How to treat asthma with anti-LIGHT antibodies

Abstract

The present disclosure relates to methods of treating asthma, including noneosinophilic asthma (NEA), with anti-LIGHT antibodies.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 296,786, filed January 5, 2022, and U.S. Provisional Application No. 63 / 396,308, filed August 9, 2022, the contents of each 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, and is incorporated herein by reference in its entirety. The XML copy created on December 5, 2022 is titled "2022-12-05_01118-0061-00PCT_Seq_List_ST26.xml" and is 109,188 bytes in size.

[0003] The present disclosure relates to methods of treating asthma, including non-eosinophilic asthma (NEA), with anti-LIGHT antibodies. [Background technology]

[0004] Asthma is a chronic lung disease characterized by airway inflammation that causes swelling and excessive mucus production. As a result, patients experience difficulty breathing, which can become life-threatening in severe cases. (Boulet et al., Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1308-1313) The prevalence of asthma in the United States is estimated at 25 million. (Asthma and Allergy Foundation of America, Asthma facts and figures, https: / / www.aafa.org / asthma-facts / (accessed January 3, 2022)) According to the CDC, more than 50% of patients with current asthma had uncontrolled asthma. (Centers for Disease Control and Prevention. AsthmaStats: Uncontrolled asthma among adults, 2016, https: / / www.cdc.gov / asthma / asthma_stats / uncontrolled-asthma-adults.htm (accessed January 3, 2022)). Asthma is associated with environmental and / or host factors such as smoking, pollution, infection, and obesity. Patients present with respiratory symptoms such as wheezing, shortness of breath, coughing, and chest tightness.

[0005] There is a classification of asthma based on the trigger (allergic vs. non-allergic) and the nature of the immune inflammatory response (Th2 or low / absent Th2) (Ray and Kolls, Trends Immunol. 2017 Dec;38(12):942-954; Wenzel et al., Am. J. Respir. Crit. Care Med. 1999;160:1001-1008; Woodruff et al., Am. J. Respir. Crit. Care Med. 2009;180(5):388-95). The allergic or Th2-biased response is associated with eosinophil subtypes and the type 2 cytokines IL-4, IL-5, and IL-13 (Lambrecht et al., Immunity. 2019;50(4):975-991). Non-allergic or low / absent Th2 responses are associated with a subpopulation of neutrophils and oligogranulocytes, which, as a group, are referred to as non-eosinophilic asthma and account for 40% to 50% of all asthma patients (Douwes et al., Thorax. 2002 Jul;57(7):643-8; Stokes and Casale, Ann. Allergy Asthma Immunol. 2016 Aug;117(2):121-5; McGrath et al., Am J Resp Crit Care Med. 2012;185(6):612-619; Jiang et al., Allergy Asthma Clin Immunol. 2021;17(1):45).

[0006] Long-term control of asthma is typically achieved by using long-acting bronchodilators in combination with inhaled corticosteroids, as needed. Biologics targeting IgE (omalizumab) or the Th2-associated cytokine pathways of IL-4 and IL-5 (mepolizumab, resilizumab, benralizumab, and dupilumab) have been approved for the treatment of patients with particularly severe allergic asthma. Cytokine pathways identified as contributing to NEA include IL-6, IL-8, IL-17, IFNγ, TNFα, and G-CSF (Lambrecht et al., Immunity. 2019;50(4):975-991). Patients with severe NEA have no approved medications related to these pathways, and therefore, a significant unmet medical need remains for these patients. Commonly used asthma medications, such as inhaled corticosteroids (ICS), may exacerbate NEA by causing elevated neutrophil levels. Many NEA patients are not controlled with existing medications (Esteban-Gorgojo et al., J Asthma Allergy. 2018;11:267-281).

[0007] LIGHT (an acronym for "homologous to Lymphotoxin, exhibits 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 additional types of antigen-presenting cells. LIGHT is considered one of the "master regulators" of the immune system and plays a key role in the signaling system that controls immune responses. LIGHT has a dual mechanism of action, exerting its effects by activating both T cells and B cells and by upregulating other inflammatory cytokines.

[0009] LIGHT activates two major receptors, herpesvirus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), both of which are expressed on lung epithelial cells. Early in infection, LIGHT is released from neutrophils and macrophages, binds to cellular receptors, triggering inflammatory cell infiltration and the release of high levels of TNF and additional pro-inflammatory cytokines. LIGHT also plays a costimulatory role in T cell activation, driving pro-inflammatory and tissue-damaging effects (Ware, Advances in Experimental Medicine and Biology 647, 146-155 (2009); Ware, Immunological Reviews 223, 186-201 (2008)). Therefore, 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 prevents its activity by competing with receptor binding. (Steinberg, et al., Seminars in Immunopathology 31, 207-221 (2009); Wroblewski, et al. Biochemical Pharmacology 65, 657-667 (2003)). In conditions of hyperinflammation and cytokine storm, DcR3 is likely overwhelmed, generating high levels of DcR3-free (active) LIGHT. Applicants have discovered that anti-LIGHT therapy may offer a therapeutic option for asthma patients, including those with poorly controlled NEA. For example, human bronchial epithelial (BEC) cells express the receptor for LIGHT (LTβR), and in vitro LIGHT stimulation of BECs results in widespread gene expression of proinflammatory mediators that are resistant to corticosteroid treatment, consistent with the clinical presentation of NEA (da Silva Antunes et al., J. Immunol., 2015;195:2429-41). Soluble proinflammatory mediators such as IL-6, IL-8, OSM, and MCP-1 were also detected in this in vitro system. Clinically, administration of an oral CXCR2 antagonist resulted in a reduction in sputum neutrophil counts and mild exacerbations (Nair et al., Clin Exp Allergy. 2012;42(7):1097-103). Elevated LIGHT levels in sputum from asthmatic patients were found to be inversely associated with lung function (forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC)) (Romeo et al., J Allergy Clin Immunol. 2013;131(2 Suppl):AB203). LIGHT was generally elevated in patients with high neutrophil counts (Hastie et al., J Allergy Clin Immunol. 2010;125(5):1028-1036). Elevated LIGHT was associated with increased cellular infiltration and Th1 cytokine levels and decreased lung function in asthma. (Romeo et al., J Allergy Clin Immunol. 2013;131(2 Suppl):AB203; Kowal et al., J Allergy Clin Immunol. 2019 Feb;143(2) supplement (Abstract); see also Doherty et al., Nat Med. 2011;17(5):596-603.) Along with soluble LIGHT detected in sputum, others have observed elevated serum levels of DcR3 in asthma patients, which are even greater during asthma exacerbations suggesting a response to elevated LIGHT levels associated with asthma and disease activity.(Kowal et al., J Allergy Clin Immunol. 2019 Feb;143(2)supplement(Abstract)).

Prior Technology Literature

Non-licensed literature

[0010] [Non-licensed document 1] Boulet et al.,Am J Respir Crit Care Med.2000 Oct;162(4 Pt 1):1308-1313 [Non-licensed document 2] Asthma and Allergy Foundation of America,Asthma facts and figures,https: / / www.aafa.org / asthma-facts / [Non-licensed document 3] Centers for Disease Control and Prevention. AsthmaStats: Uncontrolled asthma among adults, 2016, https: / / www.cdc.gov / asthma / asthma_stats / uncontrolled-asthma-adults.htm

