Methods of Treating Ulcerative Colitis with Anti-LIGHT Antibodies

Abstract

The present disclosure relates to methods of treating ulcerative colitis with anti-LIGHT antibodies, and also relates to assaying free LIGHT before, during, or after administration of an anti-LIGHT antibody to treat ulcerative colitis.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 225,675, filed July 26, 2021, the contents of which are incorporated herein by reference for all purposes.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. This XML copy, created on July 6, 2022, is named "01118-0054-00PCT_ST26.xml" and is 109,180 bytes in size.

[0003] The present disclosure relates to methods of treating ulcerative colitis with anti-LIGHT antibodies, and also relates to assaying free LIGHT before, during, or after administration of an anti-LIGHT antibody to treat ulcerative colitis. [Background technology]

[0004] Inflammatory bowel disease (IBD) has two major forms: Crohn's disease (CD) and ulcerative colitis (UC). (Wang et al., The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease, J. Immunol., 2005:174; 8173-82). IBD, including CD and UC, is characterized by chronic relapsing inflammation of the gastrointestinal tract. Ibid.

[0005] UC is most commonly associated with bloody stools and diarrhea. (Ungaro et al., Ulcerative colitis, Lancet, 2017:389;1756-1770). Symptoms may include urgency, incontinence, fatigue, increased frequency of bowel movements, mucus discharge, nocturnal bowel movements, and abdominal discomfort. Ibid. The primary goal of treatment is to induce and maintain remission with the long-term goal of disability, colectomy, and prevention of colorectal cancer. Ibid. Potential goals of remission are resolution of clinical symptoms, defined as cessation of rectal bleeding and improvement of bowel habits, and endoscopic cure. Ibid.

[0006] Multiple factors, including genetics, environmental factors, luminal factors, and mucosal immune dysregulation, are suggested to play a role in the development of UC. Ibid. The incidence and prevalence of ulcerative colitis have increased over time worldwide. Ibid. There is a strong need for new and improved methods to treat ulcerative colitis.

[0007] LIGHT (an acronym for "homologous to lymphotoxin, inducible expression, and competes with HSV glycoprotein D for binding to HVEM (herpesvirus entry mediator), a receptor expressed on T lymphocytes"), also known as TNFSF14 (tumor necrosis factor superfamily member 14), is an important regulatory cytokine.

[0008] LIGHT (TNFSF14) belongs to the tumor necrosis factor superfamily and is expressed by activated T cells, monocytes-macrophages, and other types of antigen-presenting cells. LIGHT is considered one of the "master regulators" of the immune system and plays a key role in the communication system that controls the immune response. LIGHT has a dual mechanism of action, exerting its effects by activating both T and B cells and upregulating other inflammatory cytokines.

[0009] LIGHT activates two key receptors expressed on lung epithelial cells: herpesvirus entry mediator (HVEM) and lymphotoxin β receptor (LTβR). Early in infection, LIGHT released from neutrophils and macrophages binds to cell receptors, triggering inflammatory cell infiltration and releasing high levels of TNF and additional proinflammatory cytokines. LIGHT also has a costimulatory role in T cell activation, which promotes proinflammatory and tissue damaging effects. (Ware, CF Advances in experimental medicine and biology 647, 146-155 (2009); Ware, CF Immunological reviews 223, 186-201 (2008)). Thus, LIGHT plays a role in many immune-mediated pathologies, such as Crohn's disease, IBD, rheumatoid arthritis, and fibrosis. An additional receptor for LIGHT is the decoy receptor (DCR3), which binds to LIGHT and interferes with its activity by competing with receptor binding. (Steinberg, MW, et al., M. Seminars in immunopathology 31, 207-221 (2009); Wroblewski, VJ et al. Biochemical pharmacology 65, 657-667 (2003)). In conditions of excessive inflammation and cytokine storm, DcR3 is likely to be overwhelmed, resulting in high production of DCR3-free (active) LIGHT.

[0010] LIGHT plays a role as a key mediator in mucosal inflammation and the development of inflammatory bowel disease (IBD) (Cohavy et al., LIGHT expression by mucosal T cells may regulate IFN-gamma expression in the intestine, J.Immunol., 2004;173(1):251-8; Ware, CF, Network Communications: Lymphotoxins, LIGHT and TNF, Annual Rev.Immunol., 2005:23:787-819; Cohavy et al., LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2-mediated signaling, J.Immunol., 2005:174:646-53; Wang et al., The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease, J.Immunol., 2005:174;8173-82). The human LIGHT gene maps to chromosome 19p13.3, a region thought to be involved in the pathogenesis of IBD. Ibid. The concept that LIGHT provides an important proinflammatory signal during the cellular immune response is strengthened by studies in IBD patients. LIGHT messenger ribonucleic acid (RNA) is upregulated in biopsies from inflamed areas of the small intestine (Cohavy et al., LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2-mediated signaling, J. Immunol., 2005:174:646-53). Furthermore, LIGHT is present at higher levels in UC subjects compared to healthy subjects.(Moraes et al.,Systemic inflammatory protein profiles distinguish Irritable Bowel Syndrome (IBS) and Ulcerative Colitis,irrespective of inflammation or IBS-like symptoms,Inflammatory Bowel Disease,2020:26:874-884). Furthermore, overexpression of LIGHT increases intestinal inflammation in mice, and anti-LIGHT antibodies reduce signs of intestinal inflammation in a mouse model of ulcerative colitis. (Jungbeck et al.,Neutralization of LIGHT ameliorates acute dextran sodium sulphate-induced intestinal inflammation,Immunology,2009:128:451-58;Shaikh et al.,Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation,and tissue destruction,J.Immunol.,2001:167:6330-6337). In some models, knocking out the LIGHT (or its ligand, HVEM) gene reduces intestinal inflammation (Schaer et al., HVEM Signalling Promotes Colitis, PLoS One, 2011:6(4):e18495).

[0011] Decoy receptor 3 belongs to the TNF superfamily (TNFRSF6B) (Yu et al., A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis, J. Biol. Chem., 1999:274(20):13733-6). It acts as a decoy receptor that competes with death receptors for ligand binding, and is hypothesized to play a regulatory role in suppressing Fas ligand (FasL)- and LIGHT-mediated cell death and T cell activation, as well as induce angiogenesis through neutralization of TNF-like ligand 1A (TL1A) (Yu et al. 1999). Recently, defective variants of DcR3 have been observed in patients with pediatric-onset IBD, further suggesting an important protective role for DcR3 (Cardinale et al., Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease, Genes Immun. 2013:Oct;14(7):447-52), potentially by mitigating the effects of TNF and LIGHT. The above-mentioned roles of LIGHT and DcR3 in the pathogenesis of IBD provide a rationale for the study of anti-LIGHT monoclonal antibodies in UC patients with or without loss-of-function mutations in DcR3. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Wang et al.,The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease,J.Immunol.,2005:174;8173-82 [Non-Patent Document 2] Ungaro et al.,Ulcerative colitis,Lancet,2017:389;1756-1770 [Non-Patent Document 3] Ware,CFAdvances in experimental medicine and biology 647,146-155(2009) [Non-Patent Document 4] Ware, CFI mmunological reviews 223, 186-201 (2008) [Non-Patent Document 5] Steinberg,MW,et al.,M.Seminars in immunopathology 31,207-221(2009) [Non-Patent Document 6] Wroblewski, VJet al.Biochemical pharmacology 65,657-667(2003) Summary of the Invention [Means for solving the problem]

[0013] The present disclosure includes, for example, any one or combination of the following embodiments.

