenterology, 30(1), 15.). Therefore, the tfR-F index may be useful for IBD subjects in the active phase of IBD. In some implementations, IBD subjects with a high tfR index have IBD-associated anemia. In some implementations, the severity of IBD increases with increasing tfR-F index levels. Generally, the sTfR level in healthy subjects is between 0.63 and 1.8. In some embodiments, the subject's TfR index (e.g., before treatment with the anti-HJV antibody) is determined and compared to the subject's post-treatment TfR index. In some embodiments, compared to before administration, after administration of the anti-HJV antibody, the subject's TfR index decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0132] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have a decreased transferrin saturation percentage (TSAT%) (i.e., a measure of the amount of iron bound to transferrin in the blood). In some embodiments, IBD subjects with decreased TSAT% levels have IBD-related anemia. In some embodiments, the severity of IBD increases with decreasing TSAT% levels. Generally, a normal TSAT% is about 20% to about 50%. In some embodiments, a subject's TSAT% (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment TSAT%. In some implementations, compared to before administration, the TSAT% of subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50% after administration of anti-HJV antibodies. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the TSAT% of the subject increases by more than 100% (e.g., at least 2, at least 3, at least 5, at least 10, at least 20, at least 50, at least 100, at least 500, at least 1000 or more) after administration of the anti-HJV antibody compared to before administration.

[0133] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have decreased serum iron levels. In some embodiments, IBD subjects with decreased iron levels have IBD-related anemia. In some embodiments, the severity of IBD increases with decreasing serum iron levels. Generally, normal serum iron levels are from about 60 μg / dL to about 170 μg / dL. In some embodiments, the subject's serum iron level (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment serum iron level. In some implementations, compared with before administration, serum iron levels in subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50% after administration of anti-HJV antibodies. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the serum iron level of the subject increased by more than 100% (e.g., at least 2, at least 3, at least 5, at least 10, at least 20, at least 50, at least 100, at least 500, at least 1000 or more) after administration of the anti-HJV antibody compared to before administration.

[0134] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have anemia and elevated serum ferritin levels compared to healthy subjects. In some embodiments, subjects with IBD and elevated serum ferritin levels have IBD-associated anemia. In some embodiments, the severity of IBD increases with increasing serum ferritin levels. The normal range for serum ferritin is 24–336 µg / L for men and 11–307 µg / L for women. In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have serum ferritin levels > 75 µg / L. In some embodiments, a subject's serum ferritin level is determined (e.g., before treatment with anti-HJV antibodies) and compared to the subject's post-treatment ferritin level. In some implementations, compared to before administration, serum ferritin levels in subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50% after administration of anti-HJV antibodies. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0135] In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have elevated serum hepcidin levels compared to healthy subjects. In some embodiments, subjects with IBD and elevated serum hepcidin levels have IBD-related anemia. In some embodiments, the severity of IBD increases with increasing serum hepcidin levels. The normal range for serum hepcidin is 1–55 ng / mL. In some embodiments, subjects with IBD (e.g., UC, CD, IBD-U) have serum hepcidin levels > 55 ng / mL. In some embodiments, a subject's serum hepcidin level (e.g., before treatment with an anti-HJV antibody) is determined and compared to the subject's post-treatment HGB level. In some embodiments, after administration of an anti-HJV antibody, a subject's serum hepcidin level decreases by approximately 1 ng / mL to approximately 300 ng / mL. In some implementations, the serum hepcidin level of the subject is reduced by about 1 ng / mL to about 200 ng / mL, about 1 ng / mL to about 100 ng / mL, about 1 ng / mL to about 50 ng / mL, about 1 ng / mL to about 10 ng / mL, about 10 ng / mL to about 100 ng / mL, or about 10 ng / mL to about 50 ng / mL.

[0136] In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) have reduced reticulocyte hemoglobin levels (CHr or RET-He). Reticulocyte hemoglobin level measures the amount of hemoglobin in reticulocytes. Generally, the normal range for CHr is approximately 28 to 36 pg / cell. In some implementations, the subject's CHr is below the normal range. In some implementations, the subject's CHr is less than 28 pg / ml. In some implementations, the subject's CHr is determined (e.g., before treatment with anti-HJV antibodies) and compared to the subject's post-treatment HGB level. In some implementations, compared with before administration, after administration of anti-HJV antibody, the subjects' CHr increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 2 0% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the CHr of the subject is increased by more than 100% after administration of the anti-HJV antibody compared with before administration (e.g., at least 2-fold, at least 3-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold or more).

[0137] In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) have elevated total iron-binding capacity (TIBC). Total iron-binding capacity (TIBC) can be used as an indirect assessment of transferrin concentration. In iron-deficient individuals (e.g., in IBD subjects with anemia), the relative transferrin content compared to iron content is elevated, resulting in high TIBC levels. In some implementations, IBD subjects with high TIBC have IBD-associated anemia. In some implementations, the severity of IBD increases with increasing TIBC levels. Generally, the TIBC of healthy subjects is 240 to 450 mcg / dL. In some implementations, the subject's TIBC (e.g., before treatment with anti-HJV antibodies) is determined and compared to the subject's post-treatment TIBC index. In some implementations, compared to before administration, after administration of the anti-HJV antibody, the subject's TIBC index decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. In some implementations, the TIBC of the subject is increased by more than 100% after administration of the anti-HJV antibody compared with that before administration (e.g., at least 2-fold, at least 3-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1000-fold or more).

[0138] In some implementations, subjects with IBD (e.g., UC, CD, IBD-U) have elevated zinc protoporphyrin (ZPP) levels (see: e.g., Leventi, Eleni, et al. "Zinc protoporphyrin is a reliable marker of functional iron deficiency in patients with inflammatory bowel disease." Diagnostics 11.2 (2021): 366.). Zinc protoporphyrin (ZPP) refers to the end product of zinc incorporation into protoporphyrin IX (PPIX). In healthy subjects, PPIX is normally incorporated with iron during erythropoiesis to produce heme; however, when iron availability is low, zinc is incorporated instead, producing ZPP. Therefore, ZPP can provide a measure of iron status during erythropoiesis and can be a useful marker of iron deficiency (e.g., in IBD subjects with anemia). In some implementations, IBD subjects with high ZPP levels have IBD-associated anemia. In some implementations, the severity of IBD increases with increasing ZPP levels. Generally, the ZPP level in healthy subjects is less than 80 µmol / mol heme. In some implementations, the subject's ZPP level (e.g., before treatment with anti-HJV antibodies) is determined and compared with the subject's post-treatment ZPP level.In some implementations, compared to before administration, after administration of anti-HJV antibodies, the subjects' ZPP levels decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, and 20% to 50%. 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0139] In some implementations, subjects with severe IBD (e.g., UC, CD, IBD-U) as described herein require hospitalization. In some implementations, administration of anti-HJV antibodies reduces the frequency of hospitalization associated with severe IBD (e.g., UC, CD, IBD-U) by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 20 ... % to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0140] In some implementations, subjects with IBD do not have elevated serum iron. In some implementations, subjects with IBD do not have a condition or disease that induces iron overload (e.g., hereditary hemochromatosis).

[0141] i. Ulcerative colitis

[0142] In some implementations, the condition associated with barrier dysfunction is ulcerative colitis. Ulcerative colitis (UC) is a relapsing and remission-prone IBD characterized by mucosal inflammation that begins distally and can extend proximally to involve the entire colon. In some implementations, the subject has ulcerative colitis (UC). The most common presentation of ulcerative colitis is bloody diarrhea with or without mucus. Patients typically describe tenesmus (i.e., a feeling of incomplete emptying) and abdominal pain. Physical examination may primarily reveal pain in the left lower or left upper quadrant. Signs of acute abdomen, including guarding, rebound tenderness, or percussion tenderness, necessitate examination for toxic megacolon.

[0143] In some implementations, subjects with UC have intestinal mucosal inflammation. In some implementations, intestinal mucosal inflammation manifests as edema, ulceration, bleeding (e.g., bloody diarrhea with or without mucus), and / or electrolyte loss. In some implementations, after administration of anti-HJV antibodies, the mucosal inflammation is reduced compared to subjects who did not receive anti-HJV antibodies. Some non-limiting methods for assessing mucosal inflammation include colonoscopy, sigmoidoscopy (e.g., flexible sigmoidoscopy), histological evaluation of biopsies, magnetic resonance enterography (MRE), computed tomography (CT) of the small intestine, laboratory tests (e.g., C-reactive protein and erythrocyte sedimentation rate), fecal calprotectin testing, and small bowel endoscopy. In some implementations, subjects with UC experience tenesmus, abdominal pain, and / or pancolitis (inflammation throughout the colon). As UC becomes chronic, the colon typically becomes more rigid and shortened (e.g., intestinal stenosis), leading to the loss of haustral markings and a “lead-pipe” appearance, which can be observed via barium enema, enhanced computed tomography, or abdominal X-ray (Pandit et al., “Lead-Pipe Colon” ​​of Chronic Ulcerative Colitis on Abdominal X-Ray. Indian J Surg 83, 1086–1087 (2021)). In some implementations, subjects with UC have a lead-pipe colon.

[0144] In some implementations, subjects do not have lead-tube colons after treatment with anti-HJV antibodies. In some implementations, subjects with intestinal strictures have improved intestinal rigidity and / or colon length after treatment with anti-HJV antibodies. In some implementations, compared with subjects before or without anti-HJV antibody treatment, after treatment with anti-HJV antibodies, the colon length of subjects increased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 2 0% to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.In some implementations, compared with subjects before or without anti-HJV antibody treatment, the intestinal stiffness of subjects treated with anti-HJV antibodies decreased by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to ... % to 50%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. Methods for assessing intestinal stiffness and colon length are known in the art, and any of these methods can be used (e.g., colonoscopy, ultrasound, CT colonography, MRI, biopsy, and histological evaluation) (see, for example, Kawasaki et al., CancerImaging. 2021 Dec 7;21(66):2641; Utano et al., Jpn J Radiol. 2022;40(3):298-307).

[0145] In some implementations, subjects with UC have extraintestinal manifestations such as arthritis, osteoporosis, kidney stones, uveitis, corneal ulcers, retinal vascular disease, psoriasis, oral Crohn's disease, and fatigue (Levine and Burakoff, Gastroenterol Hepatol (NY). 2011 Apr;7(4):235-241). In some implementations, anti-HJV antibodies are used to treat the extraintestinal manifestations of UC. In some implementations, after treatment with anti-HJV antibodies, subjects experience a reduction in arthritis, osteoporosis, kidney stones, uveitis, corneal ulcers, retinal vascular disease, psoriasis, and / or oral Crohn's disease. In some implementations, after treatment with anti-HJV antibodies, subjects with UC experience an improvement in quality of life (e.g., assessed by a self-report questionnaire).

[0146] In some embodiments, subjects with UC may experience fatigue (i.e., feelings of tiredness, exhaustion, lethargy, or lack of energy that do not disappear with a normal amount of rest or sleep). In some embodiments, subjects with UC experience physical fatigue (e.g., low energy or strength, or a feeling of heaviness). In some embodiments, subjects with UC experience mental fatigue (e.g., low motivation, attention, or alertness). In some embodiments, subjects with UC experience both physical and mental fatigue. In some embodiments, subjects with active UC experience fatigue associated with UC (i.e., an episode). In some embodiments, subjects who have previously undergone surgical treatment for UC are more likely to experience fatigue (i.e., are more likely to experience fatigue compared to UC subjects who have not undergone surgery). In some embodiments, female UC subjects are more likely to experience fatigue compared to male UC subjects. In some embodiments, UC subjects who also have depression or anxiety are more likely to experience fatigue compared to UC subjects who do not have depression or anxiety. In some embodiments, UC subjects with one or more parenteral manifestations are more likely to experience fatigue compared to subjects without parenteral manifestations. In some implementations, fatigue is assessed using: patient self-report questionnaires, fatigue severity scales (FSS), visual analog scales (VAS), numeric rating scales (NRS), multidimensional fatigue inventory (MFI), mental fatigue scales (MFS), Wood mental fatigue inventory (WMFI), fatigue-assessment scales (FAS), functional assessment of chronic illness therapy-fatigue (FACIT-F), interviews and clinical assessments, activity monitoring (e.g., wearable devices), and / or any other method known in the art (Billones et al., Brain Behav Immun Health. 202) Aug;15:100266).Other non-limiting examples of methods for assessing fatigue include the Fatigue Catastrophizing Scale, the Multidimensional Assessment of Fatigue (MAF), the revised Piper Fatigue Scale (PFS), the Checklist of Individual Strength (CIS), the Isometric Muscle Strength Test (a physiological test for fatigue), the Manchester COPD Fatigue Scale, the revised Fatigue Effects Scale, the Multidimensional Daily Diary of Fatigue-Fibro-17 (MDF-Fibro-17) instrument, the Brugmann Fatigue Scale (BFS), the Chalder Fatigue Scale, the Fatigue Assessment Scale (FAS), the Fatigue Effects Scale, the Fatigue Symptom Inventory (FSI), the Health Assessment Questionnaire (HAQ), the Cancer Treatment Functional Assessment Scale for Anemia and Fatigue (e.g., FACT-Anemia), and the MG Fatigue Scale. scale, MGFS).

[0147] In some implementations, fatigue can be assessed using the Inflammatory Bowel Disease-Fatigue (IBD-F) Patient Self-Assessment Scale (see, e.g., Varbobitis et al., The IBD-F Patient Self-Assessment Scale Accurately Depicts the Level of Fatigue and Predicts a Negative Effect on the Quality of Life of Patients With IBD in Clinical Remission, Inflamm Bowel Dis. 2021 May 17;27(6):826-835), the contents of which are incorporated herein by reference. The IBD-F Patient Self-Assessment Scale is a scoring system consisting of two parts of questions for the subject. Scoring 1 is a fatigue assessment scale consisting of five questions that measure the severity of fatigue on a scoring range of 0-20. If the subject scores 1 or higher on Scoring 1, the subject should proceed to answer the questions in Scoring 2. Part 2 of the IBD Fatigue Rating Scale is the IBD-Impact on Daily Activities Scale, which consists of 30 questions and measures the impact of fatigue on quality of life (QoL), with a score range of 0 to 120. In some implementations, a score greater than 7.5 indicates significant fatigue (e.g., clinically significant fatigue).In some implementations, the scores 1 of the IBD-F Patient Self-Assessment Scale for subjects with UC and fatigue fall within the following ranges: 7.5 to 20, 7.5 to 19, 7.5 to 18, 7.5 to 17, 7.5 to 16, 7.5 to 15, 7.5 to 14, 7.5 to 13, 7.5 to 12, 7.5 to 11, 7.5 to 10, 7.5 to 9, 7.5 to 8, 8 to 20, 8 to 1 9, 8 to 18, 8 to 17, 8 to 16, 8 to 15, 8 to 14, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 20, 9 to 19, 9 to 18, 9 to 17, 9 to 16, 9 to 15, 9 to 14, 9 to 13, 9 to 12, 9 to 11, 9 to 10, 10 to 20, 10 to 19, 10 to 18, 10 to 17, 10 to 16, 10 to 15, 10 to 1 4, 10 to 13, 10 to 12, 10 to 11, 11 to 20, 11 to 19, 11 to 18, 11 to 17, 11 to 16, 11 to 15, 11 to 14, 11 to 13, 11 to 12, 12 to 20, 12 to 19, 12 to 18, 12 to 17, 12 to 16, 12 to 15, 12 to 14, 12 to 13, 13 to 20, 13 to 19, 13 to 18, 13 to 17 13 to 16, 13 to 15, 13 to 14, 14 to 20, 14 to 19, 14 to 18, 14 to 17, 14 to 16, 14 to 15, 15 to 20, 15 to 19, 15 to 18, 15 to 17, 15 to 16, 16 to 20, 16 to 19, 16 to 18, 16 to 17, 17 to 20, 17 to 19, 17 to 18, 18 to 20, 18 to 19, or 19 to 20. In some implementations, subjects with UC and accompanying fatigue experience an impact on their quality of life (QoL).In some implementations, the scores2 of the IBD-F Patient Self-Assessment Scale for subjects with UC and fatigue fall within the following ranges: 0-120, 5-120, 10-120, 20-120, 30-120, 40-120, 50-120, 60-120, 70-120, 80-120, 90-120, 100-120, 110-120, 0-110, 5-110, 1 0-110, 20-110, 30-110, 40-110, 50-110, 60-110, 70-110, 80-110, 90-110, 100-110, 0-100, 5-100, 10-100, 20-100, 30-100, 40-100, 50-100, 60-100, 70-100, 80-100, 90-100, 0-90, 5- 90, 10-90, 20-90, 30-90, 40-90, 50-90, 60-90, 70-90, 80-90, 0-80, 5-80, 10-80, 20-80, 30-80, 40-80, 50-80, 60-80, 70-80, 0-70, 5-70, 10-70, 20-70, 30-70, 40-70, 50-70, 60-70, 0-6 0, 5-60, 10-60, 20-60, 30-60, 40-60, 50-60, 0-50, 5-50, 10-50, 20-50, 30-50, 40-50, 0-40, 5-40, 10-40, 20-40, 30-40, 0-30, 5-30, 10-30, 20-30, 0-20, 5-20, 10-20, 0-10, 5-10, or 0-5. In some implementations, the application reduces fatigue in subjects relative to those before application or relative to those who did not receive the application. In some implementations, the application reduces fatigue in subjects based on the IBD-F Patient Self-Assessment Scale, relative to those before application or relative to those who did not receive the application. In some implementations, the application reduces the subject's IBD-F Patient Self-Assessment Scale score by at least 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points compared to the subject before the application or compared to the subject who did not receive the application.In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration reduced the subject's IBD-F Patient Self-Assessment Scale score by the following ranges: 1-2, 1-5, 1-10, 1-15, 1-20, 2-5, 2-8, 2-10, 2-12, 2-15, 2-20, 5-8, 5-10, 5-12. 5-15 points, 5-18 points, 5-20 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 12-15 points, 12-15 points, 12-18 points, 12-20 points, 15-18 points, 15-20 points, 16-18 points, 16-20 points, or 18-20 points. In some implementations, the application reduces a subject's IBD-F Patient Self-Assessment Scale score by at least 1, at least 5, at least 10, at least 15, at least 25, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, or at least 120 points compared to the subject before the application or compared to the subject who did not receive the application.In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration reduced the subject's IBD-F Patient Self-Assessment Scale score by the following ranges: 1-120, 1-110, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 5-120, 5-110, 5-100, 5-90, 5-80, 5 -70 points, 5-60 points, 5-50 points, 5-40 points, 5-30 points, 5-20 points, 5-10 points, 10-120 points, 10-110 points, 10-100 points, 10-90 points, 10-80 points, 10-70 points, 10- 60 points, 10-50 points, 10-40 points, 10-30 points, 10-20 points, 20-120 points, 20-110 points, 20-100 points, 20-90 points, 20-80 points, 20-70 points, 20-60 points, 20-50 points , 20-40 points, 20-30 points, 30-120 points, 30-110 points, 30-100 points, 30-90 points, 30-80 points, 30-70 points, 30-60 points, 30-50 points, 30-40 points, 40-120 points, 40-110 points, 40-100 points, 40-90 points, 40-80 points, 40-70 points, 40-60 points, 40-50 points, 50-120 points, 50-110 points, 50-100 points, 50-90 points, 50-80 points, 5 0-70 points, 50-60 points, 60-120 points, 60-110 points, 60-100 points, 60-90 points, 60-80 points, 60-70 points, 70-120 points, 70-110 points, 70-100 points, 70-90 points, 70-80 points, 80-120 points, 80-110 points, 80-100 points, 80-90 points, 90-120 points, 90-110 points, 90-100 points, 100-120 points, 100-110 points, or 110-120 points.