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0011] The disclosure includes, for example, methods of treating a subject having asthma, including non-eosinophilic asthma (NEA), comprising administering to a subject in need thereof an effective amount of an anti-LIGHT antibody. Embodiment 1. A method of treating asthma, including non-eosinophilic asthma (NEA), comprising administering to a subject in need thereof an effective amount of an anti-LIGHT antibody. Embodiment 2. The anti-LIGHT antibody comprises the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: (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) the heavy chain and light chain together comprise one of SEQ ID NOs: 52, 53, 54, 55, 56, and 57. Embodiment 3. The method of embodiment 1 or 2, wherein the anti-LIGHT antibody comprises a heavy chain and a light chain that together comprise the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: SEQ ID NOs: 2, 3, 4, 5, 6, and 7. Embodiment 4. The method of any one of embodiments 1-3, wherein the subject has poorly controlled asthma as determined by an Asthma Control Questionnaire (ACQ) score of 1.5 or greater. Embodiment 5. The method of any one of embodiments 1-3, wherein the subject has asthma that is uncontrolled on a long-acting beta agonist (LABA) and an inhaled corticosteroid (ICS). Embodiment 6 The method of embodiment 5, wherein the LABA is salmeterol. Embodiment 7 The method of embodiment 5 or 6, wherein the ICS is fluticasone. Embodiment 8 The method of any one of embodiments 1-7, wherein the subject has experienced an asthma exacerbation within 25 months prior to administration of the first dose of anti-LIGHT antibody. Embodiment 9. The method of any one of embodiments 1-8, wherein the subject has a blood eosinophil count of less than 300 cells / μL. Embodiment 10. The method of any one of embodiments 1-9, wherein the subject has a blood eosinophil count of less than 150 cells / μL. Embodiment 11. The method of any one of embodiments 1-10, wherein the subject is receiving a LABA at the time of administration of the first dose of the anti-LIGHT antibody, and the LABA is discontinued about 14 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 12. The method of any one of embodiments 1-11, wherein the subject is receiving ICS at the time of administration of the first dose of the anti-LIGHT antibody, and the ICS is reduced by 50% about 28 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 13 The method of embodiment 12, wherein the ICS is discontinued about 42 days after administration of the first dose of anti-LIGHT antibody. Embodiment 14. The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of 3-12 mg / kg, 3-11 mg / kg, 3-10 mg / kg, 3-9 mg / kg, 3-8 mg / kg, 3-7 mg / kg, 3-6 mg / kg, 3-5 mg / kg, or 3-4 mg / kg. Embodiment 15 The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of 6 mg / kg. Embodiment 16 The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of 8 mg / kg. Embodiment 17. The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, or 100-200 mg. Embodiment 18 The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of about 600 mg. Embodiment 19 The method of any one of embodiments 1-18, wherein the anti-LIGHT antibody is administered about every 14 days, about every 21 days, about every 28 days, about every 35 days, about every 42 days, about every 49 days, about every 56 days, or monthly. Embodiment 20 The method of any one of embodiments 1-18, wherein the anti-LIGHT antibody is administered about every 28 days. Embodiment 21 The method of any one of embodiments 1-18, wherein the anti-LIGHT antibody is administered monthly. Embodiment 22 The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of 600 mg every 28 days. Embodiment 23 The method of any one of embodiments 1-13, wherein the anti-LIGHT antibody is administered at a dose of 600 mg monthly. Embodiment 24 The method of any one of embodiments 1-23, wherein at least three doses of an anti-LIGHT antibody are administered. Embodiment 25 The method of any one of embodiments 1-24, wherein the LIGHT antibody is administered subcutaneously. Embodiment 26 The method of any one of embodiments 1-24, wherein the LIGHT antibody is administered intravenously. Embodiment 27. The method of any one of embodiments 1 to 26, wherein the subject is a human. Embodiment 28. The method of any one of embodiments 1 to 26, wherein the subject is an adult. Embodiment 29. The method of any one of embodiments 1 to 27, wherein the subject is a pediatric subject. Embodiment 30 The method of any one of embodiments 1-29, wherein the anti-LIGHT antibody comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 84. Embodiment 31 The method of any one of embodiments 1-30, wherein the anti-LIGHT antibody comprises a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO: 85. Embodiment 32 The method of any one of embodiments 1-31, wherein the anti-LIGHT antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:8. Embodiment 33 The method of any one of embodiments 1-32, wherein the anti-LIGHT antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:9. Embodiment 34 The method of any one of embodiments 1-33, wherein administration of an anti-LIGHT antibody increases the time to an asthma-related event in the subject. Embodiment 35 The method of any one of embodiments 1-34, wherein administration of an anti-LIGHT antibody reduces the proportion of subjects in a population of subjects who have an asthma-related event. Embodiment 36. The method of embodiment 34 or 35, wherein the asthma-related event is an additional 6 or more short-acting beta-agonist (SABA) reliever puffs compared to baseline in a 24-hour period on two consecutive days, where baseline SABA use is determined by average use in the 7 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 37. The method of embodiment 34 or 35, wherein the asthma-related event is an increase in ICS dose of 4-fold or more above the baseline dose, where the baseline ICS dose is defined as the dose the subject received in the 30 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 38. The method of embodiment 34 or 35, wherein the asthma-related event is a decrease in peak flow (compared to baseline) of 30% or more on two consecutive days of treatment, where baseline peak flow is determined by averaging measurements over the 7 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 39 The method of embodiment 34 or 35, wherein the asthma-related event is an asthma exacerbation requiring the use of systemic corticosteroids for at least 3 days. Embodiment 40 The method of embodiment 34 or 35, wherein the asthma-related event is a hospitalization or emergency department visit due to an asthma exacerbation. Embodiment 41 The method of any one of embodiments 1-40, wherein administration of the anti-LIGHT antibody increases the subject's forced expiratory volume in 1 second (FEV1). Embodiment 42 The method of any one of embodiments 1-41, wherein administration of an anti-LIGHT antibody reduces exhaled nitric oxide levels (FeNO) in the subject. Embodiment 43 The method of any one of embodiments 1-42, wherein administration of the anti-LIGHT antibody reduces the subject's Asthma Control Questionnaire (ACQ) score. Embodiment 44 The method of any one of embodiments 1-43, wherein administration of the anti-LIGHT antibody increases the subject's Standardized Asthma Quality of Life Questionnaire for Ages 12 and Older (AQLQ(S)+12) score. Embodiment 45 The method of any one of embodiments 1-44, wherein administration of an anti-LIGHT antibody reduces the subject's asthma symptom diary score. Embodiment 46 The method of any one of embodiments 1-45, wherein administration of an anti-LIGHT antibody improves the subject's European Quality of Life-5 Dimension 5 Level Questionnaire score. Embodiment 47 The method of any one of embodiments 1-46, wherein administration of an anti-LIGHT antibody improves the patient's global impression score of the change / severity of the subject. Embodiment 48 The method of any one of embodiments 1-47, wherein administration of an anti-LIGHT antibody improves the subject's Clinician's Global Impression of Improvement / Severity score. Embodiment 49 The method of any one of embodiments 1-48, wherein administration of an anti-LIGHT antibody reduces the subject's frequency of SABA use. Embodiment 50 The method of any one of embodiments 1-49, wherein the method further comprises assaying free LIGHT before, during, or after administration of an anti-LIGHT antibody. Embodiment 51 The method of any one of embodiments 1 to 50, wherein the method further comprises assaying total LIGHT before, during, or after administration of an anti-LIGHT antibody. Embodiment 52 The method of any one of embodiments 1-51, wherein the method further comprises assaying DcR3 before, during, or after administration of an anti-LIGHT antibody. Embodiment 53 The method of any one of embodiments 1-52, wherein the subject has elevated free LIGHT. Embodiment 54 The method of any one of embodiments 1-53, wherein administration of an anti-LIGHT antibody reduces serum free LIGHT in the subject. Embodiment 55. Use of an anti-LIGHT antibody in the manufacture of a medicament for treating asthma, including non-eosinophilic asthma (NEA). Embodiment 56. The anti-LIGHT antibody comprises the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: (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) The use of embodiment 55, comprising a heavy chain and a light chain that together comprise one of SEQ ID NOs: 52, 53, 54, 55, 56, and 57. Embodiment 57. The use of embodiment 55 or 56, wherein the anti-LIGHT antibody comprises a heavy chain and a light chain that together comprise the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: SEQ ID NOs: 2, 3, 4, 5, 6, and 7. Embodiment 58. The use of any one of embodiments 55-57, wherein the subject has poorly controlled asthma as determined by an Asthma Control Questionnaire (ACQ) score of 1.5 or greater. Embodiment 59. The use of any one of embodiments 55-57, wherein the subject has asthma that is poorly controlled with a long-acting beta agonist (LABA) and an inhaled corticosteroid (ICS). Embodiment 60. The use of embodiment 59, wherein the LABA is salmeterol. Embodiment 61. The use of embodiment 59 or 60, wherein the ICS is fluticasone. Embodiment 62. The use of any one of embodiments 55-61, wherein the subject has experienced an asthma exacerbation within 25 months prior to administration of the first dose of anti-LIGHT antibody. Embodiment 63. The use of any one of embodiments 55 to 62, wherein the subject's blood eosinophil count is less than 300 cells / μL. Embodiment 64. The use of any one of embodiments 55 to 63, wherein the subject's blood eosinophil count is less than 150 cells / μL. Embodiment 65. The use of any one of embodiments 55-64, wherein the subject is receiving a LABA at the time of administration of the first dose of the anti-LIGHT antibody, and the LABA is discontinued about 14 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 66. The use of any one of embodiments 55-65, wherein the subject is receiving ICS at the time of administration of the first dose of the anti-LIGHT antibody, and the ICS is reduced by 50% about 28 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 67 The use of embodiment 66, wherein the ICS is discontinued about 42 days after administration of the first dose of anti-LIGHT antibody. Embodiment 68. The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of 3-12 mg / kg, 3-11 mg / kg, 3-10 mg / kg, 3-9 mg / kg, 3-8 mg / kg, 3-7 mg / kg, 3-6 mg / kg, 3-5 mg / kg, or 3-4 mg / kg. Embodiment 69. The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of 6 mg / kg. Embodiment 70 The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of 8 mg / kg. Embodiment 71. The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, or 100-200 mg. Embodiment 72 The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of about 600 mg. Embodiment 73. The use of any one of embodiments 55-72, wherein the anti-LIGHT antibody is administered about every 14 days, about every 21 days, about every 28 days, about every 35 days, about every 42 days, about every 49 days, about every 56 days, or monthly. Embodiment 74 The use of any one of embodiments 55-72, wherein the anti-LIGHT antibody is administered about every 28 days. Embodiment 75 The use of any one of embodiments 55-72, wherein the anti-LIGHT antibody is administered monthly. Embodiment 76. The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of 600 mg every 28 days. Embodiment 77. The use of any one of embodiments 55-67, wherein the anti-LIGHT antibody is administered at a dose of 600 mg monthly. Embodiment 78. The use of any one of embodiments 55-77, wherein at least three doses of an anti-LIGHT antibody are administered. Embodiment 79 The use of any one of embodiments 55 to 78, wherein the anti-LIGHT antibody is administered subcutaneously. Embodiment 80 The use of any one of embodiments 55-78, wherein the anti-LIGHT antibody is administered intravenously. Embodiment 81. The use of any one of embodiments 55 to 80, wherein the subject is a human. Embodiment 82. The use of any one of embodiments 55 to 81, wherein the subject is an adult. Embodiment 83. The use of any one of embodiments 55 to 81, wherein the subject is a pediatric subject. Embodiment 84 The use of any one of embodiments 55-83, wherein the anti-LIGHT antibody comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 84. Embodiment 85 The use of any one of embodiments 55-84, wherein the anti-LIGHT antibody comprises a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO: 85. Embodiment 86 The use of any one of embodiments 55 to 85, wherein the anti-LIGHT antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:8. Embodiment 87 The use of any one of embodiments 55 to 86, wherein the anti-LIGHT antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 9. Embodiment 88 The use of any one of embodiments 55-87, wherein