[0014] Embodiment 1. A method of treating ulcerative colitis or an inflammatory disorder associated with ulcerative colitis, comprising administering to a subject in need thereof an anti-LIGHT antibody, wherein the anti-LIGHT antibody is: a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7; b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15; c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21; d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27; e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33; f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39; g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and i) comprising a heavy chain and a light chain which together comprise one of the sets of amino acid sequences for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 selected from SEQ ID NOs: 52, 53, 54, 55, 56, and 57.

[0015] Embodiment 2. A method of treating ulcerative colitis or an inflammatory disease associated with ulcerative colitis, comprising administering to a subject in need thereof an anti-LIGHT antibody, wherein the subject in need thereof has failed treatment with an approved therapeutic dose of an anti-TNFα monoclonal antibody, where there is no initial response or there is an initial response to induction followed by loss of response, and the anti-LIGHT antibody is one of the following: a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7; b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15; c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21; d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27; e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33; f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39; g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and i) comprising a heavy chain and a light chain which together comprise one of the sets of amino acid sequences for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 selected from SEQ ID NOs: 52, 53, 54, 55, 56, and 57.

[0016] Embodiment 3. A method of treating ulcerative colitis or an inflammatory disorder associated with ulcerative colitis, comprising administering to a subject in need thereof an anti-LIGHT antibody, wherein the anti-LIGHT antibody: a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7; b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15; c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21; d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27; e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33; f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39; g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and i) heavy and light chains which together comprise one of the following sets of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences selected from SEQ ID NOs: 52, 53, 54, 55, 56, and 57;

[0017] Anti-LIGHT antibody will be administered at a dose of 1.0 mg / kg or 3.0 mg / kg every 14 days.

[0018] Embodiment 4. A method of treating ulcerative colitis or an inflammatory disease associated with ulcerative colitis, comprising administering to a subject in need thereof an anti-LIGHT antibody, wherein the subject in need thereof has failed treatment with an approved therapeutic dose of an anti-TNFα monoclonal antibody, where there is no initial response or there is an initial response to induction followed by loss of response, and the anti-LIGHT antibody is one of the following: a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7; b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15; c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21; d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27; e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33; f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39; g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and i) heavy and light chains which together comprise one of the sets of amino acid sequences for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 selected from SEQ ID NOs: 52, 53, 54, 55, 56, and 57;

[0019] Anti-LIGHT antibody will be administered at a dose of 1.0 mg / kg or 3.0 mg / kg every 14 days.

[0020] Embodiment 5. The method of any one of the preceding embodiments, wherein the anti-LIGHT antibody is administered subcutaneously.

[0021] Embodiment 6 The method of any one of the preceding embodiments, wherein the method further comprises assaying for free LIGHT before, during, or after administration of an anti-LIGHT antibody.

[0022] Embodiment 7 The method of any one of the preceding embodiments, wherein the subject has elevated free LIGHT.

[0023] Embodiment 8. The method of any one of the preceding embodiments, wherein the subject is a human.

[0024] Embodiment 9. The method of any one of the preceding embodiments, wherein the subject is an adult.

[0025] Embodiment 10. The method of any one of the preceding embodiments, wherein the subject is a pediatric subject.

[0026] Embodiment 11 The method of any one of the preceding embodiments, wherein the antibody comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO:84.

[0027] Embodiment 12 The method of any one of the preceding embodiments, wherein the antibody comprises a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:85.

[0028] Embodiment 13 The method of any one of the preceding embodiments, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:8.

[0029] Embodiment 14 The method of any one of the preceding embodiments, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:9.

[0030] Embodiment 15. The method of any one of embodiments 1-14, wherein administration of an anti-LIGHT antibody reduces the subject's endoscopic Mayo score.

[0031] Embodiment 16 The method of any one of embodiments 1-15, wherein administration of an anti-LIGHT antibody reduces the subject's total Mayo score.

[0032] Embodiment 17. The method of any one of embodiments 1-16, wherein administration of an anti-LIGHT antibody increases the IBD-Q score of said subject.

[0033] Embodiment 18 The method of any one of the preceding embodiments, wherein administration of an anti-LIGHT antibody reduces serum free LIGHT in the subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The following definitions are provided to facilitate understanding of the invention. They are not intended to limit the invention in any way.

[0035] definition For purposes of the present invention, "a" or "an" entity refers to one or more of that entity, e.g., "a cDNA" refers to one or more cDNAs, or at least one cDNA. Thus, the terms "a" or "an," "one or more," and "at least one" can be used interchangeably herein. It should also be noted that the terms "comprise," "comprise," and "have" can be used interchangeably. Furthermore, a compound "selected from the group consisting of" refers to one or more compounds in the following list, including a mixture (i.e., combination) of two or more compounds. According to the present invention, an "isolated" or "biologically pure" molecule is a compound that has been removed from its natural environment. Thus, the terms "isolated" and "biologically pure" do not necessarily reflect the extent to which a compound is purified. An isolated compound of the present invention can be obtained from its natural source, can be produced using laboratory synthesis techniques, or can be produced by any such chemical synthesis route.

[0036] "LIGHT" or "TNFSF14" as used herein refers to a specific member protein of the tumor necrosis factor superfamily expressed by activated T cells, monocytes, macrophages, and additional types of antigen presenting cells. "LIGHT" is an acronym for "homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for binding to HVEM (herpes virus entry mediator), a receptor expressed on T lymphocytes."

[0037] "Free LIGHT" or "free (active) LIGHT" herein refers to the active form of LIGHT, i.e., unbound LIGHT (e.g., LIGHT bound to DcR3). In humans, free LIGHT is neutralized (inactivated) by DcR3, a unique soluble member of the TNFR superfamily, which binds LIGHT with high affinity and inhibits its interaction with two TNF receptors (HVEM and LTβR). "Bound LIGHT" and the like refers to LIGHT bound to a natural ligand, where the natural ligand is HVEM, LTβR, or DcR3 in some cases. "Total LIGHT" and the like refers to the total amount of free LIGHT and bound LIGHT.