[0148] In some implementations, fatigue can be assessed using: the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F) scale (see, for example, Tinsley, A., Macklin, EA, Korzenik, JR, & Sands, BE (2011). Validation of the Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F) in patients with inflammatory bowel disease. Alimentarypharmacology & therapeutics, 34(11-12), 1328-1336; and facit.org / measures / facit-f) and / or the Functional Assessment of Cancer Therapy (FACT)-Anemia (FACT-An) scale (see, for example, Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in canceranemia). and fatigue. Seminars in Hematology. 1997 Jul;34(3 Supplement 2):13-19; and fact-an. The FACIT-F scale contains 40 questions across five health categories: physical health (7 questions), social health (7 questions), emotional health (6 questions), functional health (7 questions), and fatigue (13 questions). The FACT-An scale contains the questions from the FACIT-F scale plus 7 additional questions related to anemia. For both assessments, patients provide a score of 0-4 (inclusive) for each item. For each category, the individual items are summed, multiplied by the number of items presented, and divided by the number of items answered to calculate the category score; for example, the fatigue category score for either FACIT-F or FACT-An could be 0-52. The category scores are then summed to obtain a total score, ranging from 0-160 for FACIT-F or 0-188 for FACT-An. Higher scores within these ranges indicate a better quality of life (QoL).Typically, healthy individuals have a FACIT-F fatigue category score of 40 or higher (e.g., Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States population. Cancer. 2002;94(2):528–38). In some implementations, a score of less than approximately 40 in the fatigue category of the FACIT-F scale indicates significant fatigue (e.g., clinically significant fatigue). In some implementations, the FACIT-F fatigue category score of subjects with UC and accompanying fatigue falls within the following ranges: 0-40, 0-39, 0-38, 0-37, 0-36, 0-35, 0-34, 0-33, 0-32, 0-31, 0-30, 0-29, 0-28, 0-27, 0-26, 0-25, 0-24, 0-23, 0-22, 0-21, 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 0-10, 0-9, 0-8, 9-7, 0-6, or 0-5. In some implementations, the application reduces the subject's fatigue based on the FACIT-F scale, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application improves the subject's FACIT-F fatigue category score by at least 0.5 points, at least 1 point, at least 2 points, at least 2.5 points, at least 3 points, at least 4 points, at least 5 points, at least 7 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, or at least 20 points, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application improves the subject's FACIT-F fatigue category score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 5-8 points, 5-10 points, 5-12 points, 5... -15 points, 5-18 points, 5-20 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 12-15 points, 12-15 points, 12-18 points, 12-20 points, 15-18 points, 15-20 points, 16-18 points, 16-20 points, or 18-20 points.

[0149] In some implementations, administration improves the patient's quality of life (QoL). In some implementations, QoL is assessed using the Patient's Global Impression of Change (PGI-C) self-assessment (see: Hurst, Hugh, and Jennifer Bolton. "Assessing the clinical significance of change scores recorded on subjective outcome measures." Journal of manipulative and physiological therapeutics 27.1 (2004): 26-35.). The PGI-C self-assessment includes questions related to changes in the condition since the start of treatment, scored on a numerical scale of 1-7. Patients scoring 6-7 on the PGI-C scale are considered to have experienced clinically significant improvement in their condition. In some implementations, the QoL of administration-improved subjects is compared to those who did not receive administration. In some implementations, subjects with UC who received administration reported PGI-C scores of 5, 6, or 7.

[0150] In some implementations, QoL is assessed using the Short Form for Medical Outcomes Study 36 (SF-36) (see, for example: Garratt AM, Schmidt L, Mackintosh A, Fitzpatrick R. Quality of life measurement: bibliographic study of patient assessed health outcome measures. Brit Med J. 2002;324:1417–9; Contopoulos-Ioannidis DG, Karvouni A, Kouri I, Ioannidis JPA. SF-36 outcomes in randomized trials: a systematic review. Brit Med J. 2009;338:a3006). The SF-36 consists of eight subscales: 1) physical functioning; 2) role limitation due to physical problems; 3) overall perceived health; 4) vitality; 5) social functioning; 6) role limitation due to emotional problems; 7) overall mental health; and 8) health transformation. The items in each subscale are summed, multiplied by 10, and then added to 50 to linearly transform each value to fit a scale range from 0 (negative health) to 100 (positive health), where 50 represents the mean; the transformed value is the corresponding score for each subscale. Some subscale scores may be assessed together based on factor analysis to generate a physical component summary (PCS) or a mental components summary (MCS) (e.g., Ware JE, Kosinski M, Bayliss MS, McHorney C, Rogers WH, Raczek A. Comparison of methods for scoring and statistical analysis of the SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care. 1995;33:AS264–79.). In some implementations, the administration reduces fatigue in subjects relative to those before administration or relative to those who did not receive administration. In some implementations, the application reduces fatigue based on the IBD-F Patient Self-Assessment Scale relative to the subject before application or relative to the subject who did not receive the application.In some implementations, the application improves the subject's SF-36 subscale score by at least 1, at least 2, at least 3, 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, at least 27, at least 28, at least 29, or at least 30 points compared to the subject before application or compared to the subject who did not receive the application. In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration improved the SF-36 subscale score of subjects by the following ranges: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 1-25 points, 1-30 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 2-25 points, 2-30 points, 5-8 points, 5-10 points, 5-12 points, 5-15 points, 5-18 points, 5-20 points, 5-25 points. 5-30 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 8-25 points, 5-30 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 10-25 points, 10-30 points, 12-15 points, 12-18 points, 12-20 points, 12-25 points, 12-30 points, 15-18 points, 15-20 points, 15-25 points, 15-30 points, 20-25 points, 20-30 points, or 25-30 points. In some implementations, the application improves the subject's SF-36 PCS score by at least 1, at least 2, at least 3, 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, at least 27, at least 28, at least 29, or at least 30 points, relative to the subject before application or relative to the subject who did not receive the application.In some implementations, the application improves the subject's SF-36 PCS score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 1-25 points, 1-30 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 2-25 points, 2-30 points, 5-8 points, 5-10 points, 5-12 points, 5-15 points, 5-18 points, 5-20 points, 5-25 points. 5-30 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 8-25 points, 5-30 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 10-25 points, 10-30 points, 12-15 points, 12-18 points, 12-20 points, 12-25 points, 12-30 points, 15-18 points, 15-20 points, 15-25 points, 15-30 points, 20-25 points, 20-30 points, or 25-30 points. In some implementations, the application improves the subject's SF-36 MCS score by at least 1, at least 2, at least 3, 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, at least 27, at least 28, at least 29, or at least 30 points, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application improves the subject's SF-36 MCS score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 1-25 points, 1-30 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 2-25 points, 2-30 points, 5-8 points, 5-10 points, 5-12 points, 5-15 points, 5-18 points, 5-20 points, 5-25 points. 5-30 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 8-25 points, 5-30 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 10-25 points, 10-30 points, 12-15 points, 12-18 points, 12-20 points, 12-25 points, 12-30 points, 15-18 points, 15-20 points, 15-25 points, 15-30 points, 20-25 points, 20-30 points, or 25-30 points.

[0151] The etiology of UC involves the interaction between environment, immune system, gut microbiome and genetic predisposition (Kobayashi et al., Nat Rev Dis Primers. 2020 Sep 10;6(1):74). In some implementations, the severity of UC is assessed using the following: Truelove and Richards Index (Truelove and Richards, Br Med J. 1956 Jun 9;1(4979):

[1315] -1318, 1322-2), Gomes Index (Gomes et al., Gut. 1986 Jan;27(1):92-95), Riley Score (Riley et al., Gut. 1991 Feb;32(2):174-178), Geboes Score (Geboes et al., Gut. 2000 Sep; 47(3):404-409), Harpaz / Mount Sinai Index (Fiel et al., Modern Pathology. 2003;83(1):118A), and Modified Riley Score (Feagan et al., N Eng J Med. 2005 Jun). 16;352(24):2499-507), Chicago / Rubin / Histological Inflammation Activity Scale (Rubin et al., InGasteroenterol. 2007 Apr 1;134(4):A19-A19), Modified Harpaz Index (Theede et al., ClinGastroenterol Hepatol. 2015 Nov;13(11):1929-36.31), Simplified Geboes Score (Jauregui-Amezaga et al., J Crohns Colitis. 2017 Mar 1;11(3):305-313), Nancy Index (Marchal-Bressenot et al., Gut. 2017 Jan;66(1):43-49), Robarts Histopathological Score (Hosli et al., Gut. 2017 Jan;66(1):50-58). In some implementations, MRI imaging is used to classify UC patients. In some implementations, subjects with UC are classified using the Montreal Classification System (Satsangi et al., Gut. 2006 Jun;55(6):749-753) and / or the Truelove-Witts criteria (Truelove and Witts, Br Med J. 1955 Oct 29;2(4947):1041-8). In some implementations, UC severity is classified as mild, moderate, or severe.In some implementations, UC severity is classified as mild, moderate to severe, or fulminant (Pabla et al., GastroenterolClin North Am. 2020 Dec;49(4):671-688).

[0152] In some implementations, the term “disease activity” for UC refers to a cross-sectional, moment-in-time assessment of inflammation. In some implementations, the term “disease severity” for UC refers to longitudinal and historical factors of the patient, such as previous biologic failures, history of maximum disease severity, and indicators of healthcare use, such as hospitalization and disability scoring tools. In some implementations, disease severity of IBD is assessed by: (1) the impact of the disease on the patient (e.g., clinical symptoms, patient-reported outcomes, quality of life, and disability); (2) the inflammatory burden (e.g., the extent, location, and severity of bowel involvement at a given time); and (3) the course of the disease, including structural damage (Peyrin-Biroulet et al., Clin Gastroenterol Hepatol. 2016 Mar;14(3):348-354.e17). Besides disease severity, major risk factors for colorectal cancer in UC include disease duration, active inflammation (endoscopic or histological), presence of strictures, presence of post-inflammatory polyps, family history of colorectal cancer, and associated primary sclerosing cholangitis. Intestinal strictures refer to narrowing or constriction of the intestinal lumen. In some implementations, anti-HJV antibodies are administered to prevent or treat intestinal strictures. In some implementations, anti-HJV antibodies are used to prevent the development of colorectal cancer associated with UC. In some implementations, treatment with anti-HJV antibodies reduces the need for hospitalization in subjects with UC. In some implementations, subjects receiving anti-HJV antibodies are hospitalized less frequently compared to those not receiving them.

[0153] In some embodiments, a subject with UC is currently taking or has taken additional treatment for the treatment of UC and / or its related symptoms. In some embodiments, a subject with UC does not respond to additional treatment for the treatment of UC and / or its related symptoms. In some embodiments, a subject with UC cannot tolerate additional treatment for the treatment of UC and / or its related symptoms. As used herein, "additional treatment" refers to treatment that is not an HJV antagonist. Some non-limiting examples of UC treatment include aminosalicylic acids (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators (e.g., estrasimod, ozanimod), immunomodulators (e.g., azathioprine, 6-mercaptopurine, cyclosporine, or tacrolimus), Janus kinase (JAK) inhibitors (e.g., utpatinib, tofacitinib), tumor necrosis factor (TNF) inhibitors (e.g., adalimumab, cetuzumab, infliximab, golimumab), integrin antagonists (e.g., natezumab, vedolzumab), interleukin (IL)-23 antagonists (e.g., levosinicillin), or IL-12 / IL23 antagonists (e.g., uterotonicumab), nicotine, sulfasalazine (e.g., azulfidine, salazopyrin, sulazine), mesalazine (e.g., Delzicol, Canasa, Asacol). HD, Sfrowasa, Apriso, Lialda, Pentasa), oxalacil, balsalazine, or azathioprine. In some embodiments, the subject with UC is currently taking or has taken corticosteroids for the treatment of UC and / or its related symptoms. In some embodiments, the subject with US is unresponsive to corticosteroids for the treatment of UC and / or its related symptoms. In some embodiments, the subject with UC cannot tolerate corticosteroids for the treatment of UC and / or its related symptoms. Some non-limiting examples of corticosteroids used to treat UC include hydrocortisone, prednisone (e.g., Prednisone Intensol, Deltasone, Rayos), methylprednisolone (e.g., Depo-Medrol, Medrol, Solu-Medrol, P-Care D80, ReadySharp Methylprednisolone, P-Care D40), prednisolone (e.g., Omnipred, Pred Mild, Pred Forte, Orapred ODT, Millipred DP, Veripred 20, Pediapred), and budesonide (e.g., Entocort, Uceris, Rhinocort Allergy, Pulmicort Flexhaler, Pulmicort).In some implementations, the subject is currently taking or has taken topical corticosteroids as acute treatment for distal colitis. In some implementations, anti-HJV antibodies reduce the need for corticosteroid use in subjects with UC.

[0154] In some implementations, anti-HJV antibodies are used to promote and / or maintain remission of UC in subjects. In some implementations, severity and remission are assessed via patient-reported outcomes (PROs). In some implementations, PROs are patient questionnaires, such as those assessing quality of life and validated symptom scores. In some implementations, severity and remission are assessed by the resolution of clinical UC symptoms. In some implementations, remission includes a reduction or cessation of rectal bleeding. In some implementations, remission includes improvement in bowel habits (e.g., bowel frequency). In some implementations, remission includes endoscopic cure. In some implementations, remission in subjects is assessed via activity indices, such as the Mayo Criterion, Seo Index, Rachmilewitz Index, Simple Clinical Colitis Activity Index (SCCAI), PRO2, or Pediatric UC Activity Index (PUCAI) (Rubin et al., Am. J of Gastroenterol. 2019Mar;114(3):384-413).

[0155] In some implementations, UC severity and remission are assessed using the Disease Activity Index (DAI). In some implementations, the DAI used to assess UC severity and remission is the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The UCEIS scoring system for assessing ulcerative colitis severity ranges from 0 to 8, with higher scores indicating more severe disease. The score is the sum of three sub-scores: (1) vascular pattern (score 0-2); (2) bleeding (score 0-3); and erosion and ulceration (score 0-3) (Ikeya et al., J Crohns Colitis. 2016 Mar;10(3):286-295). In some implementations, subjects with a UCEIS score of 5-8 have severe UC. In some implementations, subjects with a UCEIS score of 2-4 have mild to moderate UC. In some implementations, subjects with a UCEIS score of 0-1 are in remission. In some implementations, UC mitigation is represented by a UCEIS score of 1. In some implementations, UC mitigation is represented by a UCEIS score of 0. In some implementations, an object is considered to be in UC mitigation if none of its individual UCEIS sub-scores are greater than 1. In some implementations, an object is considered to be in UC mitigation if none of its individual sub-scores are greater than 0.

[0156] In some implementations, the DAI used to assess the severity and remission of UC is the Mayo Criterion (i.e., the Mayo Disease Activity Index) (Ungaro et al., Lancet. 2017 Apr 29;389(10080):1756-1770). The Mayo Criterion system used to assess ulcerative colitis activity ranges from 0 to 12, with higher scores indicating more severe disease. The score is the sum of four sub-scores: (1) defecation frequency; (2) rectal bleeding; (3) endoscopy; and (4) physician’s overall assessment, each sub-score ranging from 0 (normal) to 3 (severe disease) (Rutgeerts et al., N Engl J Med 2005;353:2462-2476). In some implementations, subjects with a Mayo Criterion score of 8-12 have severe UC. In some implementations, subjects with a Mayo Criterion score of 5-7 have moderate UC. In some implementations, subjects with a Mayo Criterion score of 2-4 have mild UC. In some implementations, UC mitigation is represented by a Mayo score of 2. In some implementations, UC mitigation is represented by a Mayo score of 1. In some implementations, UC mitigation is represented by a Mayo score of 0. In some implementations, an object is considered to be in UC mitigation if none of the individual Mayo scores are greater than 1. In some implementations, an object is considered to be in UC mitigation if none of the individual Mayo scores are greater than 0. In some implementations, an object is considered to be in UC mitigation if each individual Mayo score is 0 or 1.

[0157] In some implementations, the DAI used to assess UC severity and remission is the Partial Mayo Score (PMS) (i.e., the Mayo Score without endoscopy). The PMS ranges from 0 (normal or no active disease) to 9 (severe disease) and is calculated as the sum of three sub-scores (defecation frequency, rectal bleeding, and physician overall assessment), each ranging from 0 (normal) to 3 (severe disease). In some implementations, subjects with a PMS of 7–9 have severe UC. In some implementations, subjects with a PMS of 5–6 (inclusive) have moderate disease. In some implementations, subjects with a PMS of 2–4 (inclusive) have mild disease. In some implementations, subjects with a PMS of 1 are in UC remission. In some implementations, subjects with a PMS of 0 are in UC remission. In some implementations, a subject is considered to be in UC remission if none of the individual PMS sub-scores is greater than 1. In some implementations, a subject is considered to be in UC remission if none of the individual PMS sub-scores is greater than 0. In some implementations, if each individual PMS sub-score is 0 or 1, the object is considered to be in UC remission.

[0158] In some implementations, the DAI used to assess UC severity and remission is the Ulcerative Colitis Colonoscopic Index of Severity (UCCIS) (Samuel et al., Clin Gastroenterol Hepatol. 2013 Jan;11(1):49-54.31). The UCCIS scoring system for assessing ulcerative colitis severity includes sub-scores based on: vascular pattern (0-2), granularity (0-2), erosion / ulceration (0-4), bleeding fragility (0-2), segmental endoscopic severity (4-subscale), and overall endoscopic severity (4-subscale and 10-cm visual analog scale). A higher UCCIS score indicates more severe disease.