administration of the anti-LIGHT antibody increases the time to an asthma-related event in the subject. Embodiment 89 The use of any one of embodiments 55-88, wherein administration of an anti-LIGHT antibody reduces the proportion of subjects in a population of subjects who have an asthma-related event. Embodiment 90. The use of embodiment 88 or 89, wherein the asthma-related event is an additional 6 or more short-acting beta-agonist (SABA) reliever puffs compared to baseline in a 24-hour period on two consecutive days, where baseline SABA use is determined by average use in the 7 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 91. The use of embodiment 88 or 89, wherein the asthma-related event is an increase in ICS dose of 4-fold or more above the baseline dose, where the baseline ICS dose is defined as the dose the subject received in the 30 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 92. The use of embodiment 88 or 89, wherein the asthma-related event is a decrease in peak flow (compared to baseline) of 30% or more on two consecutive days of treatment, where baseline peak flow is determined by averaging measurements over the 7 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 93. The use of embodiment 88 or 89, wherein the asthma-related event is an asthma exacerbation requiring the use of systemic corticosteroids for at least 3 days. Embodiment 94. The use of embodiment 88 or 89, wherein the asthma-related event is hospitalization or emergency department visit due to an asthma exacerbation. Embodiment 95 The use of any one of embodiments 55-94, wherein administration of the anti-LIGHT antibody increases the subject's forced expiratory volume in 1 second (FEV1). Embodiment 96 The use of any one of embodiments 55-95, wherein administration of the anti-LIGHT antibody reduces exhaled nitric oxide levels (FeNO) in the subject. Embodiment 97 The use of any one of embodiments 55-96, wherein administration of the anti-LIGHT antibody reduces the subject's Asthma Control Questionnaire (ACQ) score. Embodiment 98. The use of any one of embodiments 55-97, wherein administration of the anti-LIGHT antibody increases the subject's Standardized Asthma Quality of Life Questionnaire for Ages 12 and Older (AQLQ(S)+12) score. Embodiment 99 The use of any one of embodiments 55-98, wherein administration of the anti-LIGHT antibody reduces the subject's asthma symptom diary score. Embodiment 100. The use of any one of embodiments 55-99, wherein administration of an anti-LIGHT antibody improves the subject's European Quality of Life-5 Dimension 5 Level Questionnaire score. Embodiment 101 The use of any one of embodiments 55-100, wherein administration of an anti-LIGHT antibody improves the patient's global impression score of the change / severity of the subject. Embodiment 102 The use of any one of embodiments 55-101, wherein administration of an anti-LIGHT antibody improves the Clinician's Global Impression of Improvement / Severity score of the subject. Embodiment 103 The use of any one of embodiments 55-102, wherein administration of the anti-LIGHT antibody reduces the subject's frequency of SABA use. Embodiment 104 The use of any one of embodiments 55 to 103, wherein the method further comprises assaying free LIGHT before, during, or after administration of an anti-LIGHT antibody. Embodiment 105 The use of any one of embodiments 55 to 104, wherein the method further comprises assaying total LIGHT before, during, or after administration of an anti-LIGHT antibody. Embodiment 106 The use of any one of embodiments 55 to 105, wherein the method further comprises assaying DcR3 before, during, or after administration of an anti-LIGHT antibody. Embodiment 107. The use of any one of embodiments 55 to 106, wherein the subject has elevated free LIGHT. Embodiment 108 The use of any one of embodiments 55 to 107, wherein administration of the anti-LIGHT antibody reduces serum free LIGHT in the subject. Embodiment 109. An anti-LIGHT antibody for use in the treatment of asthma, including non-eosinophilic asthma (NEA). Embodiment 110. The anti-LIGHT antibody comprises the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: (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) The antibody for use of embodiment 109, comprising a heavy chain and a light chain that together comprise one of SEQ ID NOs: 52, 53, 54, 55, 56, and 57. Embodiment 111. The antibody for use of embodiment 109 or 110, wherein the anti-LIGHT antibody comprises a heavy chain and a light chain that together comprise the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: SEQ ID NOs: 2, 3, 4, 5, 6, and 7. Embodiment 112. The antibody for use of any one of embodiments 109 to 111, wherein the subject has poorly controlled asthma as determined by an Asthma Control Questionnaire (ACQ) score of 1.5 or greater. Embodiment 113. The antibody for use of any one of embodiments 109 to 111, wherein the subject has asthma that is poorly controlled with a long-acting beta agonist (LABA) and an inhaled corticosteroid (ICS). Embodiment 114. The antibody for use of embodiment 113, wherein the LABA is salmeterol. Embodiment 115. The antibody for use in embodiment 113 or 114, wherein the ICS is fluticasone. Embodiment 116. The antibody for use of any one of embodiments 109-115, wherein the subject has experienced an asthma exacerbation within 25 months prior to administration of the first dose of anti-LIGHT antibody. Embodiment 117. The antibody for use in any one of embodiments 109 to 116, wherein the subject has a blood eosinophil count of less than 300 cells / μL. Embodiment 118. The antibody for use in any one of embodiments 109 to 117, wherein the subject has a blood eosinophil count of less than 150 cells / μL. Embodiment 119. The antibody for use of any one of embodiments 109-118, wherein the subject is receiving a LABA at the time of administration of the first dose of the anti-LIGHT antibody, and the LABA is discontinued about 14 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 120. The antibody for use of any one of embodiments 109-119, wherein the subject is receiving ICS at the time of administration of the first dose of the anti-LIGHT antibody, and the ICS is reduced by 50% about 28 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 121. The antibody for use of embodiment 120, wherein the ICS is discontinued about 42 days after administration of the first dose of the anti-LIGHT antibody. Embodiment 122. The antibody for use of any one of embodiments 109-121, wherein the anti-LIGHT antibody is administered at a dose of 3-12 mg / kg, 3-11 mg / kg, 3-10 mg / kg, 3-9 mg / kg, 3-8 mg / kg, 3-7 mg / kg, 3-6 mg / kg, 3-5 mg / kg, or 3-4 mg / kg. Embodiment 123 The antibody for use of any one of embodiments 109-121, wherein the anti-LIGHT antibody is administered at a dose of 6 mg / kg. Embodiment 124. The antibody for use of any one of embodiments 109-121, wherein the anti-LIGHT antibody is administered at a dose of 8 mg / kg. Embodiment 125. The antibody for use of any one of embodiments 109-121, wherein the anti-LIGHT antibody is administered at a dose of 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, or 100-200 mg. Embodiment 126 The antibody for use of any one of embodiments 109 to 121, wherein the anti-LIGHT antibody is administered at a dose of about 600 mg. Embodiment 127. The antibody for use of any one of embodiments 109-126, wherein the anti-LIGHT antibody is administered about every 14 days, about every 21 days, about every 28 days, about every 35 days, about every 42 days, about every 49 days, about every 56 days, or monthly. Embodiment 128 The antibody for use of any one of embodiments 109-126, wherein the anti-LIGHT antibody is administered about every 28 days. Embodiment 129. The antibody for use of any one of embodiments 109 to 126, wherein the anti-LIGHT antibody is administered monthly. Embodiment 130. The antibody for use of any one of embodiments 109-121, wherein the anti-LIGHT antibody is administered at a dose of 600 mg every 28 days. Embodiment 131. The antibody for use of any one of embodiments 109-121, wherein the anti-LIGHT antibody is administered at a dose of 600 mg monthly. Embodiment 132. The antibody for use of any one of embodiments 109-131, wherein at least three doses of the anti-LIGHT antibody are administered. Embodiment 133. The antibody for use of any one of embodiments 109 to 132, wherein the anti-LIGHT antibody is administered subcutaneously. Embodiment 134. The antibody for use of any one of embodiments 109 to 132, wherein the anti-LIGHT antibody is administered intravenously. Embodiment 135. The antibody for use of any one of embodiments 109 to 134, wherein the subject is a human. Embodiment 136. The antibody for use of any one of embodiments 109 to 135, wherein the subject is an adult. Embodiment 137. The antibody for use of any one of embodiments 109 to 135, wherein the subject is a pediatric subject. Embodiment 138. The antibody for use of any one of embodiments 109 to 137, wherein the anti-LIGHT antibody comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 84. Embodiment 139. The antibody for use of any one of embodiments 109 to 138, wherein the anti-LIGHT antibody comprises a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO: 85. Embodiment 140. The antibody for use of any one of embodiments 109 to 139, wherein the anti-LIGHT antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:8. Embodiment 141. The antibody for use of any one of embodiments 109 to 140, wherein the anti-LIGHT antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:9. Embodiment 142 The antibody for use of any one of embodiments 109-141, wherein administration of the anti-LIGHT antibody increases the time to an asthma-related event in the subject. Embodiment 143 The antibody for use of any one of embodiments 109-142, wherein administration of the anti-LIGHT antibody reduces the proportion of subjects in a population of subjects who have an asthma-related event. Embodiment 144. The antibody for use of embodiment 142 or 143, wherein the asthma-related event is an additional 6 or more short-acting beta-agonist (SABA) reliever puffs compared to baseline in a 24-hour period on two consecutive days, where baseline SABA use is determined by average use in the 7 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 145. The antibody for use of embodiment 142 or 143, wherein the asthma-related event is an increase in ICS dose of 4-fold or more above the baseline dose, where the baseline ICS dose is defined as the dose the subject received in the 30 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 146. The antibody for use in embodiment 142 or 143, wherein the asthma-related event is a decrease in peak flow (compared to baseline) of 30% or more on two consecutive days of treatment, where baseline peak flow is determined by averaging measurements over the 7 days prior to administration of the first dose of anti-LIGHT antibody. Embodiment 147. The antibody for use in embodiment 142 or 143, wherein the asthma-related event is an asthma exacerbation requiring the use of systemic corticosteroids for at least 3 days. Embodiment 148. The antibody for use in embodiment 142 or 143, wherein the asthma-related event is hospitalization or emergency department visit due to an asthma exacerbation. Embodiment 149. The antibody for use in any one of embodiments 109-148, wherein administration of the anti-LIGHT antibody increases the subject's forced expiratory volume in 1 second (FEV1). Embodiment 150. The antibody for use of any one of embodiments 109-149, wherein administration of the anti-LIGHT antibody reduces exhaled nitric oxide levels (FeNO) in the subject. Embodiment 151. The antibody for use of any one of embodiments 109-150, wherein administration of the anti-LIGHT antibody reduces the subject's Asthma Control Questionnaire (ACQ) score. Embodiment 152. The antibody for use in any one of embodiments 109-151, wherein administration of the anti-LIGHT antibody increases the subject's Standardized Asthma Quality of Life Questionnaire for Ages 12 and Older (AQLQ(S)+12) score. Embodiment 153 The antibody for use of any one of embodiments 109-152, wherein administration of the anti-LIGHT antibody reduces the subject's asthma symptom diary score. Embodiment 154. The antibody for use of any one of embodiments 109 to 153, wherein administration of the anti-LIGHT antibody improves the subject's European Quality of Life-5 Dimension 5 Level Questionnaire score. Embodiment 155. The antibody for use of any one of embodiments 109-154, wherein administration of the anti-LIGHT antibody improves the patient's global impression score of the change / severity of the subject. Embodiment 156. The antibody for use of any one of embodiments 109-155, wherein administration of the anti-LIGHT antibody improves the subject's Clinician's Global Impression of Improvement / Severity score. Embodiment 157. The antibody for use of any one of embodiments 109-156, wherein administration of the anti-LIGHT antibody reduces the subject's frequency of SABA use. Embodiment 158 ​​The antibody for use of any one of embodiments 109 to 157, wherein the method further comprises assaying for free LIGHT before, during, or after administration of the anti-LIGHT antibody. Embodiment 159. The antibody for use of any one of embodiments 109 to 158, wherein the method further comprises assaying total LIGHT before, during, or after administration of the anti-LIGHT antibody. Embodiment 160. The antibody for use of any one of embodiments 109 to 159, wherein the method further comprises assaying DcR3 before, during, or after administration of the anti-LIGHT antibody. Embodiment 161. The antibody for use of any one of embodiments 109 to 160, wherein the subject has elevated free LIGHT. Embodiment 162 The antibody for use of any one of embodiments 109-161, wherein administration of the anti-LIGHT antibody reduces serum free LIGHT in the subject. [Brief explanation of the drawings]