[0038] "Elevated free LIGHT" as used herein refers to the level of free LIGHT detected in a subject being higher than that of normal control.Normal control can be determined by those skilled in the art as applicable to a particular situation.In some cases, normal control is an industry standard agreed upon by those skilled in the art as being a typical level or range of levels for individuals without LIGHT-related conditions.In some cases, normal control is a reference level of LIGHT from the same individual taken at a certain time point, and whether the subject's LIGHT is elevated is determined based on a sample taken from the same individual taken at a different, usually later, time point.

[0039] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity. As used herein, the term refers to a molecule that contains at least complementarity determining region (CDR)1, CDR2, and CDR3 of a heavy chain, and at least CDR1, CDR2, and CDR3 of a light chain, and is capable of binding to an antigen. The term antibody includes, but is not limited to, fragments capable of binding to an antigen, such as Fv, single chain Fv (scFv), Fab, Fab', and (Fab')2. The term antibody also includes, but is not limited to, chimeric antibodies, humanized antibodies, human antibodies, and antibodies of various species, such as mouse, cynomolgus monkey, etc.

[0040] The term "heavy chain" refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain includes at least a portion of a heavy chain constant region. The term "full-length heavy chain" refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0041] The term "heavy chain variable region" refers to the region of a heavy chain that comprises heavy chain complementarity determining region (CDR)1, framework region (FR)2, CDR2, FR3, and CDR3. In some embodiments, the heavy chain variable region also comprises at least a portion of FR1 and / or at least a portion of FR4. In some embodiments, heavy chain CDR1 corresponds to Kabat residues 31-35, heavy chain CDR2 corresponds to Kabat residues 50-65, and heavy chain CDR3 corresponds to Kabat residues 95-102. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).

[0042] The term "light chain" refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, the light chain comprises at least a portion of a light chain constant region. The term "full-length light chain" refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence. The term "light chain variable region" refers to a region comprising light chain CDR1, FR2, HVR2, FR3, and HVR3. In some embodiments, the light chain variable region also comprises FR1 and / or FR4. In some embodiments, light chain CDR1 corresponds to Kabat residues 24-34, light chain CDR2 corresponds to Kabat residues 50-56, and light chain CDR3 corresponds to Kabat residues 89-97. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.).

[0043] "Chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remaining portion of the heavy and / or light chain is derived from a different source or species. In some embodiments, a chimeric antibody refers to an antibody that comprises at least one variable region from a first species (mouse, rat, cynomolgus monkey, etc.) and at least one constant region from a second species (human, cynomolgus monkey, etc.). In some embodiments, a chimeric antibody comprises at least one mouse variable region and at least one human constant region. In some embodiments, a chimeric antibody comprises at least one cynomolgus monkey variable region and at least one human constant region. In some embodiments, all of the variable regions of the chimeric antibody are derived from a first species and all of the constant regions of the chimeric antibody are derived from a second species.

[0044] "Humanized antibody" refers to an antibody in which at least one amino acid in a framework region of a non-human variable region is replaced with the corresponding amino acid in a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or fragment thereof. In some embodiments, the humanized antibody is a Fab, scFv, (Fab')2, etc.

[0045] As used herein, "human antibody" refers to antibodies produced in humans, antibodies produced in non-human animals that contain human immunoglobulin genes, such as the XenoMouse®, and antibodies selected using in vitro methods, such as phage display, where the antibody repertoire is based on human immunoglobulin sequences.

[0046] The term "leader sequence" refers to a sequence of amino acid residues located at the N-terminus of a polypeptide that facilitates secretion of the polypeptide from a mammalian cell. Leader sequences may be cleaved to form the mature protein during transport of the polypeptide from a mammalian cell. Leader sequences may be natural or synthetic and may be heterologous or homologous to the protein to which they are attached.

[0047] "Percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, and do not take into account conservative substitutions as part of the sequence identity, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways that are within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared.

[0048] The term "inhibition" or "inhibiting" refers to the reduction or cessation of any event (such as ligand binding of a protein) to the reduction or cessation of any phenotypic trait, or the reduction or cessation of the incidence, extent, or likelihood of that trait. "Reduce" or "inhibit" means to decrease, decrease, or stop an activity, function, and / or amount compared to a reference. Inhibition or reduction need not be complete. For example, in certain embodiments, "reduce" or "inhibit" refers to the ability to cause an overall reduction of 20% or more. In another embodiment, "reduce" or "inhibit" refers to the ability to cause an overall reduction of 50% or more. In yet another embodiment, "reduce" or "inhibit" refers to the ability to cause an overall reduction of 75%, 85%, 90%, 95%, or more.

[0049] "Sample" or "subject sample" or "biological sample" generally refers to a sample that can be tested for a particular molecule. Samples include, but are not limited to, cells, bodily fluids including blood, serum, plasma, urine, saliva, stool, tears, pleural fluid, etc.

[0050] The terms "agent" and "test compound" are used interchangeably herein and refer to a chemical compound, a mixture of compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Biopolymers include siRNAs, shRNAs, antisense oligonucleotides, peptides, peptide / DNA complexes, and any nucleic acid-based molecule that exhibits the ability to modulate the activity of SNP-containing nucleic acids or their encoded proteins as described herein. Agents are evaluated for potential biological activity by inclusion in screening assays described below.

[0051] A "subject" may be a mammalian animal. In any of the embodiments involving a subject, the subject may be a human. In any of the embodiments involving a subject, the subject may be a cow, a pig, a monkey, a sheep, a dog, a cat, a fish, or a poultry.

[0052] As used herein, a "pediatric" subject is a human under the age of 18, while an "adult" subject is 18 or older.

[0053] "Treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Subjects in need of treatment include those already with the disorder, those susceptible to the disorder, or those in which the disorder is to be prevented. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, a stable (i.e., not worsening) state of disease, a delay or slowing of disease progression, improvement or palliation of the disease state, and remission (partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Subjects in need of treatment include those already with the condition or disorder, those susceptible to the condition or disorder, or those in which the condition or disorder is to be prevented.

[0054] The term "effective amount" or "therapeutically effective amount" refers to an amount of a drug effective to treat a disease or disorder in a subject, such as partially or completely alleviating one or more symptoms. In some embodiments, an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0055] Methods of Treating Ulcerative Colitis with Anti-LIGHT Antibodies In some embodiments, a method of treating a subject having ulcerative colitis or an inflammatory disease associated with ulcerative colitis is provided, the method comprising administering an anti-LIGHT antibody to a subject in need thereof. In some embodiments, the subject has failed treatment with an approved therapeutic dose of an anti-TNFα monoclonal antibody, where there is no initial response or there is an initial response to induction followed by loss of response. In some embodiments, the anti-LIGHT antibody is administered at a dose of about 1.0 mg / kg to about 3.0 mg / kg every 14 days. In some embodiments, the anti-LIGHT antibody is administered at a dose of 1.0 mg / kg every 14 days. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3.0 mg / kg every 14 days. In some embodiments, the anti-LIGHT antibody is administered subcutaneously. In some embodiments, the method further comprises assaying free LIGHT before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the subject has elevated free LIGHT. In some embodiments, the subject is a human. In some embodiments, the subject is an adult. In some embodiments, the subject is a pediatric subject.