[0159] In some embodiments, an HJV antagonist (e.g., an anti-HJV antibody) reduces the severity of UC. In some embodiments, an HJV antagonist (e.g., an anti-HJV antibody) maintains remission of UC. In some embodiments, administration of an anti-HJV antibody reduces a subject's UCEIS classification from severe (i.e., a UCEIS score of 5-8) to mild to moderate (i.e., a UCEIS score of 2-4). In some embodiments, administration of an anti-HJV antibody reduces a subject's UCEIS classification from severe (i.e., a UCEIS score of 5-8) to remission (i.e., a UCEIS score of 0 or 1). In some embodiments, administration of an anti-HJV antibody reduces a subject's UCEIS classification from mild to moderate (i.e., a UCEIS score of 2-4) to remission (i.e., a UCEIS score of 0 or 1). In some embodiments, administration of an anti-HJV antibody maintains the subject's UCEIS classification in remission (i.e., a UCEIS score of 0 or 1) after administration.

[0160] In some embodiments, administration of anti-HJV antibodies reduces a subject's Mayo Criterion (MCC) classification from severe (i.e., MCC score of 8–12) to moderate (i.e., MCC score of 5–7). In some embodiments, administration of anti-HJV antibodies reduces a subject's MCC classification from severe (i.e., MCC score of 8–12) to mild (i.e., MCC score of 2–4). In some embodiments, administration of anti-HJV antibodies reduces a subject's MCC classification from severe (i.e., MCC score of 8–12) to remission (i.e., MCC score of 0 or 1). In some embodiments, administration of anti-HJV antibodies reduces a subject's MCC classification from moderate (i.e., MCC score of 5–7) to mild (i.e., MCC score of 2–4). In some embodiments, administration of anti-HJV antibodies reduces a subject's MCC classification from mild (i.e., MCC score of 2–4) to remission (i.e., MCC score of 0 or 1). In some embodiments, administration of anti-HJV antibodies reduces a subject's Mayo Criterion (MCC) classification from mild (i.e., a MCC score of 2–4) to remission (i.e., a MCC score of 0 or 1). In some embodiments, administration of anti-HJV antibodies maintains a subject's MCC classification at remission (i.e., a MCC score of 0 or 1) after administration.

[0161] In some embodiments, administration of anti-HJV antibodies reduces the PMS classification of the subject from severe (i.e., PMS 7-9) to moderate (i.e., PMS 5-6). In some embodiments, administration of anti-HJV antibodies reduces the PMS classification of the subject from severe (i.e., PMS 7-9) to mild (i.e., PMS 2-4). In some embodiments, administration of anti-HJV antibodies reduces the PMS classification of the subject from severe (i.e., PMS 7-9) to remission (i.e., PMS 0 or 1). In some embodiments, administration of anti-HJV antibodies reduces the PMS classification of the subject from moderate (i.e., PMS 5-6) to mild (i.e., PMS 2-4). In some embodiments, administration of anti-HJV antibodies reduces the PMS classification of the subject from moderate (i.e., PMS 5-6) to remission (i.e., PMS 0 or 1). In some embodiments, administration of anti-HJV antibodies reduces the subject's PMS classification from mild (i.e., PMS 2-4) to remission (i.e., PMS 0 or 1). In some embodiments, administration of anti-HJV antibodies maintains the subject's PMS classification at remission (i.e., PMS 0 or 1) after administration.

[0162] As used herein, the term “remission” encompasses clinical remission, endoscopic remission, histological remission, biomarker-based (e.g., biochemical) remission, radiological remission, and patient-reported remission. In some implementations, radiological remission is assessed by evaluating inflammation in the gut using imaging studies (e.g., CT or MRI) (Shaban et al., Gastroenterol. 2022;13:e28-e34). In some implementations, patient-reported remission (e.g., the Manitoba IBD Index (MIBDI)) is used to assess overall remission (Clara et al., Am J Gastroenterol. 2009 Ju;104(7):1754-63). In some implementations, patient-reported outcomes encompass quality of life, overall health, and the ability to perform daily activities. In some implementations, patient-reported remission is assessed using patient questionnaires. In some implementations, biomarker-based (i.e., biochemical) remission is based on the measurement of inflammatory biomarkers (e.g., C-reactive protein) (Kessel et al., Sci Rep. 2021 Mar 23;11:6690). In some implementations, inflammatory biomarkers can be used to assess the level of inflammation in the body, and low or normal levels of these biomarkers indicate remission.

[0163] In some implementations, clinical remission includes the absence or significant reduction of IBD-related clinical symptoms such as abdominal pain, diarrhea, fatigue, weight loss, and rectal bleeding (Vuitton et al., Aliment Pharmacol Ther. 2017 Mar;45(6):801-813). In some implementations, after administration of anti-HJV antibodies, subjects experienced reductions in abdominal pain, diarrhea, fatigue, weight loss, and / or rectal bleeding compared to before administration or to subjects not administered anti-HJV antibodies. In some implementations, clinical remission is assessed through patient-reported outcomes. In some implementations, clinical remission is assessed using the Clinical Activity Index (CAI), which comprises seven items: bowel movement frequency (0-3); blood in stool (0-4); general health (0-3); abdominal discomfort (0-3); fever (0-3); extraintestinal manifestations (0-9); and laboratory findings (erythrocyte sedimentation rate and hemoglobin) (0-4) (Rachmilewitz D, BMJ. 1989 Jan14;298(6666):82-6), where a higher CAI score indicates more severe disease. In some implementations, clinical remission is defined as a CAI ≤ 3. In some implementations, after administering anti-HJV antibodies to subjects with UC, the CAI score decreased by the following ranges relative to subjects before administration or relative to subjects who did not receive administration: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%. %, 20%-50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%.

[0164] In some implementations, the severity of UC (e.g., remission) is assessed by endoscopy. In some implementations, endoscopic remission is assessed by an endoscopic index. Some non-limiting examples of endoscopic indices include the Baron score (Baron et al., Br Med J. 1964 Jan 11;1(5375):89-91), the Rachmilewitz index (also known as CAI, as described above), the Ulcerative Colitis Endoscopic Severity Index, the Mayo Clinic Endoscopic Subscore, and the Ulcerative Colitis Colonoscopic Severity Index. In some implementations, endoscopic remission is assessed by endoscopy by the presence of edema, loss of vascular texture, erythema, mucosal granularity and fragility, erythema, erosion and ulceration, and pseudopolyps (Spiceland and Lodhia, World J Gastroenterol. 2018 Sep 21;24(35):4014-4020). In some implementations, endoscopic remission is determined by examining the mucosal lining of the digestive tract using endoscopy (Kim KO, ClinEndosc. 2022 Jul;55(4):480-4). In some implementations, remission (e.g., endoscopic remission) is indicated by mucosal healing. In some implementations, mucosal healing is characterized by a reduction or absence of erythematous mucosa, fragility, bleeding, erosion, ulceration, or other signs of intestinal inflammation (D'Haens et al., Gastroenterol. 2007 Feb;132(2):763-86). In some implementations, mucosal healing is characterized by the absence of all microscopic and macroscopic mucosal ulcers, providing a sigmoidoscopy score of 0, as assessed by the Ulcerative Colitis Disease Activity Index (Lichtenstein and Rutgeerts, Inflamm Bowel Dis. 2010 Feb;16(2):338-46). In some embodiments, the absence of visible signs of intestinal inflammation indicates endoscopic remission and / or mucosal healing. In some embodiments, signs of improved mucosal appearance indicate endoscopic remission and / or mucosal healing. In some embodiments, improved intestinal vascular patterns indicate endoscopic remission and / or mucosal healing. In some embodiments, a reduction in intestinal erosion and / or ulceration indicates endoscopic remission and / or mucosal healing. In some embodiments, a reduction in intestinal (e.g., colonic) bleeding indicates endoscopic remission and / or mucosal healing. In some embodiments, a reduction in intestinal erythema mucosa indicates endoscopic remission and / or mucosal healing. In some embodiments, administration of anti-HJV antibodies promotes mucosal healing in the subject.In some implementations, the endoscopic index decreased by the following ranges after administration of anti-HJV antibodies to subjects with UC, relative to subjects before administration or relative to subjects not receiving administration: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%. 0%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100% (e.g., as assessed by any of the above indices or any other suitable method). In some implementations, after administering anti-HJV antibodies to subjects with UC, the subjects showed improved intestinal vascular patterns, reduced intestinal erosion, reduced intestinal ulceration, reduced intestinal bleeding, reduced intestinal erythema mucosa, and / or decreased intestinal fragility compared to before administration of anti-HJV antibodies or compared to subjects who did not receive anti-HJV antibodies.

[0165] In some implementations, histological remission (also known as “histological improvement” or “histological healing”) is based on microscopic examination of tissue samples (i.e., biopsies) taken during endoscopy (Bryant et al., J Crohns Colitis. 2014 Dec;8(12):1582-97). In some implementations, even if the mucosa appears normal during endoscopy, histological remission needs to be confirmed at the cellular level to indicate the absence of microscopic inflammation. Some non-restrictive examples of methods for evaluating histological remission include the following study designs: Truelove and Richards (Br Med J. 1956;1:1315-1318), Riley et al. (Riley et al., Gut. 1991;32:174-178), Geboes et al. (Geboes et al., Gut. 2000;47:404-409), Florén et al. (Florén et al., Scand J Gastroenterol. 1987;22:459-462), Hanauer et al. (Hanauer et al., Am J Gastroenterol. 1993;88:1188-1197; Hanauer et al., Gastroenterology. 1998;115:525-532), and Gupta et al. (Gupta et al., Gastroenterology). 2007;133:1099-1105). In some implementations, histological improvements are assessed by intestinal structure, chronic inflammatory cell infiltration, surface epithelial integrity, mucin depletion, crypt abscesses or deformities, glandular hyperplasia, glandular and mucosal atrophy, fulminant inflammation, neutrophils in the epithelium, neutrophils and eosinophils in the lamina propria, crypt destruction and / or erosion or ulceration (Peyrin-Biroulet et al., Clin Gastroenterol Hepatol. 2014Jun;12(6):929-34.e2).

[0166] In some implementations, compared with subjects before administration of anti-HJV antibodies or with subjects not administered anti-HJV antibodies, after administration of anti-HJV antibodies to subjects, the intestinal structure of the subjects is improved, chronic inflammatory cell infiltration is reduced, surface epithelial integrity is increased, mucin depletion is reduced, crypt abscesses or deformities are reduced, glandular and mucosal atrophy is reduced, fulminant inflammation is reduced, neutrophils in the epithelium are reduced, neutrophils and eosinophils in the lamina propria are reduced, crypt destruction is reduced, and / or intestinal erosion or ulceration is reduced (e.g., as assessed by the methods described above or any known in the art).

[0167] In some implementations, if the Mayo Criterion score of the subject decreases by at least 1%, at least 2%, at least 3%, 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 22%, at least 24%, at least 26%, at least 28%, at least 30%, at least 32.5%, at least 35%, at least 37.5%, at least 40%, at least 42.5%, at least 45%, at least 47.5%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% relative to baseline after administration of the anti-HJV antibody, then the anti-HJV antibody promotes remission in the subject. In some implementations, if the Mayo score of a subject decreases by the following ranges relative to the subject before application or relative to a subject that has not received application: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40% If the percentages are 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%, then the anti-HJV antibody promotes remission in the target population.

[0168] In some embodiments, if the subject's Mayo Criterion score decreases by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 relative to baseline after administration of the anti-HJV antibody, the anti-HJV antibody promotes remission in the subject. In some embodiments, if the subject's Mayo Criterion score decreases by the following ranges relative to the subject before administration or relative to the subject who did not receive administration: 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4- 12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-12, 6-11, 6-10, 6-9, 6-8, 6-7, 7-12, 7-11, 7-10, 7-9, 7-8, 8-12, 8-11, 8-10, 8-9, 9-12, 9-11, 9-10, 10-12, 10-11, or 11-12, then the anti-HJV antibody promotes remission in the subject.

[0169] In some implementations, if an anti-HJV antibody is administered to a subject with UC (e.g., a Mayo score > 2) and the subject's Mayo score is in the range of 0-1 or 1-2, the anti-HJV antibody promotes remission in the subject.

[0170] In some implementations, if, after administration of the anti-HJV antibody, the subject's PMS decreases relative to baseline by at least 1%, at least 2%, at least 3%, 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 22%, at least 24%, at least 26%, at least 28%, at least 30%, at least 32.5%, at least 35%, at least 37.5%, at least 40%, at least 42.5%, at least 45%, at least 47.5%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%, the anti-HJV antibody promotes remission in the subject. In some implementations, if the PMS of the object decreases relative to the object before application or relative to the object that was not applied, the following ranges apply: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%. If the percentages are 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%, then the anti-HJV antibody promotes remission in the target population. In some implementations, if the subject's PMS decreases by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or 9 relative to baseline after administration of the anti-HJV antibody, the anti-HJV antibody promotes remission in the subject.In some implementations, anti-HJV antibodies promote remission in the subject if the PMS of the subject decreases by 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 4-9, 5-6, 5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 7-8, 7-9, or 8-9. In some implementations, anti-HJV antibodies promote remission in the subject if they are suffering from active (i.e., acute) UC (e.g., PMS). > 2) If, after administration of anti-HJV antibody to a subject, the subject's Mayo score is in the range of 0-1 or 1-2, then the anti-HJV antibody promotes remission in the subject.

[0171] In some implementations, if a subject with acute (e.g., active) IBD (i.e., a Mayo Criterion score of 2–12 or a PMS score of 2–9) experiences a recovery time of less than 5 days, less than 6 days, less than 7 days, less than 8 days, less than 9 days, less than 10 days, less than 11 days, less than 12 days, less than 13 days, less than 14 days, less than 15 days, less than 16 days, less than 17 days, less than 18 days, less than 19 days, less than 20 days, less than 22 days, less than 24 days, less than 26 days, less than 28 days, less than 30 days, less than 32 days, less than 34 days, less than 36 days, less than 38 days, less than 40 days, less than 42 days, or less than 44 days after administration of anti-HJV antibody, If remission is achieved within 10 days, less than 46 days, less than 48 days, less than 50 days, less than 55 days, less than 60 days, less than 65 days, less than 70 days, less than 75 days, less than 80 days, less than 85 days, less than 90 days, less than 95 days, less than 100 days, less than 110 days, less than 120 days, less than 130 days, less than 140 days, less than 150 days, less than 160 days, less than 170 days, less than 180 days, less than 190 days, or less than 200 days, less than 220 days, less than 240 days, less than 260 days, less than 280 days, or less than 280 days (i.e., Mayo score or PMS is 0 or 1), then the anti-HJV antibody promotes remission in the subject. In some implementations, if a subject with active (i.e., acute) IBD (i.e., a Mayo Criterion score of 2–12 or a PMS score of 2–9) experiences a positive response to anti-HJV antibody treatment within 5–10 days, 10–15 days, 15–20 days, 20–25 days, 25–30 days, 30–35 days, 35–40 days, 40–45 days, 45–50 days, 50–55 days, 55–60 days, 60–65 days, 65–70 days, 70–75 days, 75–80 days, 80–85 days, 85–90 days, or 90–90 days, the response rate is determined based on the individual's condition. If remission is achieved within 5 days, 95-100 days, 100-110 days, 110-120 days, 120-130 days, 130-140 days, 140-150 days, 150-160 days, 160-170 days, 170-180 days, 180-190 days, 190-200 days, 200-220 days, 220-240 days, 240-260 days, 260-280 days, or 280-300 days (i.e., Mayo score or PMS is 0 or 1), then anti-HJV antibody promotes remission in the subject.

[0172] In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains remission in subjects with IBD. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains endoscopic remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains clinical remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains biomarker-based (i.e., biochemical) remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains histological remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains radiation remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains patient-reported remission in subjects.

[0173] In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains remission in subjects with IBD. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains endoscopic remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains clinical remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains biomarker-based (i.e., biochemical) remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains histological remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains radiation remission in subjects. In some embodiments, administration of an HJV antagonist (e.g., an anti-HJV antibody) maintains patient-reported remission in subjects.

[0174] In some embodiments, if a subject with IBD exhibits a longer duration of remission compared to a subject not treated with an HJV antagonist, then the HJV antagonist (e.g., an anti-HJV antibody) is considered to maintain the subject's remission. In some embodiments, if a subject with IBD exhibits a longer duration of remission compared to the time spent in remission before treatment with the HJV antagonist, then the HJV antagonist (e.g., an anti-HJV antibody) is considered to maintain the subject's remission. In some embodiments, if a subject with a Mayo Criterion score of 1 maintains a Mayo Criterion score of 1 after treatment with the anti-HJV antibody, then the anti-HJV antibody maintains the subject's remission. In some embodiments, if a subject with a Mayo Criterion score of 1 maintains a Mayo Criterion score of 0 after treatment with the anti-HJV antibody, then the anti-HJV antibody maintains the subject's remission. In some embodiments, if a subject with a Mayo Criterion score of 0 maintains a Mayo Criterion score of 1 after treatment with the anti-HJV antibody, then the anti-HJV antibody maintains the subject's remission. In some implementations, if a subject with a Mayo Criterion score of 0 maintains a Mayo Criterion score of 0 after administration of the anti-HJV antibody, the anti-HJV antibody maintains the subject's remission. In some implementations, if a subject with a Mayo Criterion score of 0-1 (inclusive) maintains a Mayo Criterion score of 0-1 (inclusive) after administration of the anti-HJV antibody, the anti-HJV antibody maintains the subject's remission.

[0175] In some embodiments, if a subject with a PMS of 1 has a PMS of 1 after administration of the anti-HJV antibody, the anti-HJV antibody maintains the subject's remission. In some embodiments, if a subject with a PMS of 1 has a PMS of 0 after administration of the anti-HJV antibody, the anti-HJV antibody maintains the subject's remission. In some embodiments, if a subject with a PMS of 0 has a PMS of 1 after administration of the anti-HJV antibody, the anti-HJV antibody maintains the subject's remission. In some embodiments, if a subject with a PMS of 0-1 (inclusive) has a PMS of 0-1 (inclusive) after administration of the anti-HJV antibody, the anti-HJV antibody maintains the subject's remission.