[0012] [Figure 1] 1 shows a clinical trial design for treating patients with asthma, including NEA, with Antibody A. Antibody A refers to an anti-LIGHT antibody, which comprises the following six CDRs: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:2, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:3, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:4, a light chain CDR1 having the amino acid sequence of SEQ ID NO:5, a light chain CDR2 having the amino acid sequence of SEQ ID NO:6, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:7. DETAILED DESCRIPTION OF THE INVENTION

[0013] The following definitions are provided to facilitate understanding of the invention and are not intended to limit the invention in any way.

[0014] definition For purposes of the present invention, "a" or "an" entity refers to one or more of that entity; for example, "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 is also noted that the terms "comprising," "including," and "having" can be used interchangeably. Furthermore, a compound "selected from the group consisting of" refers to one or more of the compounds in the accompanying list, including mixtures (i.e., combinations) of two or more compounds. In accordance with 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 has been 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.

[0015] As used herein, "LIGHT" or "TNFSF14" refers to a specific member protein of the tumor necrosis factor superfamily expressed by activated T cells, monocyte-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 (herpesvirus entry mediator), a receptor expressed on T lymphocytes."

[0016] "Free LIGHT" or "free (active) LIGHT" herein refers to the unbound form of LIGHT (e.g., LIGHT bound to DcR3), which is the active form of LIGHT. In humans, free LIGHT is neutralized (inactivated) by DcR3, a unique soluble member of the TNFR superfamily that binds to 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, optionally the natural ligand being HVEM, LTβR, or DcR3. "Total LIGHT" and the like refers to the total amount of free LIGHT and bound LIGHT.

[0017] As used herein, "elevated free LIGHT" refers to a level of free LIGHT detected in a subject that is higher than a normal control. The normal control can be determined by one skilled in the art as applicable to a particular situation. In some cases, the normal control is an industry standard agreed upon by one skilled in the art as a typical level or range of levels for individuals who do not have a LIGHT-associated condition. In some cases, the normal control is a reference level of LIGHT from the same individual taken at a certain time point, and whether a subject has elevated LIGHT is determined based on a sample from the same individual taken at a different, typically later, time point.

[0018] The term "antibody" as used 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 comprising at least the complementarity-determining regions (CDRs) 1, 2, and 3 of a heavy chain and at least the CDRs 1, 2, and 3 of a light chain, wherein the molecule 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 and cynomolgus monkey.

[0019] 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 also comprises 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.

[0020] The term "heavy chain variable region" refers to the region of a heavy chain comprising 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.).

[0021] 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, a light chain includes 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 the 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.).

[0022] A "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, with the remainder of the heavy and / or light chain derived from a different source or species. In some embodiments, a chimeric antibody refers to an antibody comprising 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 a chimeric antibody are from a first species and all of the constant regions of a chimeric antibody are from a second species.

[0023] A "humanized antibody" refers to an antibody in which at least one amino acid in a framework region of a non-human variable region has been replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or fragment thereof. In some embodiments, a humanized antibody is a Fab, scFv, (Fab')2, etc.

[0024] As used herein, "human antibody" refers to antibodies produced in humans, antibodies produced in non-human animals that contain human immunoglobulin genes, such as XenoMouse®, and antibodies selected using in vitro methods, such as phage display, where the antibody repertoire is based on human immunoglobulin sequences.

[0025] 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 upon export of the polypeptide from a mammalian cell to form the mature protein. Leader sequences may be natural or synthetic, and they may be heterologous or homologous to the protein to which they are attached.

[0026] With respect to peptide, polypeptide, or antibody sequences, "percent (%) amino acid sequence identity" and "homology" are defined as the percentage of amino acid residues in a candidate sequence that are identical with amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of 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 needed to achieve maximal alignment over the full length of the sequences being compared.

[0027] The term "inhibition" or "inhibiting" refers to the reduction or cessation of any event (such as protein-ligand binding), or the reduction or cessation of any phenotypic characteristic, or the reduction or cessation of the incidence, degree, or likelihood of that characteristic. "Reducing" or "inhibiting" is the decrease, reduction, or cessation of an activity, function, and / or amount compared to a reference. Inhibition or reduction need not be complete. For example, in certain embodiments, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 20% or more. In other embodiments, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 50% or more. In yet other embodiments, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 75%, 85%, 90%, 95%, or more.

[0028] A "sample" or "subject sample" or "biological sample" generally refers to a sample that can be tested for a particular molecule. Samples can include, but are not limited to, cells, bodily fluids, including blood, serum, plasma, urine, saliva, feces, tears, pleural effusions, etc.

[0029] The terms "agent" and "test compound" are used interchangeably herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract obtained from biological material such as a bacterial, plant, fungal, or animal (especially mammalian) cell or tissue. Biological macromolecules include siRNA, shRNA, antisense oligonucleotides, peptides, peptide / DNA complexes, and any nucleic acid-based molecule that exhibits the ability to modulate the activity of the SNP-containing nucleic acids described herein or their encoded proteins. Agents are evaluated for potential biological activity by inclusion in screening assays described below.

[0030] A "subject" can be a mammal. In any of the embodiments including a subject, the subject can be a human. In any of the embodiments including a subject, the subject can be a cow, pig, monkey, sheep, dog, cat, fish, or poultry.

[0031] As used herein, a "pediatric" subject is a human under the age of 18, while an "adult" subject is 18 or older.

[0032] "Treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom 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, reduction in extent of disease, stable (i.e., not worsening) state of disease, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (partial or total), whether detectable or not. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, or those in whom the condition or disorder is to be prevented.

[0033] The term "effective amount" or "therapeutically effective amount" refers to an amount of a drug effective for treating a disease or disorder in a subject, e.g., to partially or completely alleviate 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 a desired therapeutic or prophylactic result.

[0034] The term "non-eosinophilic asthma" or "NEA" refers to NEA characterized by airway inflammation with the absence or low number of eosinophils following activation of the non-dominant type 2 immune pathway. In other words, NEA typically lacks the characteristics of T-helper cell type 2 asthma and is generally based on the presence of neutrophils in sputum or the absence (or normal levels) of eosinophils or other T2 markers in sputum, biopsy samples, or blood. It can be defined by sputum eosinophil counts, e.g., less than 2% or less than 3%. It can also be defined as blood eosinophil concentrations below a certain threshold, e.g., less than 300 eosinophils / μL. It can also include subphenotypes. NEA patients typically do not respond well to inhaled corticosteroids.

[0035] The term "FEV1" refers to forced expiratory capacity, which is a measure of the amount of air a person can exhale during a forced breath. FEV1 can be measured during spirometry using an instrument called a spirometer. FEV1 can be used to describe the degree of airway obstruction caused by asthma. FEV1 can be calculated by converting the spirometer reading to a percentage of what is expected to be normal (i.e., compared to a standard or expected FEV1 score based on a healthy person, taking into account gender, height, and race). People with asthma usually have a lower FEV1 than healthy people. FEV1 is sometimes included as part of the FEV1 / FVC ratio. FVC refers to forced vital capacity, i.e., the total amount of air that can be forcefully exhaled in a complete breath.

[0036] The term "peak flow" refers to a measure of how quickly air leaves the lungs when a person forcefully exhales after a full inhale. This is also called "peak expiratory flow" ("PEF") or peak expiratory rate ("PEFR"). Peak flow may be measured with a device. A commonly used device for measuring peak flow is a peak flow meter ("PFM"). A person's "normal" peak flow may be based on the person's age, height, sex, and race. Peak flow is typically divided into three zones: green, yellow, and red. The green zone is 80 to 100 percent of a person's usual or "normal" peak velocity and indicates an all-clear reading. A reading in this zone means the person's asthma is well controlled. The yellow zone is 50 to 80 percent of a person's usual or "normal" peak velocity and indicates caution. This zone indicates that the person's airway is narrowing and the person needs to take action. The red zone is less than 50% of a person's usual or "normal" peak velocity and indicates a medical alert. This zone indicates severe airway narrowing.

[0037] The term "FeNO" refers to exhaled nitric oxide or exhaled nitric oxide concentration, in other words, the level of nitric oxide in exhaled breath. FeNO is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines. FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An exemplary assay for measuring FeNO is by using the NIOX® instrument by Circassia AB. Assessment may be performed before spirometry and after at least one hour of fasting.

[0038] The term "LABA" refers to a long-acting beta-agonist. LABAs are bronchodilators. Examples of LABAs include, but are not limited to, salmeterol (e.g., Serevent™), formoterol (e.g., Foradil™), and the like. LABAs may be administered as part of a combination therapy with an inhaled corticosteroid (ICS). Such combination therapies include, for example, ADVAIR® (GlaxoSmithKline) (fluticasone + salmeterol), SYMBICORT® (AstraZeneca) (budesonide + formoterol), and DULERA® (Organon) (mometasone + formoterol).

[0039] The term "ICS" refers to inhaled corticosteroids. Inhaled corticosteroids help control asthma symptoms. Examples of inhaled corticosteroids include, but are not limited to, fluticasone (e.g., fluticasone propionate, e.g., Flovent™), budesonide, mometasone (e.g., mometasone furoate, e.g., Asmanex™), flunisolide (e.g., Aerobid™), 5-dexamethasone acetate / phenobarbital / theophylline (e.g., Azmacort™), beclomethasone dipropionate HFA (Qvar™), and the like. Inhaled corticosteroids can be administered as part of a combination therapy with a long-acting beta-agonist ("LABA"). Such combination therapies include, for example, ADVAIR® (GlaxoSmithKline) (fluticasone plus salmeterol), SYMBICORT® (AstraZeneca) (budesonide plus formoterol), DULERA® (Organon) (mometasone plus formoterol).

[0040] The term "SABA" refers to a short-acting beta-agonist. SABAs are also known as "fast-acting beta-2-adrenergic receptor agonists" or "relief medications" or "rescue medications." They are typically used to provide rapid relief from asthma symptoms. Examples of SABAs include, but are not limited to, albuterol (i.e., salbutamol, e.g., Proventil™, Ventolin™, ProAir™, etc.), levalbuterol (e.g., Xopenex™), pirbuterol (e.g., Maxair™), metaproterenol (e.g., Alupent™), and the like.

[0041] The term "LTA" refers to a leukotriene receptor antagonist (LTA). Examples of LTAs include, but are not limited to, montelukast (e.g., Singulaire™), zafirlukast (e.g., Accolate™), and the like.