[0056] In some embodiments, administration of an anti-LIGHT antibody reduces serum free LIGHT in a subject.

[0057] The Mayo score is the best-known indicator of disease activity in UC. It is a composite instrument scored on a scale of 0–12, including stool frequency (score 0–3), rectal bleeding (score 0–3), physician global assessment (score 0–3), and sigmoidoscopy / endoscopy assessment (score 0–3). (Peyrin-Biroulet et al.,Defining disease severity in inflammatory bowel diseases: current and future directions,Clinical Gastroenterology and Hepatology 2016:14:348-354;Lewis et al.,Use of the non-invasive components of the Mayo Score to assess clinical response in ulcerative colitis,Inflammatory Bowel Disease,2008:14(12):1660-1666). Parts of the Mayo score can also be used alone, such as the endoscopic Mayo score. (Ungaro et al., Ulcerative colitis, Lancet, 2017:389;1756-1770).

[0058] Patient-reported outcomes are measurements obtained directly from the patient about any aspect of their health status and can be treatment endpoints for UC. Several scales, such as the Inflammatory Bowel Disease Questionnaire (IBD-Q), are used to assess the patient's perspective on the disease (Peyrin-Biroulet 2016).

[0059] In some embodiments, administration of an anti-LIGHT antibody reduces the subject's endoscopic Mayo score compared to the subject's endoscopic Mayo score before administration of the anti-LIGHT antibody or compared to a subject not administered the anti-LIGHT antibody, hi some embodiments, administration of an anti-LIGHT antibody reduces the subject's total Mayo score compared to the subject's total Mayo score before administration of the anti-LIGHT antibody or compared to a subject not administered the anti-LIGHT antibody.

[0060] In some embodiments, administration of an anti-LIGHT antibody increases the subject's IBD-Q score, e.g., compared to the subject's IBD-Q score before administration of the anti-LIGHT antibody, or compared to a subject not administered an anti-LIGHT antibody. In some embodiments, administration of an anti-LIGHT antibody increases the subject's IBD-Q score to 170 or greater. In some embodiments, administration of an anti-LIGHT antibody increases the subject's IBD-Q score by at least 16 points. In some embodiments, administration of an anti-LIGHT antibody increases the subject's IBD-Q score by at least 32 points.

[0061] Anti-LIGHT antibody In some embodiments, anti-LIGHT antibodies are utilized for both detection / diagnostic and therapeutic purposes and in the assays described herein. The anti-LIGHT antibody used for detection or diagnostic purposes can be different or the same (even in the same subject) as the antibody used for therapeutic purposes.

[0062] In some embodiments, an anti-LIGHT antibody useful for therapeutic purposes may comprise the CDR sequences of the E1, E13, E63, F19, or F23 antibodies provided in WO2008 / 027338 and US8,058,402B2, US8,461,307B2, and US8,974,787B2, each of which is incorporated herein by reference. In some embodiments, an anti-LIGHT antibody useful for detection / diagnostic purposes is not the same as one used for therapeutic purposes.

[0063] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 2, 3, and 4, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 5, 6, and 7, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 2, 3, and 4, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 5, 6, and 7, respectively.

[0064] In some embodiments, an anti-LIGHT antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 84, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 84. In some embodiments, an anti-LIGHT antibody comprises a light chain variable region sequence comprising SEQ ID NO: 85, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 85. In some embodiments, an anti-LIGHT antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 84, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 84, and a light chain variable region sequence comprising SEQ ID NO: 85, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO: 85.

[0065] In some embodiments, an anti-LIGHT antibody comprises a heavy chain sequence comprising SEQ ID NO:8, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO:8. In some embodiments, an anti-LIGHT antibody comprises a light chain sequence comprising SEQ ID NO:9, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO:9. In some embodiments, an anti-LIGHT antibody comprises both a heavy chain comprising SEQ ID NO:8, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO:8, and a light chain comprising SEQ ID NO:9, or a sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity to SEQ ID NO:9.

[0066] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 10, 11, and 12, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 13, 14, and 15, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 10, 11, and 12, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 13, 14, and 15, respectively.

[0067] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 16, 17, and 18, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 19, 20, and 21, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 16, 17, and 18, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 19, 20, and 21, respectively.

[0068] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 22, 23, and 24, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 25, 26, and 27, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 22, 23, and 24, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 25, 26, and 27, respectively.

[0069] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 28, 29, and 30, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 31, 32, and 33, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 28, 29, and 30, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 31, 32, and 33, respectively.

[0070] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 34, 35, and 36, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 37, 38, and 39, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 34, 35, and 36, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 37, 38, and 39, respectively.

[0071] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 40, 41, and 42, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 43, 44, and 45, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 40, 41, and 42, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 43, 44, and 45, respectively.

[0072] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising SEQ ID NOs: 46, 47, and 48, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising SEQ ID NOs: 49, 50, and 51, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising SEQ ID NOs: 46, 47, and 48, respectively, and the light chain comprises three CDR sequences comprising SEQ ID NOs: 49, 50, and 51, respectively.

[0073] In some embodiments, an anti-LIGHT antibody may comprise the CDR sequences of the antibodies described in US2013 / 0323240 and US8,524,869 B2, which are incorporated herein by reference. In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 52, 53, and 54, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 55, 56, and 57, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 52, 53, and 54, respectively, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 55, 56, and 57, respectively.

[0074] In some embodiments, an anti-LIGHT antibody comprises a heavy chain variable region sequence comprising SEQ ID NO:58, or at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:58. In some embodiments, an anti-LIGHT antibody comprises a light chain variable region sequence comprising SEQ ID NO:59, or at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:59. In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising SEQ ID NO:58, or at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:58. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising SEQ ID NO:59, or at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:59. In some embodiments, an anti-LIGHT antibody comprises both a heavy chain comprising SEQ ID NO:58, or at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:58, and a light chain comprising SEQ ID NO:59, or at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:59.