[0176] In some implementations, if a subject with a Mayo Criterion score and / or PMS of 0 or 1 maintains a Mayo Criterion score and / or PMS of 0 or 1 for at least 10 days, at least 15 days, at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 70 days, at least 80 days, at least 90 days, at least 100 days, at least 110 days, at least 120 days, at least 130 days, at least 140 days, at least 150 days, at least 160 days, at least 170 days, at least 180 days, at least 190 days, at least 200 days, at least 220 days, or at least 240 days after administration of the anti-HJV antibody, The duration of remission for anti-HJV antibodies is at least 260 days, at least 280 days, at least 300 days, at least 325 days, at least 350 days, at least 375 days, at least 400 days, at least 425 days, at least 450 days, at least 475 days, at least 500 days, at least 550 days, at least 600 days, at least 650 days, at least 700 days, at least 750 days, at least 800 days, at least 850 days, at least 900 days, at least 950 days, at least 1000 days, at least 1100 days, at least 1200 days, at least 1300 days, at least 1400 days, or at least 1500 days. In some implementations, if a subject with a Mayo Criterion score and / or PMS score of 0 or 1 maintains a Mayo Criterion score and / or PMS score of 0 or 1 for approximately 10–15 days, approximately 15–20 days, approximately 20–30 days, approximately 30–40 days, approximately 40–50 days, approximately 50–60 days, approximately 60–70 days, approximately 70–80 days, approximately 80–90 days, or approximately 90–10 days after administration of the anti-HJV antibody, 0 days, approximately 100-110 days, approximately 110-120 days, approximately 120-130 days, approximately 130-140 days, approximately 140-150 days, approximately 150-160 days, approximately 160-170 days, approximately 170-180 days, approximately 180-190 days, approximately 190-200 days, approximately 200-220 days, approximately 220-240 days, approximately 240-260 days, approximately 260- 280 days, approximately 280-300 days, approximately 300-325 days, approximately 325-350 days, approximately 350-375 days, approximately 375-400 days, approximately 400-425 days, approximately 425-450 days, approximately 450-475 days, approximately 475-500 days, approximately 500-550 days, approximately 550-600 days, approximately 600-650 days, approximately 650-700 days, approximately 70 The duration of remission for patients with anti-HJV antibodies is 0-750 days, approximately 750-800 days, approximately 800-850 days, approximately 850-900 days, approximately 900-950 days, approximately 950-1000 days, approximately 1000-1100 days, approximately 1100-1200 days, approximately 1200-1300 days, approximately 1300-1400 days, approximately 1400-1500 days, or more.

[0177] In some embodiments, a subject with a rectal bleeding subscore of 1 is in remission of UC. In some embodiments, a subject with a rectal bleeding subscore of 0 is in remission of UC. In some embodiments, a subject with a rectal bleeding subscore of 2 is experiencing acute (e.g., active) UC. In some embodiments, a subject with a rectal bleeding subscore of 3 is experiencing acute (e.g., active) UC. In some embodiments, the anti-HJV antibody reduces the rectal bleeding subscore by at least 1, at least 2, or 3. In some embodiments, the anti-HJV antibody reduces the rectal bleeding subscore by 0-1, 1-2, or 2-3. In some embodiments, a subject with a baseline rectal bleeding subscore of 3 has a rectal bleeding subscore of 2 after administration of the anti-HJV antibody. In some embodiments, a subject with a baseline rectal bleeding subscore of 3 has a rectal bleeding subscore of 1 after administration of the anti-HJV antibody. In some embodiments, a subject with a rectal bleeding subscore of 3 has a rectal bleeding subscore of 0 after administration of the anti-HJV antibody. In some embodiments, a subject with a baseline rectal bleeding subscore of 2 has a rectal bleeding subscore of 1 after administration of the anti-HJV antibody. In some embodiments, subjects with a baseline rectal bleeding subscore of 2 had a rectal bleeding subscore of 0 after administration of anti-HJV antibodies. In some embodiments, subjects with a rectal bleeding subscore of 1 had a rectal bleeding subscore of 1 after administration of anti-HJV antibodies. In some embodiments, subjects with a rectal bleeding subscore of 1 had a rectal bleeding subscore of 0 after administration of anti-HJV antibodies. In some embodiments, subjects with a rectal bleeding subscore of 0 had a rectal bleeding subscore of 1 after administration of anti-HJV antibodies. In some embodiments, subjects with a rectal bleeding subscore of 0 had a rectal bleeding subscore of 0 after administration of anti-HJV antibodies.

[0178] In some embodiments, a subject with a bowel frequency subscore of 1 is in remission of UC. In some embodiments, a subject with a bowel frequency subscore of 0 is in remission of UC. In some embodiments, a subject with a bowel frequency subscore of 2 is experiencing acute (e.g., active) UC. In some embodiments, a subject with a bowel frequency subscore of 3 is experiencing acute (e.g., active) UC. In some embodiments, the anti-HJV antibody reduces the bowel frequency subscore by at least 1, at least 2, or 3. In some embodiments, the anti-HJV antibody reduces the bowel frequency subscore by 0-1, 1-2, or 2-3. In some embodiments, a subject with a bowel frequency subscore of 3 has a bowel frequency subscore of 2 after administration of the anti-HJV antibody. In some embodiments, a subject with a bowel frequency subscore of 3 has a bowel frequency subscore of 1 after administration of the anti-HJV antibody. In some embodiments, a subject with a bowel frequency subscore of 3 has a bowel frequency subscore of 0 after administration of the anti-HJV antibody. In some embodiments, a subject with a bowel frequency subscore of 2 has a bowel frequency subscore of 1 after administration of the anti-HJV antibody. In some embodiments, a subject with a defecation frequency subscore of 2 had a defecation frequency subscore of 0 after administration of anti-HJV antibodies. In some embodiments, a subject with a defecation frequency subscore of 1 had a defecation frequency subscore of 1 after administration of anti-HJV antibodies. In some embodiments, a subject with a defecation frequency subscore of 1 had a defecation frequency subscore of 0 after administration of anti-HJV antibodies. In some embodiments, a subject with a defecation frequency subscore of 0 had a defecation frequency subscore of 1 after administration of anti-HJV antibodies. In some embodiments, a subject with a defecation frequency subscore of 0 had a defecation frequency subscore of 0 after administration of anti-HJV antibodies.

[0179] In some implementations, subjects with a Physician Global Assessment (PGA) score of 1 are in remission of UC. In some implementations, subjects with a Physician Global Assessment (PGA) sub-score of 0 are in remission of UC. In some implementations, subjects with a Physician Global Assessment (PGA) sub-score of 2 are experiencing active (i.e., acute) UC. In some implementations, subjects with a Physician Global Assessment (PGA) sub-score of 3 are experiencing active (i.e., acute) UC. In some implementations, the anti-HJV antibody reduces the Physician Global Assessment (PGA) score by at least 1, at least 2, or 3. In some implementations, the anti-HJV antibody reduces the Physician Global Assessment (PGA) sub-score by 0–1, 1–2, or 2–3. In some implementations, a subject with a Physician Global Assessment (PGA) sub-score of 3 has a Physician Global Assessment (PGA) sub-score of 2 after administration of the anti-HJV antibody. In some implementations, a subject with a Physician Global Assessment (PGA) sub-score of 3 has a Physician Global Assessment (PGA) sub-score of 1 after administration of the anti-HJV antibody. In some implementations, a subject with a Physician Global Assessment (PGA) sub-score of 3 has a Physician Global Assessment (PGA) sub-score of 0 after administration of the anti-HJV antibody. In some implementations, a subject with a Physician Global Assessment (PGA) sub-score of 2 has a Physician Global Assessment (PGA) sub-score of 1 after administration of the anti-HJV antibody. In some implementations, a subject with a physician overall assessment subscore of 2 had a physician overall assessment subscore of 0 after administration of anti-HJV antibodies. In some implementations, a subject with a physician overall assessment subscore of 1 had a physician overall assessment subscore of 1 after administration of anti-HJV antibodies. In some implementations, a subject with a physician overall assessment subscore of 1 had a physician overall assessment subscore of 0 after administration of anti-HJV antibodies. In some implementations, a subject with a physician overall assessment subscore of 0 had a physician overall assessment subscore of 1 after administration of anti-HJV antibodies. In some implementations, a subject with a physician overall assessment subscore of 0 had a physician overall assessment subscore of 0 after administration of anti-HJV antibodies.

[0180] In some implementations, subjects with an endoscopic subscore (i.e., the Mayo Clinic score) of 0 are in remission of UC. In some implementations, subjects with an endoscopic subscore of 1 have mild UC. In some implementations, subjects with an endoscopic subscore of 2 have moderate UC. In some implementations, subjects with an endoscopic subscore of 3 have severe UC. In some implementations, anti-HJV antibodies reduce the endoscopic subscore by at least 1, at least 2, or at least 3. In some implementations, anti-HJV antibodies reduce the endoscopic subscore by 0–1, 1–2, or 2–3. In some implementations, a subject with an endoscopic subscore of 3 has an endoscopic subscore of 2 after administration of anti-HJV antibodies. In some implementations, a subject with an endoscopic subscore of 3 has an endoscopic subscore of 1 after administration of anti-HJV antibodies. In some implementations, a subject with an endoscopic subscore of 3 has an endoscopic subscore of 0 after administration of anti-HJV antibodies. In some implementations, a subject with an endoscopic subscore of 2 has an endoscopic subscore of 1 after administration of anti-HJV antibodies. In some embodiments, a subject with an endoscopic subscore of 2 had an endoscopic subscore of 0 after administration of anti-HJV antibody. In some embodiments, a subject with an endoscopic subscore of 1 had an endoscopic subscore of 1 after administration of anti-HJV antibody. In some embodiments, a subject with an endoscopic subscore of 1 had an endoscopic subscore of 0 after administration of anti-HJV antibody. In some embodiments, a subject with an endoscopic subscore of 0 had an endoscopic subscore of 1 after administration of anti-HJV antibody. In some embodiments, a subject with an endoscopic subscore of 0 had an endoscopic subscore of 0 after administration of anti-HJV antibody.

[0181] Other non-limiting examples of methods for assessing UC severity include biopsy, colonoscopy, sigmoidoscopy, and stool examination. In some embodiments, UC severity (e.g., remission) is assessed through quality of life. In some embodiments, anti-HJV antibodies are used to improve and / or maintain the subject's quality of life. In some embodiments, UC severity is assessed through disability. In some embodiments, anti-HJV antibodies are used to reduce the subject's disability.

[0182] ii. Crohn's disease

[0183] In some implementations, the subject has Crohn's disease (CD). Crohn's disease is a type of inflammatory bowel disease (IBD) that can affect any segment of the gastrointestinal tract. Symptoms typically include abdominal pain (e.g., lower abdominal pain), diarrhea (e.g., bloody or non-bloody diarrhea), fever, bloating, weight loss, or fatigue. Extra-gastrointestinal complications (e.g., extraintestinal manifestations) may include anemia, rash, arthritis, eye inflammation, and fatigue. The presentation of Crohn's disease varies significantly depending on the area of ​​the gastrointestinal tract affected. The presentation differs depending on the underlying cause of inflammation, fistula formation, or stenosis. In some implementations, fistula formation can lead to fecal-urinary, pneumaturia, and / or rectovaginal fistulas. In some implementations, the subject has a CD-associated abscess.

[0184] In some embodiments, this disclosure provides a method for alleviating one or more symptoms related to CD in a subject, the method comprising administering an effective amount of anti-HJV antibody to the subject. In some embodiments, the administration reduces CD-related inflammation in the subject relative to a subject prior to administration or relative to a subject who has not received administration. In some embodiments, the administration reduces the number of abdominal pain episodes (e.g., abdominal pain episodes reported by the subject) in the subject relative to a subject prior to administration or relative to a subject who has not received administration. In some embodiments, the administration reduces the number of abdominal pain episodes (e.g., abdominal pain episodes reported by the subject) by 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, or more over a period of time (e.g., 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, or longer).

[0185] In some embodiments, subjects with CD may experience fatigue (i.e., feelings of tiredness, exhaustion, lethargy, or lack of energy that do not disappear with a normal amount of rest or sleep). In some embodiments, subjects with CD experience physical fatigue (e.g., low energy or strength, or a feeling of heaviness). In some embodiments, subjects with CD experience mental fatigue (e.g., low motivation, attention, or alertness). In some embodiments, subjects with CD experience both physical and mental fatigue. In some embodiments, subjects with active CD experience CD-related fatigue (i.e., episodes). In some embodiments, subjects who have previously undergone surgical treatment for CD are more likely to experience fatigue (i.e., are more likely to experience fatigue compared to CD subjects who have not undergone surgery). In some embodiments, female CD subjects are more likely to experience fatigue than male CD subjects. In some embodiments, CD subjects who also have depression or anxiety are more likely to experience fatigue than CD subjects who do not have depression or anxiety. In some embodiments, CD subjects with one or more parenteral manifestations are more likely to experience fatigue than subjects without parenteral manifestations. In some embodiments, subjects in remission of CD experience CD-related fatigue. In some implementations, fatigue can be assessed using the Inflammatory Bowel Disease-Fatigue (IBD-F) Patient Self-Assessment Scale (see, e.g., Varbobitis et al., The IBD-F Patient Self-Assessment Scale Accurately Depicts the Level of Fatigue and Predicts a Negative Effect on the Quality of Life of Patients With IBD in Clinical Remission, Inflamm Bowel Dis. 2021 May 17;27(6):826-835), the contents of which are incorporated herein by reference. The IBD-F Patient Self-Assessment Scale is a scoring system consisting of two parts of questions for the subject. Scoring 1 is a fatigue assessment scale consisting of five questions that measure the severity of fatigue on a scoring range of 0-20. If the subject scores 1 or higher on Scoring 1, the subject should proceed to answer the questions on Scoring 2. Part 2 of the IBD Fatigue Rating Scale is the IBD-Impact on Daily Activities Scale, which consists of 30 questions and measures the impact of fatigue on quality of life (QoL), with a score range of 0-120. In some implementations, a score greater than 7.5 indicates significant fatigue (e.g., clinically significant fatigue).In some implementations, the scores 1 of the IBD-F Patient Self-Assessment Scale for subjects with CD and fatigue fall within the following ranges: 7.5 to 20, 7.5 to 19, 7.5 to 18, 7.5 to 17, 7.5 to 16, 7.5 to 15, 7.5 to 14, 7.5 to 13, 7.5 to 12, 7.5 to 11, 7.5 to 10, 7.5 to 9, 7.5 to 8, 8 to 20, 8 to 1 9, 8 to 18, 8 to 17, 8 to 16, 8 to 15, 8 to 14, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 20, 9 to 19, 9 to 18, 9 to 17, 9 to 16, 9 to 15, 9 to 14, 9 to 13, 9 to 12, 9 to 11, 9 to 10, 10 to 20, 10 to 19, 10 to 18, 10 to 17, 10 to 16, 10 to 15, 10 to 1 4, 10 to 13, 10 to 12, 10 to 11, 11 to 20, 11 to 19, 11 to 18, 11 to 17, 11 to 16, 11 to 15, 11 to 14, 11 to 13, 11 to 12, 12 to 20, 12 to 19, 12 to 18, 12 to 17, 12 to 16, 12 to 15, 12 to 14, 12 to 13, 13 to 20, 13 to 19, 13 to 18, 13 to 17 13 to 16, 13 to 15, 13 to 14, 14 to 20, 14 to 19, 14 to 18, 14 to 17, 14 to 16, 14 to 15, 15 to 20, 15 to 19, 15 to 18, 15 to 17, 15 to 16, 16 to 20, 16 to 19, 16 to 18, 16 to 17, 17 to 20, 17 to 19, 17 to 18, 18 to 20, 18 to 19, or 19 to 20. In some implementations, subjects with CD who also experience fatigue experience an impact on their quality of life (QoL).In some implementations, the scores2 of the IBD-F Patient Self-Assessment Scale for subjects with CD and fatigue fall within the following ranges: 0-120, 5-120, 10-120, 20-120, 30-120, 40-120, 50-120, 60-120, 70-120, 80-120, 90-120, 100-120, 110-120, 0-110, 5-110, 1 0-110, 20-110, 30-110, 40-110, 50-110, 60-110, 70-110, 80-110, 90-110, 100-110, 0-100, 5-100, 10-100, 20-100, 30-100, 40-100, 50-100, 60-100, 70-100, 80-100, 90-100, 0-90, 5- 90, 10-90, 20-90, 30-90, 40-90, 50-90, 60-90, 70-90, 80-90, 0-80, 5-80, 10-80, 20-80, 30-80, 40-80, 50-80, 60-80, 70-80, 0-70, 5-70, 10-70, 20-70, 30-70, 40-70, 50-70, 60-70, 0-6 0, 5-60, 10-60, 20-60, 30-60, 40-60, 50-60, 0-50, 5-50, 10-50, 20-50, 30-50, 40-50, 0-40, 5-40, 10-40, 20-40, 30-40, 0-30, 5-30, 10-30, 20-30, 0-20, 5-20, 10-20, 0-10, 5-10, or 0-5. In some implementations, the application reduces fatigue in subjects relative to those before application or relative to those who did not receive the application. In some implementations, the application reduces fatigue in subjects based on the IBD-F Patient Self-Assessment Scale, relative to those before application or relative to those who did not receive the application. In some implementations, the application reduces the subject's IBD-F Patient Self-Assessment Scale score by at least 0.5, 1, 2, 2.5, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 20 points compared to the subject before application or compared to the subject who did not receive the application.In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration reduced the subject's IBD-F Patient Self-Assessment Scale score by the following ranges: 1-2, 1-5, 1-10, 1-15, 1-20, 2-5, 2-8, 2-10, 2-12, 2-15, 2-20, 5-8, 5-10, 5-12. 5-15 points, 5-18 points, 5-20 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 12-15 points, 12-15 points, 12-18 points, 12-20 points, 15-18 points, 15-20 points, 16-18 points, 16-20 points, or 18-20 points. In some implementations, the application reduces a subject's IBD-F Patient Self-Assessment Scale score by at least 1, at least 5, at least 10, at least 15, at least 25, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, or at least 120 points compared to the subject before the application or compared to the subject who did not receive the application.In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration reduced the subject's IBD-F Patient Self-Assessment Scale score by the following ranges: 1-120, 1-110, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 5-120, 5-110, 5-100, 5-90, 5-80, 5 -70 points, 5-60 points, 5-50 points, 5-40 points, 5-30 points, 5-20 points, 5-10 points, 10-120 points, 10-110 points, 10-100 points, 10-90 points, 10-80 points, 10-70 points, 10- 60 points, 10-50 points, 10-40 points, 10-30 points, 10-20 points, 20-120 points, 20-110 points, 20-100 points, 20-90 points, 20-80 points, 20-70 points, 20-60 points, 20-50 points , 20-40 points, 20-30 points, 30-120 points, 30-110 points, 30-100 points, 30-90 points, 30-80 points, 30-70 points, 30-60 points, 30-50 points, 30-40 points, 40-120 points, 40-110 points, 40-100 points, 40-90 points, 40-80 points, 40-70 points, 40-60 points, 40-50 points, 50-120 points, 50-110 points, 50-100 points, 50-90 points, 50-80 points, 5 0-70 points, 50-60 points, 60-120 points, 60-110 points, 60-100 points, 60-90 points, 60-80 points, 60-70 points, 70-120 points, 70-110 points, 70-100 points, 70-90 points, 70-80 points, 80-120 points, 80-110 points, 80-100 points, 80-90 points, 90-120 points, 90-110 points, 90-100 points, 100-120 points, 100-110 points, or 110-120 points.