[0042] The term "ACQ" refers to the Asthma Control Questionnaire. The ACQ is a simple, validated questionnaire that measures the adequacy of asthma control and changes in asthma control that occur spontaneously or as a result of treatment. There are seven items, some of which are scaled on a 7-point scale (there are seven categories of FEV1) and some of which are scaled on a 6-point scale (0 = no impairment, 6 = greatest impairment to symptoms and relief use). Scores range from 0 (completely controlled) to 6 (severely uncontrolled). Questions are weighted equally, and the ACQ score is the average of the seven responses to a question, thus ranging from 0 (completely controlled) to 6 (severely uncontrolled). A score of 1.5 or higher may indicate poor asthma control in a subject. Lower scores generally indicate better asthma control. A score change of 0.5 on the ACQ can be considered clinically important. A shortened version of the original ACQ is available. (Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Eur Respir J 1999;14:902-907, Juniper EF, Bousquet J, Abetz L, Bateman ED. Respiratory Medicine 2006(100):616-621, Juniper EF, Svensson K, Mork AC, Stahl E. Respiratory Medicine 2005(99):553-558).

[0043] "AQLQ(S)+12" refers to the score of the Standardized Asthma Quality of Life Questionnaire for subjects aged 12 years and older, also referred to as "AQLQ12+." The AQLQ12+ was designed to measure the most bothersome functional impairments for people aged 12 years and older as a result of asthma. This instrument consists of 32 items, each rated on a 7-point Likert scale ranging from 1 to 7. The AQLQ12+ has four domains. The domains and the number of items in each domain are as follows: symptoms (12 items), activity limitations (11 items), emotional functioning (5 items), and environmental stimuli (4 items). A global score is calculated ranging from 0 to 7, and a score is calculated for each domain. Higher scores indicate better quality of life. A score of 7 = no impairment, and a score of 1 = severe impairment. The overall score is calculated as the average response to all questions. The four domain scores (symptoms, activity limitations, emotional functioning, and environmental stimuli) are measures of responses to questions in each domain.

[0044] The "Asthma Symptom Diary Score" refers to a daily score of six items related to the severity of asthma symptoms, assessing three core categories: respiratory symptoms (dyspnea, wheezing, shortness of breath), chest symptoms (chest tightness, chest pain), and cough. The Asthma Symptom Diary is intended to be completed twice daily and consists of a morning diary (completed upon waking and addressing nighttime asthma symptoms) and an evening diary (completed before bed and addressing daytime asthma symptoms). During each time frame, patients rate six symptoms at their worst using an 11-point numerical rating scale ranging from 0 ("none") to 10 ("the worst you can imagine"). (United States Food and Drug Administration.Clinical Outcome Assessments(COA)Qualification Program DDT COA #000006: Asthma Daytime Symptom Diary(ADSD)and Asthma Nighttime Symptom Diary(ANSD)(available at https: / / www.fda.gov / drugs / clinical-outcome-assessment-coa-qualification-program / ddt-coa-000006-asthma-daily-symptom-diary-adsd)).

[0045] The "European Quality of Life - 5 Dimensions 5 Levels Questionnaire Score," also referred to as "EQ5D-5L" or "EQ-5D-5L," refers to scores from a test consisting of the EQ-5D descriptor system and the EQ visual analog scale (EQ VAS). The descriptor system is composed of five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, slight problem, moderate problem, serious problem, and severe problem. The EQ VAS records subjects' self-assessed health status on a vertical VAS, with endpoints labeled "best health you can imagine" and "worst health you can imagine" (EuroQol, Group. EQ-5D-5L:About.2017 (available at https: / / euroqol.org / eq-5d-instruments / eq-5d-5l-about / EuroQol,2017)).

[0046] "Clinician's Global Impression of Improvement / Severity score" or "Clinical Global Impression Scale score" or "CGI-I, CGI-S" refer to global indices that can be used to assess the severity of a specific condition (single-state scale) from a clinician's perspective. The CGI-I is a single-question scale that asks clinicians to rate the overall state of a patient's specific condition on a 7-point scale since the start of a research study. The CGI-S is a single-question scale that asks clinicians to rate the current state of a patient's specific condition on a 7-point scale. For example, a CGI-S score of 1 may mean no illness at all (normal), a score of 2 may mean borderline illness, a score of 3 may mean mild illness, a score of 4 may mean moderate illness, a score of 5 may mean significant illness, a score of 6 may mean severe illness, and a score of 7 may mean the patient is among the most severely ill. For example, a CGI-I score of 1 may mean very much improved, a score of 2 may mean greatly improved, a score of 3 may mean minimally improved, a score of 4 may mean no change, a score of 5 may mean slightly worsened, a score of 6 may mean much worsened, and a CGI-I score of 7 may mean very worsened. See Guy W (ed) (1976) ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare, Rockville, MD.

[0047] The "Patient Global Impression of Change / Severity Score" or "PGI-C, PGI-S" scale refers to a global index that can be used to assess the severity of a specific condition (single-state scale) from the patient's perspective. The PGI-C is a single-question scale that asks the patient to rate the overall state of a specific condition on a 7-point scale. The PGI-S is a single-question scale that asks the patient to rate the current state of a specific condition on a 7-point scale. For example, a PGI-S score of 1 can mean no illness and normal, a score of 2 can mean borderline illness, a score of 3 can mean mild illness, a score of 4 can mean moderate illness, a score of 5 can mean significant illness, a score of 6 can mean severe illness, and a score of 7 can mean the patient is among the most severely ill patients. For example, a PGI-I score of 1 may mean very much improved, a score of 2 may mean greatly improved, a score of 3 may mean minimally improved, a score of 4 may mean no change, a score of 5 may mean slightly worse, a score of 6 may mean much worse, and a score of 7 may mean very worse. See Guy W (ed) (1976) ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare, Rockville, MD.

[0048] "Asthma exacerbation" or "asthma exacerbation" refers to an increase in the severity and / or frequency and / or duration of one or more symptoms or signs of asthma. It also includes a deterioration in a subject's respiratory health that requires or is treatable by therapeutic intervention for asthma (e.g., steroid therapy, inhaled corticosteroid therapy, hospitalization, etc.).

[0049] "Improved" is used herein to indicate that an asthma-related parameter is quantified at a baseline time point and at a time point after administration of an anti-LIGHT antibody. The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" in the asthma-related parameter. This can be an increase or a decrease, depending on the particular parameter being measured.

[0050] Treating NEA-Induced Asthma with Anti-LIGHT Antibodies In some embodiments, methods are provided for treating a subject with asthma, comprising administering an anti-LIGHT antibody to a subject in need thereof. In some embodiments, the subject has poorly controlled asthma as determined by an Asthma Control Questionnaire (ACQ) score of 1.5 or greater. In some embodiments, the subject has asthma that is poorly controlled with a long-acting beta-agonist (LABA) (optionally, the LABA is salmeterol) and an inhaled corticosteroid (ICS) (optionally, the ICS is fluticasone). In some embodiments, the subject has experienced an asthma exacerbation within 25 months prior to administration of the first dose of anti-LIGHT antibody. In some embodiments, the subject has experienced an asthma exacerbation within 24 months of the screening visit. In some embodiments, the subject's blood eosinophil count is less than 300 cells / μL. In some embodiments, the subject's blood eosinophil count is less than 250 cells / μL. In some embodiments, the subject's blood eosinophil count is less than 150 cells / μL. In some embodiments, the subject is receiving a LABA at the time of administration of the first dose of anti-LIGHT antibody, and the LABA is discontinued about 14 days after administration of the first dose of anti-LIGHT antibody. In some embodiments, the subject is receiving an ICS at the time of administration of the first dose of anti-LIGHT antibody, and the ICS is reduced by 50% about 28 days after administration of the first dose of anti-LIGHT antibody. In some embodiments, the ICS is discontinued about 42 days after the first administration of anti-LIGHT antibody. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-12 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-11 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-10 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-9 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-8 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-7 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-6 mg / kg.In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-5 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-4 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 6 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 7 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 8 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-1000 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-900 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-800 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-700 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-600 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-500 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-400 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-300 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-200 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of about 600 mg. In some embodiments, the anti-LIGHT antibody is administered about every 14 days. In some embodiments, the anti-LIGHT antibody is administered about every 21 days. In some embodiments, the anti-LIGHT antibody is administered about every 28 days. In some embodiments, the anti-LIGHT antibody is administered about every 35 days. In some embodiments, the anti-LIGHT antibody is administered about every 42 days. In some embodiments, the anti-LIGHT antibody is administered about every 49 days. In some embodiments, the anti-LIGHT antibody is administered about every 56 days. In some embodiments, the anti-LIGHT antibody is administered every 4 weeks. In some embodiments, the anti-LIGHT antibody is administered monthly. In some embodiments, the anti-LIGHT antibody is administered at a dose of 8 mg / kg every four weeks.In some embodiments, the anti-LIGHT antibody is administered at a dose of 8 mg / kg monthly. In some embodiments, the anti-LIGHT antibody is administered at a dose of 6 mg / kg every four weeks. In some embodiments, the anti-LIGHT antibody is administered at a dose of 6 mg / kg monthly. In some embodiments, the anti-LIGHT antibody is administered at a dose of 600 mg every 28 days. In some embodiments, the anti-LIGHT antibody is administered at a dose of 600 mg monthly. In some embodiments, the anti-LIGHT antibody is administered for 12 weeks. In some embodiments, at least three doses of the anti-LIGHT antibody are administered. In some embodiments, the anti-LIGHT antibody is administered subcutaneously. In some embodiments, the anti-LIGHT antibody is administered intravenously. 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. In some embodiments, administration of the anti-LIGHT antibody increases the time to an asthma exacerbation in the subject. In some embodiments, administration of the anti-LIGHT antibody increases the time to an asthma-related event in the subject. In some embodiments, administration of an anti-LIGHT antibody reduces the proportion of subjects in a population of subjects experiencing an asthma exacerbation. In some embodiments, administration of an anti-LIGHT antibody reduces the proportion of subjects in a population of subjects experiencing an asthma-related event. In some embodiments, an asthma-related event is an additional six or more short-acting beta-agonist (SABA) reliever puffs compared to baseline in a 24-hour period on two consecutive days, where baseline SABA use is determined by average use in the seven days prior to administration of the first dose of anti-LIGHT antibody. In some embodiments, an asthma-related event is an increase in ICS dose of four times or more above the baseline dose, where baseline ICS dose is defined as the dose the subject received in the 30 days prior to administration of the first dose of anti-LIGHT antibody. In some embodiments, an asthma-related event is a decrease in peak flow rate (compared to baseline) of 30% or more on two consecutive days of treatment, where baseline peak flow rate is determined by averaging measurements over the seven days prior to administration of the first dose of anti-LIGHT antibody.In some embodiments, the asthma-related event is an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least three days. In some embodiments, the asthma-related event is a hospitalization or emergency department visit due to an asthma exacerbation. In some embodiments, administration of an anti-LIGHT antibody increases the subject's forced expiratory volume in 1 second (FEV1). In some embodiments, administration of an anti-LIGHT antibody decreases the subject's exhaled nitric oxide (FeNO). In some embodiments, administration of an anti-LIGHT antibody decreases the subject's Asthma Control Questionnaire (ACQ) score. In some embodiments, administration of an anti-LIGHT antibody increases the subject's Standardized Asthma Quality of Life Questionnaire for Ages 12 and Over (AQLQ(S)+12) score. In some embodiments, administration of an anti-LIGHT antibody decreases the subject's Asthma Symptom Diary score. In some embodiments, administration of an anti-LIGHT antibody improves the subject's European Quality of Life-5 Dimension 5 Level Questionnaire score. In some embodiments, administration of an anti-LIGHT antibody improves the subject's Patient Global Impression of Change / Severity score. In some embodiments, administration of an anti-LIGHT antibody improves the subject's Clinician's Global Impression of Improvement / Severity score. In some embodiments, administration of an anti-LIGHT antibody reduces the subject's frequency of SABA use. In some embodiments, the method further comprises assaying free LIGHT before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the method further comprises assaying total LIGHT before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the method further comprises assaying DcR3 before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the subject has elevated free LIGHT. In some embodiments, administration of an anti-LIGHT antibody reduces serum free LIGHT in the subject.