[0075] In some embodiments, the anti-LIGHT antibody is selected from the group consisting of the following set forth in the sequence listing of US2013 / 0323240: SEQ ID NOs: 18, 19, 20 and SEQ ID NOs: 38, 41, 42 of US2013 / 0323240; SEQ ID NOs: 18, 19, 21 and SEQ ID NOs: 39, 41, 42 of US2013 / 0323240; SEQ ID NOs: 18, 19, 22 and SEQ ID NOs: 40, 41, 42 of US2013 / 0323240; SEQ ID NOs: 23, 24, 25 and SEQ ID NOs: 43, 44, 45 of US2013 / 0323240; The antibody may comprise a heavy chain and a light chain that together comprise one of the sets of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences of sequence numbers 26, 27, 28 and SEQ ID NOs: 46, 47, 48 of US2013 / 0323240, SEQ ID NOs: 29, 30, 31 and SEQ ID NOs: 49, 50, 51 of US2013 / 0323240, SEQ ID NOs: 32, 33, 34 and SEQ ID NOs: 52, 53, 54 of US2013 / 0323240, and SEQ ID NOs: 35, 36, 37 and SEQ ID NOs: 55, 50, 51 of US2013 / 0323240.

[0076] In some embodiments, an anti-LIGHT antibody comprises the CDR sequences of the 18E04, 98C07, 1C02, 1C06, 13H04, 31A10, 98C07, 42A02, 29C02, 14B09, 117C06, 114F05, and 62C01 antibodies described in WO2015 / 107331, which are also incorporated by reference herein.

[0077] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising each of SEQ ID NOs: 60, 61, and 62, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising each of SEQ ID NOs: 63, 64, and 65, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 60, 61, and 62, respectively, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 63, 64, and 65, respectively.

[0078] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising each of SEQ ID NOs: 66, 67, and 68, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising each of SEQ ID NOs: 69, 70, and 71, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 66, 67, and 68, respectively, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 69, 70, and 71, respectively.

[0079] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising each of SEQ ID NOs: 72, 73, and 74, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising each of SEQ ID NOs: 75, 76, and 77, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 72, 73, and 74, respectively, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 75, 76, and 77, respectively.

[0080] In some embodiments, an anti-LIGHT antibody comprises a heavy chain that comprises three CDR sequences comprising each of SEQ ID NOs: 78, 79, and 80, respectively. In some embodiments, an anti-LIGHT antibody comprises a light chain that comprises three CDR sequences comprising each of SEQ ID NOs: 81, 82, and 83, respectively. In some embodiments, an antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 78, 79, and 80, respectively, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 81, 82, and 83, respectively.

[0081] Free LIGHT detection assay Most of the currently available assays only measure total LIGHT, including LIGHT bound to its receptor, including DcR3.Total LIGHT may not accurately represent the level of LIGHT that causes illness, which may be unbound free LIGHT.Therefore, when the method includes the detection of free LIGHT, it may be desirable to use an assay that only measures free LIGHT. EXAMPLES

[0082] Example 1 There is an existing clinical research protocol for an escalating dose, open-label, signal-finding study to evaluate the safety, tolerability, and short-term efficacy of anti-LIGHT monoclonal antibodies in adults with moderate to severe active Crohn's disease, with or without loss-of-function mutations in decoy receptor 3 (DcR3), who have failed prior treatment with anti-TNFα agents. The anti-LIGHT monoclonal antibody comprises six CDRs: a heavy chain CDR having the amino acid sequence of SEQ ID NO:2, a heavy chain CDR having the amino acid sequence of SEQ ID NO:3, a heavy chain CDR having the amino acid sequence of SEQ ID NO:4, a light chain CDR having the amino acid sequence of SEQ ID NO:5, a light chain CDR having the amino acid sequence of SEQ ID NO:6, and a light chain CDR having the amino acid sequence of SEQ ID NO:7. In some embodiments, the anti-LIGHT monoclonal antibody has a variable heavy chain (VH) having the amino acid sequence of SEQ ID NO:84 and a variable light chain (VL) having the amino acid sequence of SEQ ID NO:85. In some embodiments, the anti-LIGHT monoclonal antibody has a heavy chain having the amino acid sequence of SEQ ID NO:8 and a light chain having the amino acid sequence of SEQ ID NO:9. This protocol will be modified to include subjects with ulcerative colitis who have failed previous treatment with an anti-TNFα agent. The following is part of the existing Crohn's disease protocol and applies to subjects currently being added to the study with UC.

[0083] Study objectives and endpoints The primary objective of this study was to evaluate the safety and tolerability of anti-LIGHT monoclonal antibody administered by SQ injection in adults with moderately to severely active CD who had failed previous treatment with anti-tumor necrosis factor α (anti-TNFα) agents.

[0084] The secondary objectives of this study are: to estimate the plasma concentrations of anti-LIGHT monoclonal antibody administered by SQ injection in adults with moderately to severely active CD and to evaluate the response to treatment with anti-LIGHT monoclonal antibody administered by SQ injection in adults with moderately to severely active CD.

[0085] Study design This is a Phase 1b, multicenter, open-label, dose-escalation, signal-finding study to evaluate the safety, tolerability, PK, and short-term efficacy of anti-LIGHT monoclonal antibody in adults with moderately to severely active CD who have failed previous anti-TNFα treatment.

[0086] Four patients with Crohn's disease who meet all eligibility criteria will be enrolled in each of two dose cohorts: Cohort 1 will receive anti-LIGHT monoclonal antibody at 1.0 mg / kg SQ every 14 days (q14);

[0087] Dose escalation will proceed after completion of the first cohort and a decision to proceed to the second cohort will be made based on review of cumulative safety, tolerability, pharmacokinetic, and efficacy data by a Data Monitoring Committee. If permitted by review of safety data, the estimated dose escalation for the second cohort will be 3.0 mg / kg SQ every 14 days.

[0088] Each subject's participation includes a screening period, which includes, as appropriate, a 12-week washout period for subjects receiving biologic therapy or who have received biologic therapy within 12 weeks of the screening visit. For subjects who require a washout, there is an optional 1-14 day period between the screening visit and the start of the washout period, as appropriate. Except for subjects who require washout of the biologic certolizumab pegol (Cimzia), only subjects who do not have detectable biologic levels after the 8-week washout will be allowed to enter the study after confirmation of undetectable levels, and all other subjects (including those receiving certolizumab pegol [Cimzia]) will be required to complete a 12-week washout period. The washout period includes the period from the last dose received prior to the screening visit. Subjects who do not require a biologic washout period will be allowed to enter the study after screening and confirmation of eligibility. Screening is followed by an 8-week open-label treatment period, with a safety follow-up visit approximately 4 weeks after the last dose. The maximum study duration is 26 weeks.

[0089] Study visits will occur at screening and on days 0, 7, 14, 21, 28, 35, 42, 49, and 56. A safety follow-up visit will occur on day 84.

[0090] Research period The study will include a screening period, an open-label treatment period, and safety follow-up visits. The 1.0 mg / kg dose cohort will complete the study period described below. Decisions will be made after reviewing the safety data.

[0091] Number of targets Four subjects will be enrolled in each of two planned dose cohorts for a maximum of eight study subjects. Subjects who discontinue the study before receiving the third dose will be allowed to refill.