[0186] In some implementations, fatigue can be assessed using: the Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT-F) scale (see, e.g., Tinsley, A., Macklin, EA, Korzenik, JR, & Sands, BE (2011). Validation of the Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F) in patients with inflammatory boweldisease. Alimentary pharmacology & therapeutics, 34(11-12), 1328-1336; and facit.org / measures / facit-f) and / or the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale (see, e.g., Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Seminars in Hematology. 1997). Jul;34(3 Supplement 2):13-19; and facit.org / measures / fact-an). The FACIT-F scale contains 40 questions across five health categories: physical health (7 questions), social health (7 questions), emotional health (6 questions), functional health (7 questions), and fatigue (13 questions). The FACT-An scale includes the questions from the FACIT-F scale plus seven additional questions related to anemia. For both assessments, patients provide a score of 0-4 (inclusive) for each item. For each category, the individual items are summed, multiplied by the number of items presented, and divided by the number of items answered to calculate the category score; for example, the fatigue category score for either FACIT-F or FACT-An could be 0-52. The category scores are then summed to arrive at a total score, ranging from 0-160 for FACIT-F or 0-188 for FACT-An. Higher scores within these ranges indicate better quality of life (QoL).Typically, healthy individuals have a FACIT-F fatigue category score of 40 or higher (e.g., Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States population. Cancer. 2002;94(2):528–38). In some implementations, a score of less than approximately 40 in the fatigue category of the FACIT-F scale indicates significant fatigue (e.g., clinically significant fatigue). In some implementations, the FACIT-F fatigue category score of subjects with CD and accompanying fatigue falls within the following ranges: 0-40, 0-39, 0-38, 0-37, 0-36, 0-35, 0-34, 0-33, 0-32, 0-31, 0-30, 0-29, 0-28, 0-27, 0-26, 0-25, 0-24, 0-23, 0-22, 0-21, 0-20, 0-19, 0-18, 0-17, 0-16, 0-15, 0-14, 0-13, 0-12, 0-11, 0-10, 0-9, 0-8, 9-7, 0-6, or 0-5. In some implementations, the application reduces the subject's fatigue based on the FACIT-F scale, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application improves the subject's FACIT-F fatigue category score by at least 0.5 points, at least 1 point, at least 2 points, at least 2.5 points, at least 3 points, at least 4 points, at least 5 points, at least 7 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, or at least 20 points, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application improves the subject's FACIT-F fatigue category score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 5-8 points, 5-10 points, 5-12 points, 5... -15 points, 5-18 points, 5-20 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 12-15 points, 12-15 points, 12-18 points, 12-20 points, 15-18 points, 15-20 points, 16-18 points, 16-20 points, or 18-20 points.

[0187] In some implementations, administration improves the patient's quality of life (QoL). In some implementations, QoL is assessed using the Patient General Impression Change (PGI-C) self-assessment (see: Hurst, Hugh, and Jennifer Bolton. "Assessing the clinical significance of change scores recorded on subjective outcome measures." Journal of manipulative and physiologicaltherapeutics 27.1 (2004): 26-35.). The PGI-C self-assessment includes questions related to changes in symptoms since the start of treatment, scored on a numerical scale of 1-7. Patients scoring 6-7 on the PGI-C scale are considered to have experienced clinically significant improvement in their condition. In some implementations, the QoL of administration-improved subjects is compared to those who did not receive administration. In some implementations, subjects with UC who received administration reported PGI-C scores of 5, 6, or 7.

[0188] In some implementations, QoL is assessed using the Short Form for Medical Outcomes Study 36 (SF-36) (see, for example: Garratt AM, Schmidt L, Mackintosh A, Fitzpatrick R. Quality of life measurement: bibliographic study of patient assessed health outcome measures. Brit Med J. 2002;324:1417–9; Contopoulos-Ioannidis DG, Karvouni A, Kouri I, Ioannidis JPA. SF-36 outcomes in randomized trials: a systematic review. Brit Med J. 2009;338:a3006). The SF-36 consists of eight subscales: 1) physical functioning; 2) role limitation due to physical problems; 3) overall perceived health; 4) vitality; 5) social functioning; 6) role limitation due to emotional problems; 7) overall mental health; and 8) health transformation. The items in each subscale are summed, multiplied by 10, and then added to 50 to linearly transform each value to fit a scale range from 0 (negative health) to 100 (positive health), where 50 represents the mean; the transformed value is the corresponding score for each subscale. Some subscale scores may be assessed together based on factor analysis to generate a physical health overall score (“PCS”) or a mental health overall score (“MCS”) (e.g., Ware JE, Kosinski M, Bayliss MS, McHorney C, Rogers WH, Raczek A. Comparison of methods for scoring and statistical analysis of the SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care. 1995;33:AS264–79.). In some implementations, the administration reduces the fatigue of the subject relative to the subject before administration or relative to the subject who did not receive administration. In some implementations, the application reduces fatigue based on the IBD-F Patient Self-Assessment Scale relative to the subject before application or relative to the subject who did not receive the application.In some implementations, the application improves the subject's SF-36 subscale score by at least 1, at least 2, at least 3, 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, at least 27, at least 28, at least 29, or at least 30 points compared to the subject before application or compared to the subject who did not receive the application. In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration improved the SF-36 subscale score of subjects by the following ranges: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 1-25 points, 1-30 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 2-25 points, 2-30 points, 5-8 points, 5-10 points, 5-12 points, 5-15 points, 5-18 points, 5-20 points, 5-25 points. 5-30 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 8-25 points, 5-30 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 10-25 points, 10-30 points, 12-15 points, 12-18 points, 12-20 points, 12-25 points, 12-30 points, 15-18 points, 15-20 points, 15-25 points, 15-30 points, 20-25 points, 20-30 points, or 25-30 points. In some implementations, the application improves the subject's SF-36 PCS score by at least 1, at least 2, at least 3, 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, at least 27, at least 28, at least 29, or at least 30 points, relative to the subject before application or relative to the subject who did not receive the application.In some implementations, the application improves the subject's SF-36 PCS score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 1-25 points, 1-30 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 2-25 points, 2-30 points, 5-8 points, 5-10 points, 5-12 points, 5-15 points, 5-18 points, 5-20 points, 5-25 points. 5-30 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 8-25 points, 5-30 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 10-25 points, 10-30 points, 12-15 points, 12-18 points, 12-20 points, 12-25 points, 12-30 points, 15-18 points, 15-20 points, 15-25 points, 15-30 points, 20-25 points, 20-30 points, or 25-30 points. In some implementations, the application improves the subject's SF-36 MCS score by at least 1, at least 2, at least 3, 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, at least 27, at least 28, at least 29, or at least 30 points, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application improves the subject's SF-36 MCS score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-2 points, 1-5 points, 1-10 points, 1-15 points, 1-20 points, 1-25 points, 1-30 points, 2-5 points, 2-8 points, 2-10 points, 2-12 points, 2-15 points, 2-20 points, 2-25 points, 2-30 points, 5-8 points, 5-10 points, 5-12 points, 5-15 points, 5-18 points, 5-20 points, 5-25 points. 5-30 points, 8-10 points, 8-12 points, 8-15 points, 8-18 points, 8-20 points, 8-25 points, 5-30 points, 10-12 points, 10-15 points, 10-18 points, 10-20 points, 10-25 points, 10-30 points, 12-15 points, 12-18 points, 12-20 points, 12-25 points, 12-30 points, 15-18 points, 15-20 points, 15-25 points, 15-30 points, 20-25 points, 20-30 points, or 25-30 points.

[0189] In some implementations, the application reduces the number of diarrhea episodes by one or more (e.g., one, two, three, four, five, six, one week, two weeks, three weeks, one month, or more) over a period of time relative to the subject before the application or relative to the subject who did not receive the application.

[0190] In some implementations, the application reduces the subject's weight loss by at least 1%, at least 5%, 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 90%, or 100% relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application reduces the subject's weight loss by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, compared to the subject before application or compared to the subject who did not receive the application. 0%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%.

[0191] In some embodiments, Crohn's disease can be classified according to the affected GI tract region. For example, in some embodiments, CD may affect the ileum (e.g., terminal ileum). In some embodiments, CD may affect the colon. In some embodiments, CD may affect the ileocolic region. In some embodiments, CD may affect the upper GI region. In some embodiments, the subject has gastroduodenal Crohn's disease affecting the stomach and duodenum. In some embodiments, the subject has jejunoileitis, resulting in patchy inflammatory plaques in the jejunum. In some embodiments, CD may affect a portion of the digestive tract from the mouth to the anus in the subject. In some embodiments, the methods provided herein reduce the extent of the intestine affected by CD, the method comprising administering an effective amount of anti-HJV antibody to the subject. In some embodiments, the administration reduces the type of intestine affected by CD (e.g., prior to treatment, the subject had CD in both the ileum and colon, and the administration reduces the affected intestinal segment to only the ileum). In some embodiments, the administration inhibits the progression of CD (e.g., pathological progression). In some embodiments, the administration inhibits the pathological progression of CD by reducing the affected area of ​​the intestine. In some implementations, the application reduces the affected intestinal area by at least 1%, at least 5%, 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 90%, or 100% relative to the affected area before application.In some implementations, relative to subjects before application or relative to subjects not treated, the application reduces the affected intestinal area by 1% to 100%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 10% to 15%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, respectively. 0%, 20% to 40%, 20% to 30%, 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100%. The intestinal region affected by CD can be measured by any suitable method, such as endoscopy, MRI, or CT scan.

[0192] In some implementations, Crohn's disease can also be classified according to its behavior during disease progression, which is standardized in the Vienna Classification of Diseases (see Gasche et al., A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998, Inflammatory Bowel Diseases. 6 (1): 8–15)). According to this classification, Crohn's disease has three disease manifestation categories: non-stenotic / non-penetrating, stenotic, and penetrating. Stenotic Crohn's disease causes narrowing of the intestine, which can lead to intestinal obstruction or changes in stool diameter. Penetrating Crohn's disease forms an abnormal channel (fistula) between the intestine and other structures, such as the skin. Non-stenotic / non-penetrating Crohn's disease causes inflammation without producing stenosis or fistulas. In some implementations, individuals with Crohn's disease are at risk of developing one or more fistulas or already have one or more fistulas.

[0193] In some embodiments, the subject has fistula-type CD. In some embodiments, the subject with CD has one or more fistulas. A fistula is a chronic granulation tissue channel between two epithelial lining surfaces. In some embodiments, chronic transmural inflammation of the intestinal wall in CD can lead to the formation of sinus tracts, which, once penetrating the serosa, can result in a fistula (an abnormal communication between two epithelialized surfaces). In some embodiments, the subject with CD has one or more internal fistulas. As used herein, an internal fistula refers to a fistula that originates internally. An internal fistula that forms internal communication with another intestinal layer is an enteroentericfistula. An internal fistula that forms communication between the intestine and other organs is an intestinal-skin fistula or enterovesophageal fistula. In some embodiments, the subject has a discharge-type intestinal-skin fistula (e.g., contents drain from the fistula upon gentle pressure). In some embodiments, the subject has one or more enteroenteric fistulas or enterovesophageal fistulas. In some embodiments, the subject with CD has one or more perianal fistulas. A perianal fistula is an abnormal connection between a portion of the intestine and the skin of the anus, rectum, and / or buttocks. In some embodiments, a subject with Crohn's disease (CD) has one or more perianal fistulas and one or more internal fistulas. (McGregor et al., Pathogenesis of Fistulating Crohn's Disease: A Review, Cellular and Molecular Gastroenterology and Hepatology, Vol. 15, No. 1, 2023, pp. 1-11). In some embodiments, this disclosure provides a method for reducing fistulas in a subject with CD, the method comprising administering an effective amount of anti-HJV antibody to the subject. In some embodiments, the administration inhibits the pathological progression of CD by reducing fistulas in a subject with CD. In some embodiments, the administration achieves fistula closure in a subject with CD. In some embodiments, the administration reduces the number of internal fistulas (e.g., discharge fistulas) by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more, relative to the number of internal fistulas in the subject before administration or the number of internal fistulas in a subject that has not received administration.In some implementations, the application reduces the number of fistulas (e.g., discharge-related enterocutaneous fistulas) by the following ranges relative to the number of fistulas in the subject before application or relative to the number of fistulas in the subject who did not receive the application: 1-20, 1-18, 1-15, 1-12, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-2, 2-20, 2-18, 2-15, 2-12, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-20, 3-18, 3-15, 3-12, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-20, 4-18, 4-15, 4-12, 4-10, 4-9. 4-8, 4-7, 4-6, 4-5, 5-20, 5-18, 5-15, 5-12, 5-10, 5-9, 5-8, 5-7, 5-6, 6-20, 6-18, 6-15, 6-12, 6-10, 6-9, 6-8, 6-7, 7-20, 7-18, 7-15, 7-12, 7-10, 7-9, 7 -8, 8-20, 8-18, 8-15, 8-12, 8-10, 8-9, 9-20, 9-18, 9-15, 9-12, 9-10, 10-20, 10-18, 10-15, 10-12, 12-20, 12-18, 12-15, 15-18, 15-20, 18-20, or 20-50. In some embodiments, the application reduces the number of fistulas (e.g., discharge-related enterocutaneous fistulas) 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 90%, or 100% relative to the number of fistulas in the subject before application or relative to the number of fistulas in the subject who did not receive the application.In some implementations, the application reduces the number of fistulas (e.g., discharge-related enterocutaneous fistulas) by the following ranges relative to the number of fistulas in the subject before application or relative to the number of fistulas in the subject who did not receive the application: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%. 20%-50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%. In some embodiments, the drug is applied to the subject to induce a fistula response. Fistula response is defined as a reduction of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% in the discharge-related enterocutaneous fistula in a CD subject during at least two consecutive clinical visits, without the need for additional medication or surgery.

[0194] In some implementations, the application reduces the number of perianal fistulas by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more, relative to the number of perianal fistulas in the subject before application or relative to the number of perianal fistulas in the subject who has not received the application. In some implementations, the application reduces the number of perianal fistulas relative to the number of fistulas in the subject before application or relative to the number of perianal fistulas in the subject who did not receive the application by the following ranges: 1-20, 1-18, 1-15, 1-12, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-2, 2-20, 2-18, 2-15, 2-12, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-20, 3-18, 3-15, 3-12, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-20, 4-18, 4-15, 4-12, 4-10, 4-9. 4-8, 4-7, 4-6, 4-5, 5-20, 5-18, 5-15, 5-12, 5-10, 5-9, 5-8, 5-7, 5-6, 6-20, 6-18, 6-15, 6-12, 6-10, 6-9, 6-8, 6-7, 7-20, 7-18, 7-15, 7-12, 7-10, 7-9, 7 -8, 8-20, 8-18, 8-15, 8-12, 8-10, 8-9, 9-20, 9-18, 9-15, 9-12, 9-10, 10-20, 10-18, 10-15, 10-12, 12-20, 12-18, 12-15, 15-18, 15-20, 18-20, or 20-50. In some embodiments, the application reduces perianal fistulas 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 90%, or 100% relative to the number of perianal fistulas in the subject before application or relative to the number of perianal fistulas in the subject who did not receive the application.In some implementations, the application reduces the number of perianal fistulas relative to the number of fistulas in the subject before application or relative to the number of fistulas in the subject who did not receive the application, by the following ranges: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%. -50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%.

[0195] In some embodiments, the subject with CD has both internal fistulas and perianal fistulas. In some embodiments, the application reduces the total number of fistulas (e.g., combinations of internal and perianal fistulas) by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more, relative to the total number of fistulas in the subject before application (e.g., combinations of internal and perianal fistulas) or relative to the total number of fistulas in the subject who did not receive application (e.g., combinations of internal and perianal fistulas). In some implementations, application reduces the total number of fistulas (e.g., combinations of internal and perianal fistulas) by the following ranges relative to the total number of fistulas in the subject before application (e.g., combinations of internal and perianal fistulas) or relative to the total number of fistulas in the subject who did not receive application (e.g., combinations of internal and perianal fistulas): 1-20, 1-18, 1-15, 1-12, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-2, 2-20, 2-18, 2-15, 2-12, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-20, 3-18, 3-15, 3-12, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-20, 4-18. 4-15, 4-12, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-20, 5-18, 5-15, 5-12, 5-10, 5-9, 5-8, 5-7, 5-6, 6-20, 6-18, 6-15, 6-12, 6-10, 6-9, 6-8, 6-7, 7-20, 7-18, 7-15, 7-12 7-10, 7-9, 7-8, 8-20, 8-18, 8-15, 8-12, 8-10, 8-9, 9-20, 9-18, 9-15, 9-12, 9-10, 10-20, 10-18, 10-15, 10-12, 12-20, 12-18, 12-15, 15-18, 15-20, 18-20, or 20-50. In some embodiments, the application reduces the total number of fistulas (e.g., combinations of internal and perianal fistulas) 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 90%, or 100% relative to the total number of fistulas in the subject before application (e.g., combinations of internal and perianal fistulas) or relative to the total number of fistulas in the subject who did not receive the application (e.g., combinations of internal and perianal fistulas).In some implementations, the application reduces the total number of fistulas (e.g., combinations of internal fistulas and perianal fistulas) relative to the total number of fistulas in the subject before application (e.g., combinations of internal fistulas and perianal fistulas) or relative to the total number of fistulas in the subject who did not receive the application (e.g., combinations of internal fistulas and perianal fistulas) within the following ranges: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%- 80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%.