[0051] In some embodiments, methods are provided for treating a subject with noneosinophilic asthma (NEA), comprising administering an anti-LIGHT antibody to a subject in need thereof. In some embodiments, the subject has poorly controlled asthma as determined by an Asthma Control Questionnaire (ACQ) score of 1.5 or greater. In some embodiments, the subject has asthma that is poorly controlled with a long-acting beta-agonist (LABA) (optionally, the LABA is salmeterol) and an inhaled corticosteroid (ICS) (optionally, the ICS is fluticasone). In some embodiments, the subject has experienced an asthma exacerbation within 25 months prior to administration of the first dose of anti-LIGHT antibody. In some embodiments, the subject has experienced an asthma exacerbation within 24 months of the screening visit. In some embodiments, the subject's blood eosinophil count is less than 300 cells / μL. In some embodiments, the subject's blood eosinophil count is less than 250 cells / μL. In some embodiments, the subject's blood eosinophil count is less than 150 cells / μL. In some embodiments, the subject's blood eosinophil count is between 25 cells / μL and 325 cells / μL. In some embodiments, the subject's blood eosinophil count is between 25 cells / μL and 300 cells / μL. In some embodiments, the subject's blood eosinophil count is between 25 cells / μL and 250 cells / μL. In some embodiments, the subject's blood eosinophil count is between 25 cells / μL and 150 cells / μL. In some embodiments, the subject's blood eosinophil count is between 50 cells / μL and 325 cells / μL. In some embodiments, the subject's blood eosinophil count is between 50 cells / μL and 300 cells / μL. In some embodiments, the subject's blood eosinophil count is between 50 cells / μL and 250 cells / μL. In some embodiments, the subject's blood eosinophil count is between 50 cells / μL and 150 cells / μL. In some embodiments, the subject's blood eosinophil count is between 75 cells / μL and 325 cells / μL. In some embodiments, the subject's blood eosinophil count is between 75 cells / μL and 300 cells / μL. In some embodiments, the subject's blood eosinophil count is between 75 cells / μL and 250 cells / μL. In some embodiments, the subject's blood eosinophil count is between 75 cells / μL and 150 cells / μL.In some embodiments, the subject's blood eosinophil count is between 100 cells / μL and 200 cells / μL. In some embodiments, the subject's blood eosinophil count is between 150 cells / μL and 250 cells / μL. In some embodiments, the subject's blood eosinophil count is between 100 cells / μL and 150 cells / μL. In some embodiments, the subject is receiving a LABA at the time of administration of the first dose of anti-LIGHT antibody, and the LABA is discontinued about 14 days after administration of the first dose of anti-LIGHT antibody. In some embodiments, the subject is receiving an ICS at the time of administration of the first dose of anti-LIGHT antibody, and the ICS is reduced by 50% about 28 days after administration of the first dose of anti-LIGHT antibody. In some embodiments, the ICS is discontinued about 42 days after the first administration of the anti-LIGHT antibody. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3 to 12 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3 to 11 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-10 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-9 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-8 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-7 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-6 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-5 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 3-4 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 6 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 7 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 8 mg / kg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-1000 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-900 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-800 mg.In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-700 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-600 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-500 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-400 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-300 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 100-200 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of about 600 mg. In some embodiments, the anti-LIGHT antibody is administered at a dose of 600 mg. In some embodiments, the anti-LIGHT antibody is administered about every 14 days. In some embodiments, the anti-LIGHT antibody is administered about every 21 days. In some embodiments, the anti-LIGHT antibody is administered about every 28 days. In some embodiments, the anti-LIGHT antibody is administered about every 35 days. In some embodiments, the anti-LIGHT antibody is administered about every 42 days. In some embodiments, the anti-LIGHT antibody is administered about every 49 days. In some embodiments, the anti-LIGHT antibody is administered about every 56 days. In some embodiments, the anti-LIGHT antibody is administered every 4 weeks. In some embodiments, the anti-LIGHT antibody is administered monthly. In some embodiments, the anti-LIGHT antibody is administered at a dose of 8 mg / kg every 4 weeks. In some embodiments, the anti-LIGHT antibody is administered at a dose of 8 mg / kg every month. In some embodiments, the anti-LIGHT antibody is administered at a dose of 6 mg / kg every 4 weeks. In some embodiments, the anti-LIGHT antibody is administered at a dose of 6 mg / kg every month. In some embodiments, the anti-LIGHT antibody is administered at a dose of 600 mg every 28 days. In some embodiments, the anti-LIGHT antibody is administered at a dose of 600 mg every month. In some embodiments, the anti-LIGHT antibody is administered for 12 weeks. In some embodiments, at least 3 doses of the anti-LIGHT antibody are administered. In some embodiments, the anti-LIGHT antibody is administered subcutaneously.In some embodiments, the anti-LIGHT antibody is administered intravenously. 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. In some embodiments, administration of the anti-LIGHT antibody increases the time to an asthma exacerbation in the subject. In some embodiments, administration of the anti-LIGHT antibody increases the time to an asthma-related event in the subject. In some embodiments, administration of the anti-LIGHT antibody reduces the proportion of subjects in a population of subjects having an asthma exacerbation. In some embodiments, administration of the anti-LIGHT antibody reduces the proportion of subjects in a population of subjects having an asthma-related event. In some embodiments, the asthma-related event is an additional 6 or more reliever puffs of a short-acting beta-agonist (SABA) compared to baseline in a 24-hour period on two consecutive days, where baseline SABA use is determined by average use in the 7 days prior to administration of the first dose of the anti-LIGHT antibody. In some embodiments, the asthma-related event is an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspensions, or injections) for at least 3 days. In some embodiments, the asthma-related event is a hospitalization or emergency department visit due to an asthma exacerbation. In some embodiments, the asthma-related event is an increase in ICS dose of 4-fold or more above the baseline dose, where the baseline ICS dose is defined as the dose the subject received in the 30 days prior to administration of the first dose of anti-LIGHT antibody. In some embodiments, the asthma-related event is a decrease in peak flow rate (compared to baseline) of 30% or more on two consecutive days of treatment, where the baseline peak flow rate is determined by averaging measurements over the 7 days prior to administration of the first dose of anti-LIGHT antibody. In some embodiments, administration of an anti-LIGHT antibody increases the subject's forced expiratory volume in 1 second (FEV1). In some embodiments, administration of an anti-LIGHT antibody decreases the subject's exhaled nitric oxide (FeNO). In some embodiments, administration of an anti-LIGHT antibody decreases the subject's Asthma Control Questionnaire (ACQ) score.In some embodiments, administration of an anti-LIGHT antibody increases a subject's Standardized Asthma Quality of Life Questionnaire for Ages 12 and Up (AQLQ(S)+12) score. In some embodiments, administration of an anti-LIGHT antibody decreases a subject's Asthma Symptom Diary score. In some embodiments, administration of an anti-LIGHT antibody improves a subject's European Quality of Life-5 Dimension 5 Level Questionnaire score. In some embodiments, administration of an anti-LIGHT antibody improves a subject's Patient Global Impression of Change / Severity score. In some embodiments, administration of an anti-LIGHT antibody improves a subject's Clinician Global Impression of Improvement / Severity score. In some embodiments, administration of an anti-LIGHT antibody reduces a subject's frequency of SABA use. In some embodiments, the method further comprises assaying free LIGHT before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the method further comprises assaying total LIGHT before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the method further comprises assaying DcR3 before, during, or after administration of the anti-LIGHT antibody. In some embodiments, the subject has elevated free LIGHT. In some embodiments, administration of an anti-LIGHT antibody reduces serum free LIGHT in the subject.

[0052] Anti-LIGHT antibody In some embodiments, anti-LIGHT antibodies useful for therapeutic purposes may comprise the CDR sequences of the E1, E13, E63, F19, or F23 antibodies provided in WO2008 / 027338, and US Pat. No. 8,058,402B2, US Pat. No. 8,461,307B2, and US Pat. No. 8,974,787B2, each of which is incorporated herein by reference.

[0053] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 2, 3, and 4. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 5, 6, and 7. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 2, 3, and 4, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 5, 6, and 7.

[0054] In some embodiments, an anti-LIGHT antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 84, or a sequence at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical 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 that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical 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 that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 84, and a light chain variable region sequence comprising SEQ ID NO: 85, or a sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 85.

[0055] In some embodiments, an anti-LIGHT antibody comprises a heavy chain sequence comprising SEQ ID NO: 8, or a sequence at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical 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 that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical 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 that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 8, and a light chain comprising SEQ ID NO: 9, or a sequence that is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 9.

[0056] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 10, 11, and 12. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 13, 14, and 15. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 10, 11, and 12, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 13, 14, and 15.

[0057] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 16, 17, and 18. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 19, 20, and 21. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 16, 17, and 18, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 19, 20, and 21.

[0058] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 22, 23, and 24. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 25, 26, and 27. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 22, 23, and 24, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 25, 26, and 27.