[0092] Treatment Allocation The first cohort of subjects will be assigned to a 1.0 mg / kg dose of anti-LIGHT monoclonal antibody. Subjects will be assigned to a second dose cohort after DMC review of safety data from the first cohort and if study discontinuation criteria are not met.

[0093] Study Inclusion Criteria Subjects who meet all of the following inclusion criteria are eligible to enroll in the study: 1. Subjects were fluent in English and provided written informed consent for this study. 2. The subjects are men or women aged 18 to 75 years. 3. Subject has a documented diagnosis of CD by endoscopy / colonoscopy and histological confirmation. 4. Subject has moderate to severe active CD as evidenced by Simplified Endoscopic Score for Crohn's Disease (SES-CD) score ≧7 and histological confirmation. 5. Subject has failed treatment with an approved therapeutic dose of anti-TNFα monoclonal antibody therapy, as defined below, either with no initial response (primary non-responder) or with an initial response to induction followed by loss of response (secondary non-responder). 6. Subject is permitted to receive concomitant treatment with oral corticosteroids and / or azathioprine, 6-mercaptopurine (6-MP), or methotrexate (MTX). 7. Subject agrees to be genotyped at the DcR3 locus.

[0094] A primary non-responder is defined as a subject who has experienced an inadequate initial response to treatment with infliximab, adalimumab, or certolizumab pegol. Details of inadequate initial response symptoms occur >2 weeks after the last dose of induction therapy. An algorithm for defining an inadequate initial response is provided below. Subjects classified as primary non-responders meet both parts of the algorithm. Required documentation includes the date and dose of induction therapy failure and lack of response details regarding disease activity recorded by the treating clinician.

[0095] The following algorithm is used in the event of an inadequate initial response to current or previous treatment with infliximab, adalimumab, or certolizumab pegol. Subjects have received induction doses of either infliximab (>5 mg / kg in two or three doses), adalimumab (>80 mg after a dose of 160 mg, or >40 mg after a dose of 80 mg), or certolizumab pegol (>400 mg in two or three doses), and the subject has not initially responded to these induction doses, as evidenced by the presence of at least one of the following signs or symptoms associated with Crohn's disease activity: lack of improvement or worsening in stool frequency, lack of improvement or worsening in daily abdominal pain, development, lack of improvement or worsening of fever associated with Crohn's disease, recurrent drainage from previously non-draining fistulas or development of new draining fistulas, lack of improvement or worsening in rectal bleeding, or initiation or increase in antidiarrheal medication.

[0096] Secondary non-responders are defined as subjects who experienced an initial response to treatment with infliximab, adalimumab, or certolizumab pegol followed by loss of response. Details of loss of response occur more than 2 weeks after the last dose of maintenance therapy. The algorithm for defining loss of response is described below. Subjects classified as secondary non-responders fulfill both parts of the algorithm. Required documentation includes dates and doses of treatment induction and maintenance, details regarding initial response and subsequent loss of response, and disease activity as recorded by the treating clinician. Below is the algorithm for loss of response to prior treatment with infliximab, adalimumab, or certolizumab pegol. The subject responded to induction therapy at the doses listed above and received at least two maintenance doses of infliximab (>5 mg / kg), adalimumab (>40 mg dose, or >20 mg if ineffective as a pediatric dose), or certolizumab pegol (>400 mg), to which the subject did not respond as evidenced by the presence of at least one of the following signs or symptoms associated with Crohn's disease activity: worsening stool frequency, worsening daily abdominal pain, development or worsening of Crohn's disease-associated fever, recurrent drainage from previously non-draining fistulas or development of new draining fistulas, worsening rectal bleeding, or initiation or increase in anti-diarrheal medication.

[0097] Exclusion criteria Subjects who meet any of the following exclusion criteria are not eligible to enroll in the study: 1. Subject is diagnosed with ulcerative colitis (UC) or indeterminate colitis. 2. Subject is unable or unwilling to undergo study procedures such as endoscopy or biopsy during the study. 3. Subject has signs or symptoms of ileus and has small bowel imaging supporting an obstruction. 4. The subject was determined by the investigator to have short bowel syndrome. 5. Subject currently has a functioning colostomy or ileostomy. 6. Subject has undergone surgical bowel resection within the past 6 months prior to screening or is scheduled for resection during the study period. 7. In the investigator's opinion, clinical suspicion of intraabdominal abscess exists. 8. Subject has concurrent intestinal metaplasia or a history of intestinal metaplasia within 5 years prior to screening. 9. Subject has known active and / or positive test for C. difficile infection. 10. Subject has a history of or current diagnosis of any cancer, except cancer that has been cured by surgical resection (e.g., non-melanoma skin cancer). 11. Subject has a history of lymphoproliferative disorders, including lymphoma, or any signs or symptoms suggestive of lymphoproliferative disorders. 12.Subject has a history of TB infection, active TB infection, or has a positive TB test at screening. 13. Subject has known viral hepatitis, acquired immune deficiency syndrome (AIDS), or known human immunodeficiency virus (HIV) infection. 14. Subject is treated with natalizumab (TYSABRI®). 15. Subject will not complete the primary vaccination series (specifically Hepatitis B, Chickenpox, Measles / Mumps / Rubella) unless immunity is documented by blood titers. 16.Subject will receive a live attenuated vaccine such as varicella-zoster, oral polio, or rubella within 3 months prior to the baseline visit. 17. Subject has any of the following abnormal screening laboratory test results: clinically significant electrocardiogram abnormalities, aspartate transaminase (AST), alanine transaminase (ALT) or total bilirubin greater than ULN, hemoglobin less than 10 g / dL, absolute neutrophil count greater than 1500 cells / mm 3 or an estimated glomerular filtration rate of 60 mL / min / 1.73 m 2 is less than. 18. Subject exhibits abnormal vital signs during Screening (Visit 1) or prior to enrollment at the Baseline visit (Visit 2). 19. Subject is a pregnant or nursing mother. 20. Subject is sexually active but does not use effective contraception. 21. Subject has a history of substance abuse that may prevent participation in a clinical study. 22. Subject has a current or recent medical history (within 6 months prior to screening) of significant and severe renal, hepatic, hematological, gastrointestinal (other than CD or conditions listed above), endocrine, pulmonary, cardiac, or neurological disease. 23. The subject has any other clinically significant mental or physical illness or infection which, in the opinion of the investigator, may confound the results of the study, pose additional risks to the subject's participation, or may prevent or interfere with the subject's completion of the study. 24. The investigator has concerns about the subject's safety, compliance, or suitability to participate in the study.

[0098] Treatment of the subject Subjects in each dose cohort will receive the investigational drug as a single SQ injection in the abdominal area 4-10 cm from the umbilicus, with the injection site rotating for each subsequent dose. Doses of anti-LIGHT monoclonal antibody will be administered on days 0, 14, 28, and 42. After day 0, injections will occur within ±3 days of scheduled 14-day intervals.