[0196] In some embodiments, subjects with CD are at risk of developing or already have intestinal stricture. Intestinal stricture is characterized by thickening of all layers of the intestinal wall and narrowing of the intestinal lumen. In some embodiments, subjects with CD-related intestinal stricture experience intestinal obstruction. In some embodiments, subjects with CD-related intestinal stricture become resistant to CD treatment (e.g., biotherapy). In some embodiments, this disclosure provides a method for treating CD-related intestinal stricture in a subject, the method comprising administering an effective amount of an anti-HJV antibody to the subject. In some embodiments, the administration reduces the intestinal wall thickness at the site of stricture 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 90%, or 100% relative to the intestinal wall thickness at the site of stricture in the subject before administration or relative to the intestinal wall thickness at the site of stricture in a subject who has not received administration. In some implementations, relative to the intestinal wall thickness at the site of intestinal stricture in subjects before application or relative to the intestinal wall thickness at the site of intestinal stricture in subjects who have not received application, the application reduces the intestinal wall thickness at the site of intestinal stricture by the following ranges: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 2 0%-60%, 20%-50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%. In some implementations, the application reduces the number of intestinal stenosis 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 90%, or 100% relative to the number of intestinal stenosis in the subject before application or relative to the number of intestinal stenosis in the subject who did not receive the application.In some implementations, the application reduces the number of intestinal strictures by the following ranges relative to the number of strictures in the subject before application or relative to the number of strictures in the subject who did not receive the application: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 2 0%-50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%. In some implementations, the application inhibits the occurrence and / or progression of CD-related intestinal stricture 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 90%, or 100% relative to subjects before or without the application.In some implementations, relative to subjects before administration or relative to subjects who did not receive administration, administration inhibits the occurrence and / or progression of CD-related intestinal strictures within the following ranges: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-20%. %-50%, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%. In some implementations, CD can be classified based on disease severity using the Crohn's Disease Activity Index (CDAI). The CDAI is scored on a scale of 0 to 600 based on patient-reported stool form, average abdominal pain grade over seven days, overall health status daily over seven days, complications (e.g., arthralgia or established arthritis, iritis or uveitis, erythema nodosum, pyoderma gangrenosa, aphthous ulcers, anal fissures, fistulas or abscesses, other fistulas, and / or fever) during the previous week, abdominal masses, and anemia and weight changes (Chen et al., Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases, Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications, 2018, pp. 1-15). In some implementations, subjects with a CDAI score less than 150 are in remission of CD. In some implementations, subjects in remission are asymptomatic. In some implementation schemes, individuals in remission do not have any asymptomatic post-inflammatory sequelae.

[0197] In some embodiments, subjects with a CDAI score ranging from 150 to 220 have mild to moderate CD. In some embodiments, subjects with mild CD are ambulatory. In some embodiments, subjects with mild CD tolerate oral nutrition without one or more of the following: dehydration, systemic toxicity, abdominal tenderness, painful mass, intestinal obstruction, or weight loss exceeding 10%. In some embodiments, this disclosure provides for the treatment of mild to moderate CD (e.g., treatment of CDAI scores in the range of 150-220, 150-210, 150-200, 150-190, 150-180, 150-170, 150-160, 160-220, 160-210, 160-200, 160-190, 160-180, 160-170, 170). A method for administering an effective amount of anti-HJV antibody to a subject (subjects within the range of -220, 170-210, 170-200, 170-190, 170-180, 180-220, 180-210, 180-200, 180-190, 190-220, 190-210, 190-200, 200-210, 200-220, or 210-220). In some embodiments, the administration induces remission in subjects with mild to moderate CD and reduces their CDAI score to below 150. In some implementations, the application reduces the CDAI score of a subject with CD 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 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, at least 200, at least 210, or at least 220, relative to the subject before application or relative to the subject who did not receive the application. In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration reduced the CDAI score of subjects with CD by the following ranges: 10-220, 10-210, 10-200, 10-190, 10-180, 10-170, 10-160, 10-150, 10-140, 10-130, 10-120, 10-110, 10-100, 10-90, 10-80, 10-70, 10 -60, 10-50, 10-40, 10-30, 10-20, 20-220, 20-220, 20-200, 20-190, 20-180, 20-170, 20-160, 20-150, 20-140, 20-130, 20-120, 20-110, 20-100, 20-90, 20-80, 20-70, 20-60, 20-50, 20-40, 20-30, 30-22030-210、30-200、30-190、30-180、30-170、30-160、30-150、30-140、30-130、30-120、30-110、30-100、30-90、30-80、30-70、30-60、30-50、30-40、40-220、40-210、40-200、40-190、40-180、40-170、40-160、40-150、40-140、40-130、40-120、40-110、40-100、40-90、40-80、40-70、40-60、40-50、50-220、50-210、50-200、50-190、50-180、50-170、50-160、50-150、50-140、50-130、50-120、50-110、50-100、50-90、50-80、50-70、50-60、60-220、60-210、60-200、60-190、60-180、60-170、60-160、60-150、60-140、60-130、60-120、60-110、60-100、60-90、60-80、60-70、70-220、70-210、70-200、70-190、70-180、70-170、70-160、70-150、70-140、70-130、70-120、70-110、70-100、70-90、70-80、80-220、80-210、80-200、80-190、80-180、80-170、80-160、80-150、80-140、80-130、80-120、80-110、80-100、80-90、90-220、90-210、90-200、90-190、90-180、90-170、90-160、90-150、90-140、90-130、90-120、90-110、90-100、100-220、100-210、100-200、100-190、100-180、100-170、100-160、100-150、100-140、100-130、100-120、100-110、110-220、110-210、110-200、110-190、110-180、110-170、110-160、110-150、110-140、110-130、110-120、120-220、120-210、120-200、120-190、120-180、120-170、120-160、120-150, 120-140, 120-130, 130-220, 130-210, 130-200, 130-190, 130-180, 130-170, 130-160, 130-150, 130-140, 140-220, 140-210, 140-200, 140-190, 140-180, 140-170, 140-160, 140-150, 150-220, 150-210, 150-200, 150-190 150-180, 150-170, 150-160, 160-220, 160-210, 160-200, 160-190, 160-180, 160-170, 170-220, 170-210, 170-200, 170-190, 170-180, 180-220, 180-210, 180-200, 180-190, 190-220, 190-210, 190-200, 200-210, 200-220, or 210-220. In some implementations, subjects with a CDAI score in the range of 220 to 450 have moderate to severe CD. In some implementations, subjects with moderate to severe CD do not respond to treatments for mild to moderate disease. In some embodiments, subjects with moderate to severe CD have fever. In some embodiments, subjects with moderate to severe CD have significant weight loss. In some embodiments, subjects with moderate to severe CD have abdominal pain or tenderness. In some embodiments, subjects with moderate to severe CD have intermittent nausea or vomiting. In some embodiments, subjects with moderate to severe CD have significant anemia. In some embodiments, this disclosure provides a treatment for moderate to severe CD (e.g., treatment for CDAI scores of 220-450, 220-440, 220-430, 220-420, 220-410, 220-400, 220-380, 220-370, 220-360, 220-350, 220-340, 220-330, 220-320, 220-310, 220-300, 220-290, 220-280, 220-270, 220-260, 220-250, 220-240).A method for administering a therapeutically effective amount of anti-HJV antibody to a subject (subjects in the range of 220-230). In some embodiments, the administration reduces the severity of CD in the subject from moderate to severe CD to mild to moderate CD (e.g., reducing the CDAI score from the range of 220-450 to the range of 150-220). In some embodiments, the administration induces remission in subjects with moderate to severe CD and reduces the CDAI score to below 150. In some embodiments, the administration reduces the CDAI score of subjects with CD 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 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, or at least 20% relative to subjects prior to administration or relative to subjects who did not receive administration. 00, at least 210, at least 220, at least 220, at least 230, at least 240, at least 250, at least 260, at least 270, at least 280, at least 290, at least 300, at least 310, at least 320, at least 330, at least 340, at least 350, at least 360, at least 370, at least 380, at least 390, at least 400, at least 410, at least 420, at least 430, at least 440, or at least 450. In some implementations, compared to subjects before application or compared to subjects who did not receive application, application reduces the CDAI score of subjects with CD by the following ranges: 10-450, 10-400, 10-350, 10-300, 10-250, 10-200, 10-150, 10-100, 10-50, 10-20, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-100, 70-450, 70-400, 70-350, 70-300, 70-250, 70-200, 70-150, 70-100, 100-450, 100-400, 100-350. 0, 100-300, 100-250, 100-200, 100-150, 100-120, 150-450, 150-400, 150-350, 150-300, 150-250, 150-200, 150-180, 180-450, 180-400, 180-350, 180-300 180-250, 180-200, 200-450, 200-400, 200-350, 200-300, 200-250, 250-450, 250-400, 250-350, 250-300, 300-450, 300-400, 300-350, 350-450, 350-400Or 400-450.

[0198] In some implementations, subjects with a CDAI score greater than 450 have severe CD. In some implementations, subjects with severe CD have a CDAI score in the range of 450-1100 (e.g., 450-1100, 500-1100, 600-1100, 700-1100, 800-1100, 900-1100, 1000-1100). In some implementations, subjects with severe CD have persistent symptoms despite the introduction of standard treatments (e.g., 5-ASA, corticosteroids, immunomodulators, and / or biologics). In some implementations, subjects with severe CD have high fever. In some implementations, subjects with severe CD have persistent vomiting. In some implementations, subjects with severe CD have intestinal obstruction. In some implementations, subjects with severe CD have peritoneal signs, such as involuntary protective or rebound tenderness, cachexia, or abscess. (Entyvio (Vedolizumab) Common Drug Review, Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Dec). In some embodiments, administration reduces the severity of CD in subjects from severe CD to mild to moderate CD (e.g., reducing CDAI scores from a range greater than 450 to a range of 150–220). In some embodiments, administration reduces the severity of CD in subjects from severe CD to moderate to severe CD (e.g., reducing CDAI scores from a range greater than 450 to a range of 220–450). In some embodiments, administration induces remission in subjects with severe CD and reduces CDAI scores to below 150. In some implementations, the application reduces the CDAI score of a subject with CD by at least 10, at least 50, at least 70, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 650, at least 700, at least 750, at least 800, at least 850, at least 900, at least 950, at least 1000, or at least 1100, relative to the subject before application or relative to the subject who did not receive the application.In some implementations, compared to subjects before administration or compared to subjects who did not receive administration, administration reduced the CDAI score of subjects with CD by the following ranges: 10-1100, 10-1000, 10-900, 10-800, 10-700, 10-600, 10-500, 10-400, 10-300, 10-200, 10-100, 10-50, 50-1100, 50-1000, 50-900, 50-800. 50-700, 50-600, 50-500, 50-400, 50-300, 50-200, 50-100, 100-1100, 100-1000, 100-900, 100-800, 100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1100, 200-1000, 200-900, 200-800, 200- 700, 200-600, 200-500, 200-400, 200-300, 300-1100, 300-1000, 300-900, 300-800, 300-700, 300-600, 300-500, 300-400, 400-1100, 400-1000, 400-900, 400-800, 400-700, 400-600, 400-500, 500-1100, 5 00-1000, 500-900, 500-800, 500-700, 500-600, 600-1100, 600-1000, 600-900, 600-800, 600-700, 700-1100, 700-1000, 700-900, 700-800, 800-1100, 800-1000, 800-900, 900-1100, 900-1000, or 1000-1100. In some implementations, CD can be classified by the Harvey-Bradshaw index (HBI) (Elliott et al., (1980). Simple index of Crohn's disease activity. Lancet. 1 (8173): 876).The Harvey Bradshaw Index (HBI) categorizes CD solely by clinical parameters, including general health status (0 = very good, 1 = slightly below average, 2 = poor, 3 = very poor, 4 = extremely poor), abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe), frequency of loose stools per day, abdominal mass (0 = none, 1 = suspicious, 2 = definite, 3 = tenderness), and complications (e.g., joint pain (arthritis), iritis, uveitis, erythema nodosum, pyoderma gangrenosa, aphthous ulcer, anal fissure, fistula or abscess, other fistulas, and / or fever) during the previous week, each item being scored as one point. In some implementations, subjects with an HBI score less than 5 are in CD remission. In some implementations, subjects with an HBI score in the range of 5–7 have mild CD. In some implementations, subjects with an HBI score in the range of 8–16 have moderate CD. In some implementations, subjects with an HBI score greater than 16 have severe CD (Baumgart et al., Inflammatory boweldisease: clinical aspects and established and evolving therapies, Lancet. 2007 May 12;369(9573):1641-57). In some implementations, based on the HBI, CD severity is reduced from severe CD to a lower severity level (e.g., mild CD, moderate CD, or remission). In some implementations, based on the HBI, CD severity is reduced from moderate CD to a lower severity level (e.g., mild CD or remission). In some implementations, based on the HBI, CD severity is reduced from mild CD to a lower severity level (e.g., remission). In some implementations, the application reduces the HBI score by at least 1, at least 2, at least 3, 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, or at least 20 points relative to the subject before application or relative to the subject who did not receive the application.In some implementations, the application reduces the HBI score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-20, 1-18, 1-15, 1-12, 1-10, 1-8, 1-6, 1-5, 1-3, 1-2, 5-20, 5-18, 5-15, 5-12, 5-10, 5-10, 5-15, 5-20, 2-8, 2-6, 4-7, 4-10, 4-15, 3-5, 3-8, 3-12, 3-18, 10-20, 10-18, 10-15, 10-12, 15-18, 15-20, or 18-20.

[0199] In some embodiments, CD can be characterized and classified by endoscopic finding. In some embodiments, endoscopic finding of CD includes one or more of the following: a discontinuous distribution of longitudinal ulcers (i.e., ulcers ≥4 to 5 cm), a cobblestone appearance, and / or small aphthous ulcers arranged longitudinally (Lee et al., Endoscopic Diagnosis and Differentiation of Inflammatory Bowel Disease, Clin Endosc. 2016 Jul; 49(4): 370–375.). In some embodiments, this disclosure provides a method for improving the endoscopic appearance in subjects with CD, the method comprising administering an effective amount of anti-HJV antibody to the subject. In some embodiments, administration to subjects with CD induces mucosal healing (e.g., as measured by endoscopy). In some embodiments, application reduces the length of longitudinal ulcers by 1-10 cm, 2-10 cm, 5-10 cm, 8-10 cm, 1-8 cm, 3-8 cm, 5-8 cm, 7-8 cm, 1-7 cm, 2-7 cm, 4-7 cm, 6-7 cm, 6-9 cm, 6-8 cm, 6-10 cm, 7-9 cm, or 8-10 cm compared to the object before application or to the object that did not receive application. In some embodiments, application reduces the cobblestone appearance of the object compared to the object before application or to the object that did not receive application.In some implementations, the application reduces the number of small aphthous ulcers relative to the subject before application or relative to the subject who did not receive the application by the following ranges: 1%-100%, 5%-100%, 5%-90%, 5%-80%, 5%-70%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-20%, 5%-10%, 10%-100%, 10%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%. %, 20%-40%, 20%-30%, 30%-100%, 30%-90%, 30%-80%, 30%-70%, 30%-60%, 30%-50%, 30%-40%, 40%-100%, 40%-90%, 40%-80%, 40%-70%, 40%-60%, 40%-50%, 50%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-100%, 60%-90%, 60%-80%, 60%-70%, 70%-100%, 70%-90%, 70%-80%, 80%-100%, 80%-90%, or 90%-100%.

[0200] In some implementations, Crohn's disease (CD) can be characterized and classified using the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) (Daperno et al., Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD, Gastrointestinal Endoscopy, 01 Oct 2004, 60(4):505-512). In some implementations, SES-CD is scored based on the following endoscopic findings in intestinal segments (e.g., ileum, right / transverse / left colon, and rectum) of CD subjects: presence and size of ulcers (none = 0 points; diameter 0.1–0.5 cm = 1 point; 0.5–2 cm = 2 points; > 2 cm = 3 points); extent of ulcer surface (none = 0; <10% = 1; 10%–30% = 2; >30% = 3); extent of affected surface (none = 0; <50% = 1; 50%–75% = 2; >75% = 3); and presence and type of strictures (none = 0; single, passable = 1; multiple, passable = 2; impassable = 3). According to SES-CD, a higher SES-CD score indicates more severe disease. In some implementations, subjects with CD whose SES-CD score is in the range of 0–2 are in remission. In some implementations, subjects with SES-CD scores in the range of 3–6 have mild CD. In some implementations, subjects with an SES-CD score in the range of 7–15 have moderate CD. In some implementations, subjects with an SES-CD score greater than 16 have severe CD. (Koutroumpakis et al., Implementation of the Simple Endoscopic Activity Score in Crohn's Disease, Saudi J Gastroenterol. 2016 May-Jun; 22(3): 183–191). In some implementations, based on SES-CD, a CD that reduces CD severity from severe CD to a lower severity level (e.g., mild CD, moderate CD, or remission) is administered. In some implementations, based on SES-CD, a CD that reduces CD severity from moderate CD to a lower severity level (e.g., mild CD or remission) is administered. In some implementations, based on SES-CD, a CD that reduces CD severity from mild CD to a lower severity level (e.g., remission).In some implementations, the application reduces the SES-CD score by at least 1, at least 2, at least 3, 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, or at least 20 points relative to the subject before application or relative to the subject who did not receive the application. In some implementations, the application reduces the SES-CD score by the following ranges relative to the subject before application or relative to the subject who did not receive the application: 1-20, 1-18, 1-15, 1-12, 1-10, 1-8, 1-6, 1-5, 1-3, 1-2, 5-20, 5-18, 5-15, 5-12, 5-10, 5-10, 5-15, 5-20, 2-8, 2-6, 4-7, 4-10, 4-15, 3-5, 3-8, 3-12, 3-18, 10-20, 10-18, 10-15, 10-12, 15-18, 15-20, or 18-20.

[0201] Based on the teachings provided herein, it will be apparent to those skilled in the art that determining whether an antibody (e.g., an anti-HJV antibody) achieves its effect (e.g., a therapeutic effect) is appropriate. As will be appreciated by those skilled in the art, the effective amount varies depending on the specific condition being treated, the severity of the condition, individual patient parameters (including age, physical condition, body size, sex, and weight), duration of treatment, the nature of concurrent treatments (if any), the specific route of administration, and similar factors within the knowledge and professional skills of the healthcare practitioner. As discussed herein, the specific dosage regimen used in the methods described herein—i.e., the dosage, timing, and repetition—will depend on the specific subject and that subject's medical history.

[0202] Empirical considerations, such as the time to reach maximum effect, half-life, and / or time above a specific concentration, often aid in dosage determination. For example, antibodies compatible with the human immune system, such as humanized or fully human antibodies, can be used to prolong the antibody's half-life and prevent it from being attacked by the host immune system. Other reasons for dosage adjustments include differences in pharmacokinetic or pharmacodynamic responses driven by sex, age, individual response, antibody target, and / or receptor polymorphisms involved in antibody clearance. Dosage frequency can be determined and adjusted during treatment and is generally, but not necessarily, based on the treatment and / or inhibition and / or improvement and / or delay of the target disease / symptom. Alternatively, a sustained-release formulation of the antibody may be suitable. Various formulations and devices for achieving sustained release are known in the art.

[0203] The frequency of administration may vary depending on the method of protection claimed. In some embodiments, the composition may be administered once. In some embodiments, the composition may be administered multiple times. In some embodiments, the frequency of administration may be weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, or every 10 weeks; or monthly, every 2 months, or every 3 months, or for longer periods. In some embodiments, the dosing frequency is once every 20 days, once every 21 days, once every 22 days, once every 23 days, once every 24 days, once every 25 days, once every 26 days, once every 27 days, once every 28 days, once every 29 days, once every 30 days, once every 31 days, once every 32 days, once every 33 days, once every 34 days, once every 35 days, once every 36 days, once every 37 days, once every 38 days, once every 39 days, once every 40 days, once every 41 days, once every 42 days, once every 43 days, once every 44 days, or once every 45 days. In some embodiments, the composition is administered daily, every two weeks, weekly, every two months, monthly, or at any time interval that provides adequate (e.g., maximum) efficacy while minimizing safety risks to the subject. Generally, efficacy and treatment, as well as safety risks, can be monitored throughout the treatment course.