[0059] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 28, 29, and 30. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 31, 32, and 33. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 28, 29, and 30, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 31, 32, and 33.

[0060] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 34, 35, and 36. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 37, 38, and 39. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 34, 35, and 36, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 37, 38, and 39.

[0061] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 40, 41, and 42. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 43, 44, and 45. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 40, 41, and 42, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 43, 44, and 45.

[0062] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising three CDR sequences comprising each of SEQ ID NOs: 46, 47, and 48. In some embodiments, an anti-LIGHT antibody comprises a light chain comprising three CDR sequences comprising each of SEQ ID NOs: 49, 50, and 51. In some embodiments, the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises three CDR sequences comprising each of SEQ ID NOs: 46, 47, and 48, and the light chain comprises three CDR sequences comprising each of SEQ ID NOs: 49, 50, and 51.

[0063] In some embodiments, an anti-LIGHT antibody may comprise the CDR sequences of the antibodies described in US 2013 / 0323240 and US 8,524,869B2, which are incorporated herein by reference. For example, 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, the 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.

[0064] In some embodiments, an anti-LIGHT antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 58 or that is 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 that is 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 that is 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 that is 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 that comprises SEQ ID NO:58 or is 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 that comprises SEQ ID NO:59 or is at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO:59.

[0065] In some embodiments, the anti-LIGHT antibody is selected from the group consisting of the following sets of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences set forth in the sequence listing from US2013 / 0323240: SEQ ID NOs: 18, 19, 20, and 38, 41, 42 of US2013 / 0323240; SEQ ID NOs: 18, 19, 21, and 39, 41, 42 of US2013 / 0323240; SEQ ID NOs: 18, 19, 22, and 40, 41, 42 of US2013 / 0323240; The heavy chain and light chain may together comprise one of: SEQ ID NOs: 23, 24, 25, and 43, 44, 45 of US2013 / 0323240; SEQ ID NOs: 26, 27, 28, and 46, 47, 48 of US2013 / 0323240; SEQ ID NOs: 29, 30, 31, and 49, 50, 51 of US2013 / 0323240; SEQ ID NOs: 32, 33, 34, and 52, 53, 54 of US2013 / 0323240; SEQ ID NOs: 35, 36, 37, and 55, 50, 51 of US2013 / 0323240.

[0066] In some embodiments, the anti-LIGHT antibody comprises the CDR sequences of antibodies 18E04, 98C07, 1C02, 1C06, 13H04, 31A10, 98C07, 42A02, 29C02, 14B09, 117C06, 114F05, and 62C01, as described in WO2015 / 107331, which is incorporated herein by reference.

[0067] For example, in some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising 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 comprising three CDR sequences comprising each of SEQ ID NOs: 63, 64, and 65, respectively. In some embodiments, the 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.

[0068] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising 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 comprising three CDR sequences comprising each of SEQ ID NOs: 69, 70, and 71, respectively. In some embodiments, the 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.

[0069] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising 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 comprising three CDR sequences comprising each of SEQ ID NOs: 75, 76, and 77, respectively. In some embodiments, the 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.

[0070] In some embodiments, an anti-LIGHT antibody comprises a heavy chain comprising 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 comprising three CDR sequences comprising each of SEQ ID NOs: 81, 82, and 83, respectively. In some embodiments, the 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.

[0071] Free Light Detection Assay Most currently available assays only measure total LIGHT, including LIGHT bound to its receptor, including DcR3.Total LIGHT may not provide an accurate depiction of the level of disease-causing LIGHT, which may be free, unbound LIGHT.Therefore, when a method involves detecting free LIGHT, it may be desirable to use an assay that measures only free LIGHT.An assay for measuring free LIGHT is described in WO2021 / 202649, which is incorporated herein by reference in its entirety, particularly for its description of free LIGHT assay. [Example]

[0072] The following examples are provided to illustrate certain disclosed embodiments and should not be construed as limiting the scope of the present disclosure in any way. In the examples discussed below, "Antibody A" refers to an anti-LIGHT antibody that comprises the following six CDRs: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:2, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:3, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:4, a light chain CDR1 having the amino acid sequence of SEQ ID NO:5, a light chain CDR2 having the amino acid sequence of SEQ ID NO:6, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:7. In some embodiments, Antibody A 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, Antibody A 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.

[0073] Example 1 - Phase 2 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of Antibody A for the Treatment of Uncontrolled Non-Eosinophilic Asthma Example 1.1 - Study Objectives and Endpoints The primary objective of the study is to evaluate the ability of Antibody A to improve asthma control in subjects with poorly controlled NEA, based on the proportion of patients experiencing asthma-related events.

[0074] Secondary objectives of the study are to evaluate the safety and tolerability of Antibody A, to evaluate biomarkers of pharmacodynamic (PD) activity and the mechanism of action of Antibody A, and to evaluate the immunogenicity of Antibody A.

[0075] The exploratory objectives of this study are to evaluate the ability of Antibody A to improve asthma control in subjects with poorly controlled NEA of less than 150 eosinophils / μL, to evaluate sputum soluble LIGHT levels and gene expression in a select subset of subjects, to evaluate inflammatory proteins including, but not limited to, interleukin (IL)-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), and to evaluate the PK / PD relationship.

[0076] The primary endpoint of the study was the proportion of patients who experienced any of the following asthma-related events: 6 or more additional reliever puffs of SABA (compared to baseline) in a 24-hour period on 2 consecutive days (baseline SABA use was determined by the average use during the 7 days prior to Visit 2); an increase in ICS dose of 4-fold or more above the baseline dose (baseline ICS dose was defined as the dose the subject received during the 30-day run-in period); a decrease in peak flow rate of 30% or more on 2 consecutive days of treatment (compared to baseline) (baseline peak flow rate was determined by the average of measurements during the 7 days prior to Visit 2); an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days; or a hospitalization or emergency department visit due to an asthma exacerbation.

[0077] Secondary endpoints of this study included change from baseline in forced expiratory volume in 1 second (FEV1) at weeks 2, 4, 6, 8, 12, and 14; time to asthma-related events; change from baseline in exhaled nitric oxide (FeNO) at weeks 2, 4, 6, 8, 12, and 14; change from baseline in the Asthma Control Questionnaire (ACQ) at weeks 2, 4, 6, 8, 12, and 14; change from baseline in the Standardized Asthma Quality of Life Questionnaire for Ages 12 and Older (AQLQ(S)+12) at weeks 2, 4, 6, 8, 12, and 14; change from baseline in the Asthma Symptom Diary score at weeks 2, 4, 6, 8, 12, and 14; and change from baseline in the European Quality of Life-5 Dimension 5-Level Questionnaire at weeks 2, 4, 6, 8, 12, and 14. change from baseline in patient global impression of change / severity at weeks 2, 4, 6, 8, 12, and 14; change from baseline in clinician global impression of improvement / severity at weeks 2, 4, 6, 8, 12, and 14; frequency of short-acting beta-agonist (SABA) use at weeks 2, 4, 6, 8, 12, and 14; change from baseline in serum soluble LIGHT levels at weeks 2, 4, 6, 8, 12, and 14; incidence of adverse events (AEs) and change from baseline in clinical laboratory tests, vital sign measurements, and physical examination at weeks 2, 4, 6, 8, 12, and 14; and incidence of ADAs at weeks 2, 4, 6, 8, 12, and 14.

[0078] Exploratory endpoints of this study are the occurrence of asthma-related events in subjects with <150 eosinophils / μL, change from baseline in sputum soluble LIGHT and gene expression (selected subsets of sites / subjects only), change from baseline in inflammatory proteins including, but not limited to: IL-6, IFN-γ, and tumor necrosis factor alpha (TNF-α); and PK / PD assessments.

[0079] Example 1.2 - Study Design This is a randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the safety and efficacy of Antibody A for the treatment of poorly controlled NEA. Once eligibility is confirmed, subjects will complete a 30-day lead-in period of stable salmeterol and fluticasone therapy prior to randomization. At baseline, subjects will be randomized to receive one of three doses of 600 mg of Antibody A (Days 0, 28, and 56) or three doses of placebo at the same time points. Subjects will then begin discontinuing salmeterol and fluticasone therapy. Subjects will discontinue salmeterol on Day 14 and then taper fluticasone to 50% on Day 28. Fluticasone will be completely discontinued on Day 42. Subjects will be followed up until Day 98.

[0080] An adequate number of subjects will be enrolled to ensure that approximately 80 subjects complete the study.

[0081] All subjects will undergo efficacy, safety, PK / PD, and immunogenicity assessments. Antibody A efficacy will be determined by the occurrence of asthma-related events (primary endpoint), time to asthma-related events, and change from baseline in the following parameters: FEV1; FeNO; ACQ; AQLQ(S)+12; Asthma Symptom Diary score; European Quality of Life-5 Dimension 5 Level Questionnaire; Patient Global Impression of Change / Severity (PGI-C / S); Clinician Global Impression of Improvement / Severity (CGI-I / S); and frequency of short-acting beta-agonist (SABA) use. All subjects will be monitored for AEs and undergo physical examinations, vital signs, and regular safety laboratory tests. PK / PD of Antibody A will be determined by measuring levels of Antibody A and LIGHT, in addition to other biomarkers of NEA. Finally, immunogenicity of Antibody A will be determined by measuring ADA levels.

[0082] The test schema is shown in Figure 1.

[0083] This study will evaluate the safety and efficacy of Antibody A in subjects with poorly controlled non-eosinophilic asthma.

[0084] Subjects will be assessed for enrollment at the screening visit. If deemed eligible for enrollment, they will undergo a 30-day stable dose run-in period with a LABA (salmeterol) and an ICS (fluticasone). If a subject is switched to salmeterol and fluticasone alone, documentation of eligibility for all inclusion and exclusion criteria is required before the subject can enter the 30-day run-in period of the study prior to Visit 2 (randomization). Verification of eligibility must occur within a reasonable time after the screening visit. If verification of eligibility cannot be made within 7 days of the screening date, the sponsor must provide approval for the subject to continue.

[0085] During the 30-day run-in, a telephone visit (Visit 1a) should occur 7 days prior to baseline, i.e., on Day -7 (-2 day window). During this telephone visit, subjects should be reminded to begin daily peak flow measurements and complete a daily diary capturing ASD, SABA use, and daily peak flow values.