[0099] Subjects in the first dose cohort will receive 1.0 mg / kg of anti-LIGHT monoclonal antibody throughout the 8-week open-label treatment period. Data from this cohort will be reviewed after all subjects have completed the treatment period and associated evaluations and before the second cohort is enrolled. There is expected to be an interval of at least 2 weeks between a subject's last visit and review of cumulative safety, tolerability, pharmacokinetic, and efficacy data.

[0100] Eligible subjects in the second dose cohort will receive 3.0 mg / kg of anti-LIGHT monoclonal antibody throughout the 8-week open-label treatment period. Data from the second cohort will be reviewed after all subjects have completed the treatment period and its associated evaluations.

[0101] Permitted Treatments Subjects will be permitted to receive concomitant treatment with oral corticosteroids and / or azathioprine, 6-MP, or MTX. Subjects will not be permitted to increase the dose of these agents during the study. If an increase in dose of permitted concomitant therapy is required, subjects will be discontinued from the study utilizing an Early Termination Visit procedure. Concomitant treatment with oral corticosteroids and / or azathioprine, 6-MP, or MTX is defined as follows: For oral corticosteroids, the prednisone dose did not exceed 40 mg / day and was a stable dose for at least 2 weeks prior to baseline; for azathioprine or 6-MP, an azathioprine dose of at least 2 mg / kg / day or a 6-MP dose of 1 to 1.5 mg / kg / day rounded to the nearest available tablet formulation or the maximum tolerated dose considered by the investigator for the subject, a stable dose for at least 8 weeks prior to baseline, or a stable dose for at least 4 weeks prior to baseline; or an MTX dose of 25 mg / week given either SQ, IM, or orally during the study for at least 8 weeks prior to baseline and a stable dose for at least 4 weeks prior to baseline.

[0102] Doses of these therapies are allowed to be reduced during the study, provided that all doses are within the combinations and dose ranges specified above. These changes will be recorded in the concomitant medication eCRF.

[0103] For subjects receiving corticosteroids at study enrollment, on-study weaning will occur according to the following rules: corticosteroid dose >20 mg with a maximum tapering rate of 10 mg per week, dose between 10 and <20 mg with a maximum tapering rate of 5 mg per week, or dose <10 mg with a maximum tapering rate of 2.5 mg per week. Subjects will be discontinued from the study if deviations from permitted concomitant therapy combinations, dose ranges, or weaning schedules are necessary.

[0104] Prohibited Treatments Concomitant use of study biologic therapy, including use of anakinra (KINERET®, Amgen), abatacept (ORENCIA®, Bristol-Myers Squibb), or tocilizumab (ACTEMRA®, Genentech), is prohibited. A washout period of up to 12 weeks is required prior to study enrollment (Visit 2) and after confirmation of eligibility via screening procedures performed at Visit 1 for all biologic therapy received within 12 weeks of the screening visit. Subjects previously treated with natalizumab (TYSABRI®, Biogen) are excluded from participation.

[0105] Vaccination with live or attenuated viruses within 3 months prior to screening and at any time during the study is prohibited.

[0106] Randomization and blinding All subjects will receive anti-LIGHT monoclonal antibody in an open-label fashion.

[0107] Investigational Drug Anti-LIGHT monoclonal antibody is the investigational product used in this study, with a heavy chain sequence of SEQ ID NO:8 and a light chain sequence of SEQ ID NO:9. It is administered in the form of a 150 mg / mL solution. The unit dose is 1.0 mg / kg or 3.0 mg / kg. The route of administration is SQ injection into an area 4-10 cm from the umbilicus in the abdomen, with rotation of the injection site for each subsequent dose. It is a colorless to slightly tan solution. It is manufactured by the Sanofi-Aventis Group.

[0108] Administration Anti-LIGHT monoclonal antibody is administered by SQ injection into an area 4-10 cm from the umbilicus in the abdomen, with the injection site rotated for each subsequent administration.

[0109] Research period The total study duration will be approximately 26 weeks (including up to 14 weeks of screening [with up to 12 weeks of washout, if necessary], 56 days of open-label treatment, and a follow-up visit approximately 28 days after the last dose of study drug).

[0110] The planned sequence and maximum duration of the studies are as follows: 1. Screening period: Approximately 14 weeks 2. Washout period (if applicable): up to 12 weeks after the last dose of the target biologic treatment 3. Open-label treatment period: 56 days (starting on day 0, dosed every 14 days) 4. Follow-up: 28 days after the last dose of study drug. The maximum study duration for each subject is approximately 26 weeks.

[0111] The maximum treatment duration for each subject will be approximately 56 days, with SQ injections beginning on day 0 and continuing every 14 (± 3) days through day 42.

[0112] NOTE: Extension of the screening window to accommodate clinical laboratory retest periods (except for endoscopy with biopsy) is permitted but not to exceed a total screening period of 16 weeks.

[0113] Safety assessment Safety assessments will include monitoring for AEs, clinical laboratory tests, vital sign measurements, physical examination (including weight measurement), and 12-lead ECG parameters. Demographic information, medical and medication history will be obtained at the screening visit.

[0114] All safety assessments will be recorded in the appropriate eCRF.

[0115] Decoy receptor 3 genotyping Two milliliters of saliva for genotyping will be collected in a designated collection vehicle according to the manufacturer's instructions.

[0116] Deoxyribonucleic acid (DNA) is isolated from each subject's saliva sample and assessed for genetic alterations in TNFRSF6B, which encodes the protein DcR3, or alterations in at least one DcR3 network gene. All genotyping is performed in a CLIA-certified laboratory as specified in the laboratory manual(s) and guidance(s). The remaining DNA sample is stored for future biomarker studies.

[0117] Exploratory analyses of LIGHT, cytokines, RNA sequencing and flow cytometry Blood samples are collected for exploratory analyses, including, but not limited to, LIGHT biomarkers, cytokines (e.g., IL-1 beta, IL-6, IL-8, TNF-α, and other exploratory cytokines), ribonucleic acid (RNA) sequencing, and flow cytometry of peripheral blood leukocytes.

[0118] Endoscopy with biology and histology All subjects enrolled in the study will undergo endoscopy with biopsy at screening and again on day 56 (visit 10) or early termination. Screening endoscopy will be performed optionally as a stand-alone endoscopy for purposes of this protocol or as clinically indicated endoscopy, provided that consent procedures for this study have been completed prior to endoscopy.

[0119] The SES-CD is used for endoscopic evaluation. The SES-CD is a simple and easy-to-use endoscopic scoring system developed specifically for CD. Four variables are assessed across four categories on a scale of 0 to 3 for each variable: ulcer size, percentage of ulcerated surface, percentage of affected surface, and presence or absence of stenosis (Daperno M, D'Haens G, Van Assche G et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastroinest Endosc. 2004 Oct;60(4):505-12). Biopsies taken at screening are evaluated for histological confirmation of disease. Each subject undergoes screening and visit 10 / ET biopsy samples saved for evaluation of exploratory parameters (including but not limited to DcR3, LIGHT, HVEM, and LTβR) that can be optionally performed after study completion.