[0204] In some embodiments, the composition provided herein (e.g., anti-HJV antibody) may be administered to the subject at one or more intervals during a defined time period. In some cases, the time periods during which the composition is administered to the subject at one or more intervals may be separated by time periods during which the composition is not administered to the subject. In some embodiments, the relative duration of the corresponding time periods may depend on the subject's response to treatment or the severity of the disease, or both, and / or may be determined based on the judgment of the treating physician. For example, in some embodiments, the anti-HJV antibody is administered to the subject during the active phase of inflammation (e.g., during an IBD flare-up), but not during the inactive phase of inflammation (e.g., when the IBD is in remission).

[0205] Typically, the dosage for any antibody described herein may be about 50 mg, 75 mg, or 100 mg. However, in some embodiments, the dosage of the anti-HJV antibody may be from 5 mg to 250 mg. In some implementations, the dosage of the anti-HJV antibody is 5 to 250 mg, 5 to 240 g / kg, 5 to 230 mg, 5 to 220 mg, 5 to 210 mg, 5 to 200 mg, 5 to 190 mg, 5 to 180 mg, 5 to 170 mg, 5 to 160 mg, 5 to 150 mg, 5 to 140 mg, 5 to 130 mg, 5 to 120 mg, 5 to 110 mg, 5 to 100 mg, 5 to 90 mg, 5 to 80 mg, 5 to 70 mg, 5 to 60 mg, 5 to 50 mg, 5 to 40 mg, 5 to 30 mg, 5 to 20 mg, 5 to 10 mg, 10 to 250 mg, 10 to 240 g / kg, 10 to 230 mg, 10 to 220 mg, 10 to 210 mg, 10 to 200 mg, 10 to 190 mg, 10 to 180 mg. mg, 10 to 170 mg, 10 to 160 mg, 10 to 150 mg, 10 to 140 mg, 10 to 130 mg, 10 to 120 mg, 10 to 110 mg, 10 to 100 mg, 10 to 90 mg, 10 to 80 mg, 10 to 70 mg, 10 to 60 mg, 10 to 50 mg, 10 to 40 mg, 10 to 30 mg, 10 to 20 mg, 20 to 250 mg, 20 to 240 g / kg, 20 to 230 mg, 20 to 220 mg, 20 to 210 mg, 20 to 200 mg, 20 to 190 mg, 20 to 180 mg, 20 to 170 mg, 20 to 160 mg, 20 to 150 mg, 20 to 140 mg, 20 to 130 mg, 20 to 120 mg, 20 to 110 mg mg, 20 to 100 mg, 20 to 90 mg, 20 to 80 mg, 20 to 70 mg, 20 to 60 mg, 20 to 50 mg, 20 to 40 mg, 20 to 30 mg, 30 to 250 mg, 30 to 240 g / kg, 30 to 230 mg, 30 to 220 mg, 30 to 210 mg, 30 to 200 mg, 30 to 190 mg, 30 to 180 mg, 30 to 170 mg, 30 to 160 mg, 30 to 150 mg, 30 to 140 mg, 30 to 130 mg, 30 to 120 mg, 30 to 110 mg, 30 to 100 mg, 30 to 90 mg, 30 to 80 mg, 30 to 70 mg, 30 to 60 mg, 30 to 50 mg, 30 to 40 mg, 40 to 250 mgmg, 40 to 240 g / kg, 40 to 230 mg, 40 to 220 mg, 40 to 210 mg, 40 to 200 mg, 40 to 190 mg, 40 to 180 mg, 40 to 170 mg, 40 to 160 mg, 40 to 150 mg, 40 to 140 mg, 40 to 130 mg, 40 to 120 mg, 40 to 110 mg, 40 to 100 mg, 40 to 90 mg, 40 to 80 mg, 40 to 70 mg, 40 to 60 mg, 40 to 50 mg, 50 to 250 mg, 50 to 240 g / kg, 50 to 230 mg, 50 to 220 mg, 50 to 210 mg, 50 to 200 mg, 50 to 190 mg, 50 to 180 mg, 50 to 170 mg, 50 to 160 mg mg, 50 to 150 mg, 50 to 140 mg, 50 to 130 mg, 50 to 120 mg, 50 to 110 mg, 50 to 100 mg, 50 to 90 mg, 50 to 80 mg, 50 to 70 mg, 50 to 60 mg, 60 to 250 mg, 60 to 240 g / kg, 60 to 230 mg, 60 to 220 mg, 60 to 210 mg, 60 to 200 mg, 60 to 190 mg, 60 to 180 mg, 60 to 170 mg, 60 to 160 mg, 60 to 150 mg, 60 to 140 mg, 60 to 130 mg, 60 to 120 mg, 60 to 110 mg, 60 to 100 mg, 60 to 90 mg, 60 to 80 mg, 60 to 70 mg, 70 to 250 mg, 70 to 240 mg / kg g / kg, 70 to 230 mg, 70 to 220 mg, 70 to 210 mg, 70 to 200 mg, 70 to 190 mg, 70 to 180 mg, 70 to 170 mg, 70 to 160 mg, 70 to 150 mg, 70 to 140 mg, 70 to 130 mg, 70 to 120 mg, 70 to 110 mg, 70 to 100 mg, 70 to 90 mg, 70 to 80 mg, 80 to 250 mg, 80 to 240 g / kg, 80 to 230 mg, 80 to 220 mg, 80 to 210 mg, 80 to 200 mg, 80 to 190 mg, 80 to 180 mg, 80 to 170 mg, 80 to 160 mg, 80 to 150 mg, 80 to 140 mg, 80 to 130 mg, 80 to 120 mg mg, 80 to 110 mg, 80 to 100 mg, 80 to 90 mg, 90 to 250 mg, 90 to 240 g / kg, 90 to 230 mg, 90 to 220 mg, 90 to 210 mg, 90 to 200 mg / kgmg, 90 to 190 mg, 90 to 180 mg, 90 to 170 mg, 90 to 160 mg, 90 to 150 mg, 90 to 140 mg, 90 to 130 mg, 90 to 120 mg, 90 to 110 mg, 90 to 100 mg, 100 to 250 mg, 100 to 240 g / kg, 100 to 230 mg, 100 to 220 mg, 100 to 210 mg, 100 to 200 mg, 100 to 190 mg, 100 to 180 mg, 100 to 170 mg, 100 to 160 mg, 100 to 150 mg, 100 to 140 mg, 100 to 130 mg, 100 to 120 mg, 100 to 110 mg, 110 to 250 mg, 110 to 240 g / kg, 110 to 230 mg mg, 110 to 220 mg, 110 to 210 mg, 110 to 200 mg, 110 to 190 mg, 110 to 180 mg, 110 to 170 mg, 110 to 160 mg, 110 to 150 mg, 110 to 140 mg, 110 to 130 mg, 110 to 120 mg, 120 to 250 mg, 120 to 240 g / kg, 120 to 230 mg, 120 to 220 mg, 120 to 210 mg, 120 to 200 mg, 120 to 190 mg, 120 to 180 mg, 120 to 170 mg, 120 to 160 mg, 120 to 150 mg, 120 to 140 mg, 120 to 130 mg, 130 to 250 mg, 130 to 240 mg / kg g / kg, 130 to 230 mg, 130 to 220 mg, 130 to 210 mg, 130 to 200 mg, 130 to 190 mg, 130 to 180 mg, 130 to 170 mg, 130 to 160 mg, 130 to 150 mg, 130 to 140 mg, 140 to 250 mg, 140 to 240 g / kg, 140 to 230 mg, 140 to 220 mg, 140 to 210 mg, 140 to 200 mg, 140 to 190 mg, 140 to 180 mg, 140 to 170 mg, 140 to 160 mg, 140 to 150 mg, 150 to 250 mg, 150 to 240 g / kg, 150 to 230 mg, 150 to 220 mg mg, 150 to 210 mg, 150 to 200 mg, 150 to 190 mg, 150 to 180 mg, 150 to 170 mg, 150 to 160 mg, 160 to 250 mg, 160 to 240 g / kg, 160 to 230 mg, 160 to 220 mg, 160 to 210 mg, 160 to 200 mg / kgmg, 160 to 190 mg, 160 to 180 mg, 160 to 170 mg, 170 to 250 mg, 170 to 240 g / kg, 170 to 230 mg, 170 to 220 mg, 170 to 210 mg, 170 to 200 mg, 170 to 190 mg, 170 to 180 mg, 180 to 250 mg, 180 to 240 g / kg, 180 to 230 mg, 180 to 220 mg, 180 to 210 mg, 180 to 200 mg, 180 to 190 mg, 190 to 250 mg, 190 to 240 g / kg, 190 to 230 mg, 190 to 220 mg, 190 to 210 mg, 190 to 200 mg, 200 to 250 mg, 200 to 240 mg g / kg, 200 to 230 mg, 200 to 220 mg, 200 to 210 mg, 210 to 250 mg, 210 to 240 g / kg, 210 to 230 mg, 210 to 220 mg, 220 to 250 mg, 220 to 240 g / kg, 220 to 230 mg, 230 to 250 mg, 230 to 240 g / kg, or 240 to 250 mg.

[0206] In some implementations, the antibody can be administered parenterally. For example, the parenterally administered composition can be administered via subcutaneous, intradermal, intravenous, intraperitoneal, intratumoral, intramuscular, intra-articular, intra-arterial, or infusion techniques. Alternatively, it can be administered via an injectable depot, such as using injectable or biodegradable materials and methods with 1-month, 3-month, or 6-month depots.

[0207] In some embodiments, the antibody (e.g., an anti-HJV antibody) is administered intravenously. In some embodiments, the antibody (e.g., an anti-HJV antibody) is administered subcutaneously. In some embodiments, subcutaneous administration of the anti-HJV antibody results in similar bioavailability compared to intravenous administration of the same antibody at the same dose.

[0208] For intravenous injection, water-soluble antibodies can be administered via infusion, thereby infusing a pharmaceutical formulation containing the antibody and a physiologically acceptable excipient. Physiologically acceptable excipients may include, for example, 5% dextran, 0.9% saline, Ringer's solution, or other suitable excipients. Other injectable compositions may contain a variety of carriers, such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (glycerol, propylene glycol, liquid polyethylene glycol, etc.). In some cases, sterile formulations, such as suitable soluble salts of antibodies, may be dissolved in pharmaceutical excipients such as water for injection, 0.9% saline, or 5% glucose solution and administered.

[0209] In one embodiment, the antibody is administered via a site-specific or targeted local delivery technique. Examples of site-specific or targeted local delivery techniques include various implantable reservoir sources or local delivery catheters for the antibody, such as infusion catheters, indwelling catheters or needle catheters, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site-specific carriers, direct injection, or direct application. See, for example, PCT Publication No. WO 00 / 53211 and U.S. Patent No. 5,981,568.

[0210] In some implementations, more than one antibody may be administered to a subject in need of treatment, or an antibody may be combined with another suitable therapeutic agent. Antibodies may also be used in combination with other agents to enhance and / or complement the effectiveness of the therapeutic agent. The therapeutic efficacy against the target disease / condition can be evaluated using methods known in the art.

[0211] Anti-HJV antibodies and treatments as described in this disclosure may be used in combination with other types of treatments for the target diseases or conditions disclosed herein. In this case, the antibody composition and the therapeutic agent may be administered simultaneously or sequentially. Some examples include chemotherapy, immunotherapy, surgery, radiation, gene therapy, and so on, or anti-infective therapy. Such treatments may be administered simultaneously or sequentially (in any order) with treatments according to this disclosure.

[0212] For example, combination therapy may include the anti-HJV antibody and pharmaceutical composition described herein, formulated and / or co-administered with at least one other therapeutic agent. Such combination therapy can advantageously utilize lower doses of the administered therapeutic agent, thereby preventing potential toxicities or complications associated with multiple monotherapy treatments.

[0213] In some embodiments, the anti-HJV antibody is administered to the subject in combination with additional therapeutic molecules. In some embodiments, the additional therapeutic molecules are aminosalicylate (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators (e.g., estrasimod, ozanimod), immunomodulators (e.g., azathioprine, 6-mercaptopurine, cyclosporine, or tacrolimus), JAK inhibitors (e.g., upadacitinib, tofacitinib), and TNF inhibitors (e.g., adalimumab, cetholizumab). pegol, infliximab, golimumab, integrin antagonists (e.g. natalizumab, vedolizumab), IL-23 antagonists (e.g., risankizumab-rzaa) or IL-12 / IL23 antagonists (e.g., Ustekinumab), nicotine, sulfasalazine (e.g., azulfidine, salazopyrin, sulazine), mesalamine, olsalazine, balsalazide, or azathioprine.

[0214] As disclosed herein, leukocyte antagonists (e.g., anti-HJV antibodies) can be administered via any suitable route. For therapeutic use, an effective amount of the antagonist and / or additional therapeutic agent can be administered to the subject by any means of delivering the agent to the desired tissue (e.g., intravenous administration). In some embodiments, leukocyte antagonists (e.g., anti-HJV antibodies) are administered subcutaneously and / or intravenously. Other suitable routes of administration include, but are not limited to, oral, parenteral, intraperitoneal, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal administration.

[0215] III. Hemojugol (HJV) antagonists

[0216] In some aspects, this document provides hemoblastin antagonists to inhibit BMP-SMAD signaling for reducing hepcidin expression and / or function, for example, to reduce inflammation and / or promote mucosal healing in subjects with this need in conditions associated with the barrier dysfunction described herein (e.g., IBD, UC, and CD). Generally, a “hemoblastin antagonist” refers to a molecule that reduces hemoblastin expression or inhibits hemoblastin activity, said reduction or inhibition being, for example, by binding to hemoblastin. In some embodiments, the hemoblastin antagonist is an antisense oligonucleotide (see, for example, U.S. Patent No. 7,534,764; U.S. Patent Publication No. US 2014 / 127325; and International Publication No. WO 2016 / 180784, which are incorporated herein by reference). In some embodiments, the hemoblastin antagonist is an antibody (e.g., the anti-HJV antibody described herein, or the anti-HJV antibody described in WO2020 / 086736, WO2021 / 231800, or WO2023 / 240171, the contents of which are incorporated herein by reference). In other embodiments, the hemoblastin antagonist is a small molecule compound that inhibits hemoblastin, for example, through competitive binding to and / or chemical modification of hemoblastin. In some embodiments, the hemoblastin antagonist is an HJV fragment (see, for example, the HJV fragment described in U.S. Patent 8,507,435, which is incorporated herein by reference) or an HJV fusion protein (e.g., the HJV-Fc fusion protein described in U.S. Patent 8,637,023, which is incorporated herein by reference).

[0217] In some implementations, the methods presented herein are based on the understanding that an increase in serum or tissue iron triggers the transcriptional induction of hepcidin via the BMP-SMAD signaling pathway. Generally, “HJV-induced BMP signaling” refers to signaling via a hemojuvein (HJV)-induced BMP receptor, a membrane-bound co-receptor for bone morphogenetic protein (BMP) signaling. As discussed in Xia Y et al., “Hemojuvein regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin,” Blood. 2008 May 15; 111(10): 5195–5204, HJV-induced BMP signaling positively regulates hepcidin mRNA expression in hepatocytes. In some implementations, HJV binds to BMP2, BMP4, BMP5, or BMP6 to induce BMP signaling, for example, to positively regulate hepcidin levels in hepatocytes. In some embodiments, cleavage of HJV by proteolytic enzyme-2 reduces the amount of cell surface HJV available for participation in BMP signaling. In some embodiments, the induction of BMP signaling by HJV is independent of neogenin. However, in some embodiments, neogenin promotes the induction of BMP signaling by HJV, as discussed in Zhao et al., Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelinin the Liver, J Biol Chem. 2016 Jun 3; 291(23): 12322–12335. In some embodiments, BMP6 is responsible for iron-dependent activation of SMAD signaling. In some embodiments, BMP6 is secreted from hepatic sinusoidal endothelial cells and binds to the BMP receptor (BMPR) on hepatocytes, thereby activating the SMAD signaling cascade. In such embodiments, HJV acts as a co-receptor for such BMP6, for example, to positively regulate hepcidin levels in hepatocytes. In some implementations, BMP transduces signals by binding to one or a combination of type I and type II serine / threonine kinase receptors. Type II BMP receptors include BMPRII, ActRIIA, and ActRIIB. Type I BMP receptors include ALK3, ALK6, and ALK2.In some embodiments, following ligand binding, a constitutively active type II receptor phosphorylates a type I receptor, and subsequently, the type I receptor phosphorylates intracellular receptor-activated Smads (R-Smads) (i.e., Smad 1, Smad 5, and / or Smad 8). In such embodiments, the activated R-Smads complex with their co-partner Smad4 and translocate to the nucleus to regulate gene transcription, such as inducing hepcidin expression. In some embodiments, the HJV acts as a BMP co-receptor to positively regulate hepcidin levels. In some cells (e.g., hepatocytes), HJV-induced BMP signaling positively regulates hepcidin mRNA expression. In such embodiments, the HJV binds to BMP2, BMP4, BMP5, and / or BMP6 to mediate BMP signaling, such as to positively regulate hepcidin levels in hepatocytes. In some embodiments, BMP transduces signals by binding to one or a combination of type I and type II serine / threonine kinase receptors. In some embodiments, following ligand binding, the constitutively active type II receptor phosphorylates the type I receptor, and the type I receptor subsequently phosphorylates intracellular receptor-activated Smads (R-Smads) (i.e., Smad 1, Smad 5, and / or Smad 8). In such embodiments, the activated R-Smads complex with their co-partner Smad4 and translocate to the nucleus to regulate gene transcription, such as inducing hepcidin expression.

[0218] In some embodiments, the leukocyte antagonist binds to one or more proteins from the repulsive guidance molecule (RGM) family, including RGMa, RGMb, and RGMc (HJV). In some embodiments, the leukocyte antagonist selectively binds to leukocyte cytokinase (RGMc) rather than RGMa and RGMb. In some embodiments, the leukocyte antagonist selectively binds to leukocyte cytokinase (RGMc) and RGMa rather than RGMb.

[0219] In some embodiments, hemojuvein antagonists are antisense oligonucleotides that reduce hemojuvein expression (see, for example, US7534764, authorized May 19, 2009, entitled "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin,"; US2014127325, authorized May 19, 2009, entitled "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin"; and WO2016180784, published November 17, 2016, entitled "Improved treatments using oligonucleotides," which are incorporated herein by reference). In some embodiments, hemojuvein antagonists are small molecule compounds that inhibit hemojuvein, for example, through competitive binding to and / or chemical modification of hemojuvein.

[0220] In some embodiments, the HJV antagonist is a soluble HJV. In some embodiments, the soluble HJV is a soluble HJV-Fc fusion protein. In some embodiments, the soluble HJV is the soluble HJV disclosed in the following: US8318167B2, authorized November 27, 2012, entitled "Methods and compositions for regulating iron homeostasis by modulation of BMP-6"; US9708379B2, authorized July 18, 2017, entitled "COMPOSITIONS FOR REGULATING IRON HOMEOSTASIS AND METHODS OF USING SAME"; US10273273B2, authorized April 30, 2019, entitled "COMPOSITIONS AND REGULATING IRON HOMEOSTASIS AND METHODS OF USING SAME"; and US7968091B2, authorized June 28, 2011, entitled "METHODS AND COMPOSITIONS TO REGULATE IRON METABOLISM; US8637023B2, authorized January 28, 2014, entitled "HEMOJUVELIN FUSION PROTEINS"; US8865168B2, authorized October 21, 2014, entitled "METHODS AND COMPOSITIONS TO REGULATE HEPCIDIN EXPRESSION"; US9556251B2, authorized January 31, 2017, entitled "METHODS AND COMPOSITIONS TO REGULATE HEPCIDIN EXPRESSION"; US8895002B2, authorized November 25, 2014, entitled "Hemojuvelin fusion proteins and uses thereof"; US7511018B2, authorized March 31, 2009, entitled "Juvenile hemochromatosis gene (HFE2A) cleavage products and uses". The contents thereof are incorporated herein by reference. In some embodiments, the sHJV-Fc fusion protein is Ferruxmax. In some embodiments, the sHJV-Fc fusion protein is FMX-8.

[0221] In some embodiments, the hemoblastin antagonist is an antibody specific to hemoblastin and / or one or more proteins in the RGM protein family (e.g., RGMa, RGMb). In some embodiments, the hemoblastin antagonist is an antibody specific to RGMa. In some embodiments, the hemoblastin antagonist is an antibody specific to hemoblastin (RGMc) and / or RGMa, but not specific to RGMb. In some embodiments, the antibody specific to hemojuglin and / or one or more RGM proteins is an anti-HJV antibody and / or one or more RGM proteins, as disclosed in: US10118958, authorized November 6, 2018, entitled "Composition and method for the diagnosis and treatment of iron-related disorders"; US9636398, authorized May 2, 2017, entitled "Composition and method for the diagnosis and treatment of iron-related disorders"; and US8507435, authorized August 13, 2013, entitled "Juvenilehemochromatosis gene (HFE2A) cleavage products and uses thereof"; and US10118958, authorized November 6, 2018, entitled "Composition and method for the diagnosis and treatment of iron-related disorders". "disorders"; US2010 / 0322941, published on December 23, 2010, entitled "Bone morphogenetic protein (BMP)-binding domains of proteins of the therepulsive guidance molecule (RGM) protein family and functional fragments thereof, and use of same"; US9040052, authorized on May 26, 2015, entitled "Precision Medicine By Targeting Rare Human PCSK9 Variants for Cholesterol Treatment";And US2017 / 0029499, published on February 2, 2017, entitled "Methods for treating hepcidin-mediated disorders"; and International Publication No. WO2007039256, published on April 12, 2007, entitled "Binding domains of proteins of the repulsive guidance molecule (rgm) protein family and functional fragments thereof, and their use"; WO2015171691, published on November 12, 2015, entitled "Compositions and methods for growth factor modulation"; WO2018 / 009624, published on January 11, 2018, entitled "Tgf-beta superfamily heteromultimers and uses thereof"; and WO2020 / 086736, published on April 30, 2020, entitled "Rgmc-selective inhibitors and use". The contents of "the thereof", each relating to anti-HJV or anti-RGMc antibodies, are incorporated herein by reference.

[0222] In some embodiments, the hemoblastin antagonist is an antibody (e.g., hHA-001-hHA-012) specific to hemoblastin and / or one or more proteins in the RGM protein family (e.g., RGMa, RGMb), as described herein in Tables 1a to 1b. In some embodiments, the anti-HJV antibody described herein also binds to RGMa. Suitable antibodies specific to hemoblastin and / or one or more RGM proteins that can be used in certain methods provided herein are provided, for example, in: U.S. Patent Nos. 10,118,958 and 8,507,435; U.S. Patent Publications Nos. US 2013 / 330343, US 2015 / 166672 and US 2017 / 029499; and International Publications Nos. WO 2015 / 171691 and WO 2018 / 009624, which are incorporated herein by reference.

[0223] In some aspects, antibodies described herein bind to human hemoblastoma (HJV) with high specificity and affinity. In some embodiments, the anti-HJV antibodies described herein specifically bind to any extracellular site of HJV or an epitope exposed to the antibody. In some embodiments, the anti-HJV antibodies provided herein specifically bind to HJV derived from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-HJV antibodies provided herein bind to human HJV. In some embodiments, the anti-HJV antibodies described herein bind to an amino acid segment of human or non-human primate HJV.

[0224] In some embodiments, the anti-HJV antibody described herein binds specifically to an epitope on human HJV. Human HJV is a 426-amino acid protein with a predicted 31-amino acid N-terminal signal peptide and a 45-amino acid C-terminal GPI linker signal. An exemplary human HJV amino acid sequence is shown in SEQ ID NO: 128:

[0225]

[0226] In some embodiments, the anti-HJV antibody described herein can bind to a fragment of human HJV. The length of the HJV fragment can be about 5 to about 425 amino acids, about 10 to about 400 amino acids, about 50 to about 350 amino acids, about 100 to about 300 amino acids, about 150 to about 250 amino acids, about 200 to about 300 amino acids, or about 75 to about 150 amino acids. The fragment may contain a consecutive number of amino acids from RGMc. Exemplary amino acids of the HJV fragment are shown in SEQ ID NO: 123:

[0227]

[0228] In some implementations, the anti-HJV antibody described herein binds to different epitopes within human HJV or human HJV fragments.

[0229] In some embodiments, the anti-HJV antibody interacts with an epitope within amino acids 160 to 190 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with an epitope having amino acid sequences of amino acids 170 to 183 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with an epitope having an amino acid sequence of SSPMALGANATATR (SEQ ID NO: 121). In some embodiments, the anti-HJV antibody interacts with different segments within SSPMALGANATATR (SEQ ID NO: 121). In some embodiments, the anti-HJV antibody interacts with amino acids 170 to 171, 171 to 180, 180 to 182, and 182 to 183 of SEQ ID NO: 123. In some embodiments, the antibody interacts with amino acids 170(S), 171(S), 180(T), 182(T), and 183(R) of SEQ ID NO: 123. In some embodiments, hHA-008 interacts with the epitope SSPMALGANATATR (SEQ ID NO: 121). In some embodiments, hHA-008 interacts with amino acids 170(S), 171(S), 180(T), 182(T), and 183(R) of SEQ ID NO: 123.

[0230] In some embodiments, the anti-HJV antibody interacts with the epitope within amino acids 160 to 190 and / or amino acids 280 to 310 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with the epitope within amino acids 169 to 182 and / or amino acids 289 to 300 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with the epitope within amino acids 169 to 182 and amino acids 289 to 300 of SEQ ID NO: 123. In some embodiments, the anti-HJV antibody interacts with the epitope having the amino acid sequence TSSPMALGANATAT (SEQ ID NO: 122) and the amino acid sequence SQRLSRSERNRR (SEQ ID NO: 127). In some embodiments, the anti-HJV antibody interacts with different segments within TSSPMALGANATAT (SEQ ID NO: 122) and SQRLSRSERNRR (SEQ ID NO: 127). In some embodiments, the anti-HJV antibody interacts with amino acids 169 to 171, 171 to 180, and 180 to 182 of SEQ ID NO: 123, as well as amino acids 289 to 293, 293 to 294, 294 to 295, 295 to 297, and 297 to 300 of SEQ ID NO: 123. In some embodiments, the antibody interacts with amino acids 169(T), 170(S), 171(S), 180(T), 182(T), 289(S), 293(S), 294(R), 295(S), 297(R), and 300(R) of SEQ ID NO: 123. In some embodiments, hHA-008-QL interacts with different segments within TSSPMALGANATAT (SEQ ID NO: 122) and SQRLSRSERNRR (SEQ ID NO: 127). In some embodiments, hHA-008-QL interacts with amino acids 169(T), 170(S), 171(S), 180(T), 182(T), 289(S), 293(S), 294(R), 295(S), 297(R), and 300(R) of SEQ ID NO: 123.

[0231] In some embodiments, the anti-HJV antibody described herein...

Claims

1. A method for suppressing inflammation in a subject, the method comprising administering an effective amount of anti-hemoblast (HJV) antibody to a subject suffering from inflammation associated with barrier dysfunction.

2. The method of claim 1, wherein the barrier dysfunction is intestinal barrier dysfunction.

3. The method of claim 2, wherein the intestinal permeability of the subject is increased relative to the subject without intestinal barrier dysfunction.

4. The method of claim 2 or 3, wherein the subject suffers from intestinal mucosal barrier dysfunction.

5. The method of any one of claims 2 to 4, wherein the subject has an abnormal immune response to the gastrointestinal (GI) microbiome.

6. The method of any one of claims 1 to 5, wherein the application alleviates systemic inflammation in the subject.

7. The method of claim 6, wherein the administration reduces the number of circulating leukocytes.

8. The method of claim 6 or 7, wherein the administration reduces the number of circulating neutrophils.

9. The method of any one of claims 1 to 8, wherein the application reduces local inflammation at the site of barrier dysfunction.

10. The method of claim 9, wherein the application reduces immune cell infiltration at the site of barrier dysfunction.

11. The method of claim 9 or 10, wherein the application reduces neutrophil infiltration at the site of barrier dysfunction.

12. The method of any one of claims 1 to 11, wherein the application improves intestinal barrier function.

13. The method of any one of claims 1 to 12, wherein the subject suffers from ulcerative colitis.

14. The method of any one of claims 1 to 12, wherein the subject suffers from Crohn's disease.

15. A method of treating a subject, the method comprising administering an effective amount of anti-hemoblastine (HJV) antibody to a subject suffering from inflammation associated with inflammatory bowel disease (IBD).

16. A method for treating inflammatory bowel disease (IBD) in a subject, the method comprising administering an effective amount of an anti-hemoblastine (HJV) antibody to the subject, wherein the subject suffers from inflammation associated with IBD.

17. A method for treating a subject with active inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-hemoblastine (HJV) antibody to the subject.

18. A method for treating a subject suffering from chronic inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-hemoblast (HJV) antibody to the subject.

19. A method for treating inflammation in a subject suffering from inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-hemoblastine (HJV) antibody to the subject.

20. The method of any one of claims 15 to 19, wherein the subject suffers from intestinal mucosal inflammation associated with IBD.

21. The method of any one of claims 15 to 20, wherein the subject has an abnormal immune response to the gastrointestinal (GI) microbiome.

22. The method of any one of claims 15 to 21, wherein the subject suffers from acute-phase IBD.

23. The method of any one of claims 15 to 21, wherein the subject suffers from chronic IBD.

24. The method of any one of claims 15 to 23, wherein the application alleviates systemic inflammation in the subject.

25. The method of claim 24, wherein the administration reduces the number of circulating leukocytes.

26. The method of claim 24 or 25, wherein the administration reduces the number of circulating neutrophils.

27. The method of any one of claims 15 to 26, wherein the application reduces intestinal mucosal inflammation at the site of barrier dysfunction.

28. The method of claim 27, wherein the administration reduces the infiltration of immune cells in the intestine.

29. The method of claim 27 or 28, wherein the administration reduces neutrophil infiltration in the intestine.

30. The method of any one of claims 15 to 29, wherein the application inhibits the occurrence of intestinal stricture.

31. The method of any one of claims 1 to 30, wherein the subject does not respond to or cannot tolerate treatment with one or more of the following: aminosalicylic acid (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators, immunomodulators, Janus kinase (JAK) inhibitors, tumor necrosis factor (TNF) inhibitors, integrin antagonists, interleukin (IL)-23 antagonists, or IL-12 antagonists.

32. The method of any one of claims 15 to 31, wherein the subject suffers from ulcerative colitis.

33. The method of claim 32, wherein the subject suffers from mild to moderate active ulcerative colitis.

34. The method of claim 32, wherein the subject suffers from moderate to severe active ulcerative colitis.

35. The method of claim 32, wherein the subject suffers from severe active ulcerative colitis.

36. The method of any one of claims 32 to 35, wherein the Mayo Criterion score of the subject prior to the application is in the range of 3 to 12.

37. The method of any one of claims 32 to 36, wherein the application reduces the Mayo score by at least 3 points.

38. The method of any one of claims 32 to 37, wherein the subject has a Mayo Cognitive Esophageal Score (MES) of 1 to 3 prior to the administration.

39. The method of any one of claims 32 to 38, wherein the application improves the endoscopic appearance of the object.

40. The method of claim 39, wherein the application reduces MES by at least 1 point.

41. The method of any one of claims 32 to 40, wherein the administration induces endoscopic relief in the subject.

42. The method of any one of claims 32 to 40, wherein the application maintains endoscopic relief of the subject.

43. The method of any one of claims 32 to 42, wherein the application reduces the frequency of bowel movements or defecation.

44. The method of any one of claims 32 to 43, wherein the application reduces rectal bleeding.

45. The method of any one of claims 32 to 44, wherein the administration induces clinical remission in the subject.

46. ​​The method of any one of claims 32 to 45, wherein the administration maintains clinical remission in the subject.

47. The method of any one of claims 32 to 46, wherein the administration reduces the need for hospitalization due to severe ulcerative colitis.

48. The method of any one of claims 32 to 47, wherein the application alleviates extraintestinal symptoms of ulcerative colitis in the subject.

49. The method of claim 48, wherein the application reduces fatigue.

50. The method of any one of claims 15 to 31, wherein the subject suffers from Crohn's disease (CD).

51. The method of claim 50, wherein the subject has a Crohn's Disease Activity Index (CDAI) of at least 150 prior to the administration.

52. The method of claim 50, wherein the CDAI of the object is in the range of 150 to 450.

53. The method of claim 50, wherein the CDAI of the object is greater than 450.

54. The method of any one of claims 52 to 53, wherein the application reduces CDAI by at least 70%.

55. The method of any one of claims 50 to 54, wherein the object has one or more fistulas.

56. The method of claim 55, wherein the application reduces the number of fistulas in the object relative to the number of fistulas in the object prior to the application.

57. The method of claim 55 or 56, wherein the application maintains fistula closure in the object.

58. The method of any one of claims 50 to 57, wherein the application reduces the number of excretory enterocutaneous fistulas in the subject.

59. The method of any one of claims 50 to 58, wherein the application improves the appearance of the endoscope.

60. The method of any one of claims 50 to 59, wherein the application promotes mucosal healing.

61. The method of any one of claims 50 to 60, wherein the application reduces hospitalization of the subject.

62. The method of any one of claims 50 to 61, wherein the application reduces the subject's need for corticosteroids.

63. The method of any one of claims 50 to 62, wherein the administration induces clinical remission in the subject.

64. The method of any one of claims 50 to 63, wherein the administration maintains clinical remission in the subject.

65. The method of any one of claims 50 to 64, wherein the application alleviates fatigue of the object.

66. A method for treating ulcerative colitis (UC), the method comprising administering an effective amount of anti-hemoblastine (HJV) antibody to a subject suffering from UC and experiencing mucosal inflammation.

67. The method of claim 66, wherein the subject suffers from acute UC.

68. The method of claim 66, wherein the subject suffers from chronic UC.

69. The method of any one of claims 66 to 68, wherein the application promotes mucosal healing of the object.

70. The method of any one of claims 66 to 69, wherein the application reduces colonic shortening of the subject.

71. The method of any one of claims 66 to 70, wherein the application reduces the weight loss of the subject.

72. The method of any one of claims 66 to 71, wherein the application reduces the frequency of defecation of the subject.

73. The method of any one of claims 66 to 72, wherein the application reduces rectal bleeding in the subject.

74. The method of any one of claims 66 to 73, wherein the application reduces systemic inflammation in the subject.

75. The method of claim 74, wherein the administration reduces the number of circulating leukocytes in the subject.

76. The method of claim 74 or 75, wherein the administration reduces the number of circulating neutrophils in the subject.

77. The method of any one of claims 66 to 76, wherein the application increases the level of circulating red blood cells in the subject.

78. The method of any one of claims 66 to 77, wherein the application increases the hemoglobin of the subject.

79. The method of any one of claims 66 to 78, wherein the application increases the mean erythrocyte hemoglobin content (MCH) of the subject.

80. The method of any one of claims 66 to 79, wherein the application increases the transferrin saturation (TSAT%) of the subject.

81. The method of any one of claims 66 to 80, wherein the application increases serum iron in the subject.

82. The method of any one of claims 1 to 81, wherein the anti-HJV antibody is administered in combination with one or more of the following: aminosalicylic acid (5-ASA), corticosteroids, sphingosine 1-phosphate receptor modulators, immunomodulators, Janus kinase (JAK) inhibitors, tumor necrosis factor (TNF) inhibitors, integrin antagonists, interleukin (IL)-23 antagonists, or IL-12 antagonists.

83. The method of any one of claims 1 to 82, wherein the anti-HJV antibody is administered intravenously or subcutaneously.

84. The method of any one of claims 1 to 83, wherein the antibody comprises: a heavy chain (HC) complementarity-determining region (CDR) 1 (HC CDR1) containing the amino acid of SEQ ID NO: 1, an HC CDR2 containing the amino acid of SEQ ID NO: 2, an HC CDR3 containing the amino acid of SEQ ID NO: 3; a light chain (LC) CDR1 containing the amino acid of SEQ ID NO: 17, an LC CDR2 containing the amino acid of SEQ ID NO: 5, and an LC CDR3 containing the amino acid of SEQ ID NO:

27.

85. The method of any one of claims 1 to 84, wherein the anti-HJV antibody comprises: a heavy chain variable region (VH) containing the amino acid sequence of SEQ ID NO: 38 and a light chain variable region (VL) containing the amino acid sequence of SEQ ID NO:

39.

86. The method of any one of claims 1 to 85, wherein the anti-HJV antibody comprises: a heavy chain containing the amino acid sequence of SEQ ID NO: 61 and a light chain containing the amino acid sequence of SEQ ID NO:

62.

87. The method of any one of claims 1 to 85, wherein the anti-HJV antibody comprises: a heavy chain containing the amino acid sequence of SEQ ID NO: 63 and a light chain containing the amino acid sequence of SEQ ID NO: 62.

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