[0120] Patient-reported assessments of health status, abdominal pain, and bowel movement frequency All subjects enrolled in the study will report in a diary (electronic or hard copy) a daily assessment of their well-being, abdominal pain, and number of bowel movements, including loose and watery stools. Abdominal pain will be rated on a scale of 0 to 3, with higher values ​​indicating greater severity of pain. Stool frequency, including the number of loose and / or watery stools per day (corresponding to a score of 6 or 7 on the Bristol Stool Scale), will be recorded.

[0121] Loose stool refers to fluffy parts with jagged edges, i.e., mushy stool. Watery stool is described as watery and devoid of solid matter (O'Donnell et al., Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate, Br. Med. J. 1990;300:439-40).

[0122] Quality of Life Assessment - Inflammatory Bowel Disease Questionnaire The IBD-Q is a 32-item questionnaire validated to measure quality of life in Crohn's disease. It assesses aspects of bowel function, emotional state, general symptoms, and social functioning (Guyatt et al., A new measure of health status for clinical trials in inflammatory bowel disease, Gastroenterol., 1989:96;804-10). The IBD-Q will be completed by all subjects at screening (Visit 1), prior to dosing (Visit 2), and at the end or early termination of the open-label treatment period (Visit 10 / ET).

[0123] Table 1 below provides the sequences referred to in this application. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Claims

1. A composition comprising an anti-LIGHT antibody for use in a method of treating ulcerative colitis or an inflammatory disease associated with ulcerative colitis, said method comprising administering said composition to a subject in need thereof, wherein said subject in need thereof has failed treatment with an approved therapeutic dose of an anti-TNFα monoclonal antibody, in which case there is no initial response or there is an initial response to induction followed by loss of response, and said anti-LIGHT antibody has the following set of amino acid sequences for CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3: (a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7, (b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15, (c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21, (d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27, (e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33, (f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39, (g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, (h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and (i) SEQ ID NOs: 52, 53, 54, 55, 56, and 57, and comprises a heavy chain and a light chain that together include one of the above, wherein said anti-LIGHT antibody is administered at a dose of 1.0 mg / kg or 3.0 mg / kg every 14 days. A composition.

2. A composition comprising an anti-LIGHT antibody for use in a method of treating ulcerative colitis or an inflammatory disease associated with ulcerative colitis, said method comprising administering said composition to a subject in need thereof, wherein said subject in need thereof has failed treatment with an approved therapeutic dose of an anti-TNFα monoclonal antibody, in which case there is no initial response or there is an initial response to induction followed by loss of response, and said anti-LIGHT antibody is as follows: (a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7, (b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15, (c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21, (d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27, (e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33, (f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39, (g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, (h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and (i) One of the sets of amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NOs: 52, 53, 54, 55, 56, and 57, A composition comprising a heavy chain and a light chain that together contain one of the sets of amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

3. A composition comprising an anti-LIGHT antibody for use in a method of treating ulcerative colitis or an inflammatory disease associated with ulcerative colitis, the method comprising administering the composition to a subject in need thereof, wherein the anti-LIGHT antibody is as follows: (a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7, (b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15, (c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21, (d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27, (e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33, (f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39, (g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, (h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and (i) SEQ ID NOs: 52, 53, 54, 55, 56, and 57, A composition comprising a heavy chain and a light chain that together contain one of the sets of amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein the anti-LIGHT antibody is administered at a dose of 1.0 mg / kg or 3.0 mg / kg every 14 days.

4. A composition comprising an anti-LIGHT antibody for use in a method of treating ulcerative colitis or an inflammatory disease associated with ulcerative colitis, the method comprising administering the composition to a subject in need thereof, wherein the anti-LIGHT antibody is as follows: (a) SEQ ID NOs: 2, 3, 4, 5, 6, and 7, (b) SEQ ID NOs: 10, 11, 12, 13, 14, and 15, (c) SEQ ID NOs: 16, 17, 18, 19, 20, and 21, (d) SEQ ID NOs: 22, 23, 24, 25, 26, and 27, (e) SEQ ID NOs: 28, 29, 30, 31, 32, and 33, (f) SEQ ID NOs: 34, 35, 36, 37, 38, and 39, (g) SEQ ID NOs: 40, 41, 42, 43, 44, and 45, (h) SEQ ID NOs: 46, 47, 48, 49, 50, and 51, and (i) SEQ ID NOs: 52, 53, 54, 55, 56, and 57, A composition comprising a heavy chain and a light chain together containing one of the sets of amino acid sequences of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

5. The composition according to claim 1, wherein the anti-LIGHT antibody is administered subcutaneously.

6. The composition according to claim 1, wherein the method further comprises assaying free LIGHT before, during, or after administration of the anti-LIGHT antibody.

7. The composition according to claim 1, wherein the subject has elevated free LIGHT.

8. The composition according to claim 1, wherein the subject is human.

9. The composition according to claim 1, wherein the subject is an adult.

10. The composition according to claim 1, wherein the subject is a pediatric subject.

11. The composition according to any one of claims 1 to 10, wherein the anti-LIGHT antibody comprises a variable heavy chain (VH) comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identity to SEQ ID NO:

84.

12. The composition according to any one of claims 1 to 10, wherein the anti-LIGHT antibody comprises a variable light chain (VL) comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identity to SEQ ID NO:

85.

13. The composition according to any one of claims 1 to 10, wherein the anti-LIGHT antibody comprises a VH comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identity to SEQ ID NO: 84, and a VL comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identity to SEQ ID NO:

85.

14. The composition according to any one of claims 1 to 10, wherein the anti-LIGHT antibody comprises a heavy chain comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identity to SEQ ID NO:

8.

15. The composition according to any one of claims 1 to 10, wherein the anti-LIGHT antibody comprises a light chain comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identity to SEQ ID NO:

9.

16. The composition according to any one of claims 1 to 10, wherein the anti-LIGHT antibody comprises a heavy chain comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to SEQ ID NO: 8, and a light chain comprising an amino acid sequence that is at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to SEQ ID NO:

9.

17. The composition according to claim 13, wherein administration of the anti-LIGHT antibody reduces the endoscopic Mayo score of the subject.

18. The composition according to claim 13, wherein administration of the anti-LIGHT antibody reduces the total Mayo score of the subject.

19. The composition according to claim 13, wherein administration of the anti-LIGHT antibody increases the IBD-Q score of the subject.

20. The composition according to claim 13, wherein administration of the anti-LIGHT antibody reduces the serum free LIGHT of the subject.