[0086] After the run-in period, subjects will be randomized to either Antibody A or placebo at the baseline visit (Day 0), administered at 600 mg. Subjects will receive Antibody A or placebo at Visits 2 (Day 0), 5 (Day 28), and 7 (Day 56). Over the first 42 days after randomization, subjects will taper off or discontinue use of the products administered during the run-in period. Salmeterol will be discontinued at Visit 4 (Day 14), fluticasone will be tapered to a 50% dose at Visit 5 (Day 28), and fluticasone will be completely discontinued at Visit 6 (Day 42). All subjects will continue with Antibody A or placebo monotherapy until Visit 9 (Day 98), which also marks the end of the study visits. Efficacy will be assessed from the baseline visit (Day 0) through Visit 9 (Day 98) according to the schedule outlined in the evaluation schedule (Table 1).

[0087] A post-screening and pre-baseline run-in period must be completed on stand-alone LABA (salmeterol) and ICS (fluticasone). The investigator will ensure that subjects are transitioned to these products at the screening visit if they are not already using these products.

[0088] If for any reason a subject must discontinue the study before Visit 9 (Day 98), the subject will be required to complete an Early Termination Visit (Day 98 of the procedure).

[0089] The study will be conducted at approximately 25 testing sites across the United States.

[0090] Subjects diagnosed with NEA (less than 300 eosinophils / μL) (measured in the blood) will be randomized into the study. An adequate number of subjects will be enrolled to ensure approximately 80 subjects complete the study.

[0091] Selection Criteria Subjects must meet the following requirements to be randomized into the study: 1. Subjects are ≥ 18 years of age at the time of informed consent. 2. Documented diagnosis of non-eosinophilic asthma (blood eosinophils less than 300 / μL). 3. Symptoms consistent with a diagnosis of poorly controlled asthma as determined by an ACQ score of 1.5 or greater. 4. Poorly controlled asthma despite LABA and ICS use for at least 3 consecutive months immediately prior to the screening visit. 5. Subjects must have had at least one asthma exacerbation in the last 24 months prior to screening. 6. Non-pregnant, non-lactating female subjects who are sexually active with the opposite sex and are of childbearing potential, and male subjects of reproductive potential who have a female sexual partner of childbearing potential, agree to use highly effective contraception during treatment and for 28 days after the final dose of study drug. Highly effective contraception is defined as a method that, when used consistently and correctly, has a low failure rate (i.e., less than 1% per year), such as oral / injectable / insertive / implantable / transdermal contraceptives, condoms with diaphragms, condoms with spermicides, diaphragms with spermicides, intrauterine hormone-releasing systems, or intrauterine devices (IUDs), or sexual abstinence. Contraception is not required if at least 6 weeks have passed since sterilization, defined as women who have undergone one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy, and men who have undergone vasectomy. If a woman is postmenopausal (defined as 12 consecutive months of spontaneous amenorrhea and age 51 or older), contraception is not necessary. Women of childbearing potential should have a negative pregnancy test as part of their screening evaluation. 7. Subject is able to understand and provide informed consent to participate in this study.

[0092] Exclusion criteria The presence of any of the following criteria will exclude a subject from the study: 1. Pulmonary disease other than asthma. 2. Currently on biologic therapy. Previous biologic therapy is tolerated with an appropriate washout period (12 weeks or 5 half-lives, whichever is longer). 3. Subjects who are current smokers, have a smoking history of 10 or more pack-days, have smoked cannabis >4 days / week in the last 3 months prior to screening, or have used e-cigarettes or vaping devices >4 days / week in the last 3 months prior to screening. 4.Currently suspected of drug or alcohol abuse. 5. Use of systemic immunosuppressants within the past 6 months. 6. Use of systemic corticosteroids within 6 weeks prior to screening or antibiotics within 4 weeks prior to screening. 7. Pregnant or breastfeeding subjects. 8. Subject has a history of neoplasia, except for curatively treated non-melanoma skin tumors or cervical carcinoma, without evidence of recurrence within 10 years prior to Visit 1. 9. The subject has a chronic active infection or other disease that predisposes to infection. 10. Subject has a chronic, severe, or uncontrolled medical disorder that may confound the results of the safety assessments conducted in this study. 11. Subject has a history of unresolved latent tuberculosis. 12. Subject has an alanine aminotransferase (ALT) / aspartate aminotransferase (AST) greater than the upper limit of normal (ULN) of 5 and / or a serum creatinine concentration greater than 1.5 mg / dL. 13. Subject has hemoglobin <10 g / dL, neutrophils <1,500 / μl, and / or platelets <75,000 / μl. 14. Subject has received a live vaccine within 12 weeks prior to Visit 2. 15. Subject is using an investigational drug, including an Emergency Use Authorization (EUA) vaccine, within 30 days of Visit 1. 16. Subject has known or suspected intolerance or hypersensitivity to the investigational drug(s), closely related compounds, or any component of the investigational drug. 17. The investigator has any concerns about the subject's safety, compliance, or suitability for participation in the study.

[0093] Screen failure Subjects missing the inclusion and / or exclusion criteria may be rescreened for the study, with sponsor approval.

[0094] Early subject withdrawal All subjects will be advised that they are free to withdraw from participation in this study at any time, regardless of reason, without prejudice. The investigator should make every reasonable attempt to retain the subject in the study, but if the subject withdraws consent to participate, the subject must withdraw from the study. The investigator should attempt to contact, by telephone or other means, subjects who do not attend a scheduled clinic visit to rule out the possibility that an AE is the cause of withdrawal. If this is the case, the AE must be documented, reported, and followed up.

[0095] Subjects may refuse to continue receiving study medication at any time during the study. If this occurs, the investigator will discuss with the subject completing an Early Termination Visit 4 weeks (± 3 days) after the last dose. If the subject refuses this visit / procedures related to this visit, data on concomitant medications and AEs will be collected if the subject consents. If the subject refuses a physical visit, data on concomitant medications and AEs may be collected by telephone.

[0096] Withdrawal of consent to a study means that the subject is unwilling or unable to undergo further protocol-required treatments or procedures and is unwilling or unable to continue further study participation. Subject data up to the withdrawal of consent may be included in the study analysis, and, if permitted, publicly available data after withdrawal of consent may be included.

[0097] The sponsor reserves the right to request subject withdrawal due to protocol deviations or other reasons.

[0098] The investigator also has the right to withdraw a subject from the study at any time for any reason. If a subject withdraws before completing the study, the subject must be followed up as directed in the assessment schedule (Table 1). The reason for withdrawal will be determined by the investigator, and the reason and date of withdrawal must be recorded in the subject's medical record and electronic case report form (eCRF). If a subject withdraws for more than one reason, each reason must be recorded in the source document, and the most clinically relevant reason must be entered in the eCRF.

[0099] Reasons for cancellation include, but are not limited to: Lack of effectiveness ●Death Protocol deviation Doctor's decision Sponsor's requirements ● Withdrawal by the subject ● Unknown to follow-up ●Other (specify). For example, pregnancy. [Table 1-1] [Table 1-2] [Table 1-3]

[0100] Example 1.3 - Treatment Investigational drug identity, dose, and mode of administration Antibody A is the investigational drug used in this study. Antibody A will be supplied in a single-use vial containing 300 mg of antibody A (concentration 150 mg / mL). Placebo will be sourced locally and provided as volume-matched saline for injection. Antibody A or placebo will be administered by SC injection into the abdomen within a zone 4-10 cm from the navel, with the injection site rotated based on the number of syringes used. Antibody A or placebo will be administered at Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 (Day 56). Antibody A will be administered at a dose of 600 mg.

[0101] Treatment administered Eligible subjects will receive 600 mg of Antibody A or placebo subcutaneously (SC) at Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 (Day 56).

[0102] Blinded and open-label treatment assignment This is a double-blind study. All subjects, investigators, and study personnel involved in the conduct of the study will be blinded to treatment assignment except as outlined in the study-specific blinding plan.

[0103] Treatment unblinding is not recommended if learning the treatment assignment would not substantially alter the planned management of the medical emergency. Unblinding is permitted in medical emergencies that require immediate knowledge of the subject's treatment assignment. Whenever possible, unblinding should be discussed with the medical monitor. In the case of emergency unblinding, the investigator may unblind in the IXRS / eCRF. If the investigator is unable to discuss treatment unblinding with the medical monitor before unblinding, he or she must notify the medical monitor of the unblinding event as soon as possible without revealing the subject's treatment assignment. The investigator or designee must record the date and reason for study discontinuation in the appropriate eCRF for that subject. In all non-urgent cases, the investigator should discuss the event with the medical monitor before unblinding the subject's treatment assignment.

[0104] If the treatment assignment is unblinded for an individual subject, the investigator will be informed of that subject's treatment assignment without unblinding the treatment assignments of the remaining subjects in the study.

[0105] Dose selection for the study In the first Phase 1 human trial, a single dose of Antibody A was administered with a median time to max It was absorbed and eliminated with a mean terminal half-life ranging from 18 to 27 days.

[0106] Preliminary pharmacokinetic data are available from a study of Antibody A in patients with Crohn's disease (clinicaltrials.gov identifier NCT03169894), confirming predicted accumulation with repeated dosing based on the Phase 1 single-dose pharmacokinetic data, with peak serum concentrations of Antibody A not achieved until Study Day 21, at least after the second dose administration (Study Day 14).

[0107] In this study, the antibody A dosing schedule is once every 28 days (600 mg dose / month) versus once every 14 days (300 mg dose twice / month) in the Crohn's disease study. Based on the PK data and favorable safety profile of biweekly dosing up to 3 mg / kg in the Crohn's disease study, the antibody A dose in this study will be 600 mg once monthly for a total of three doses. This dosing regimen is expected to provide higher serum antibody A concentrations before discontinuing salmeterol on study day 14, and the 28-day dosing interval limits the potential for accumulation with the two subsequent doses.

[0108] Dose adjustment criteria No dose adjustments are permitted.

[0109] Non-experimental therapy, ICS, and LABA use All non-study therapies, including but not limited to over-the-counter and non-pharmacological treatments, from the time of screening (Visit 1) through the end of the study must be recorded on the appropriate eCRF page. Records of ICS and LABA use should be captured for the 3 months immediately preceding screening.

[0110] Pretreatment Prior therapy includes all treatments received from the screening visit (Visit 1) until immediately prior to the first dose of study medication, with the exception of ICS and LABA, which should also be recorded for the 3 months immediately prior to screening (Visit 1). Prior therapy information must be recorded on the appropriate eCRF page.

[0111] Combination therapy Concomitant therapy refers to all therapy administered at or after the first dose of study medication through the final visit. Concomitant therapy information must be recorded on the appropriate eCRF page.

[0112] Permitted Therapies Medications deemed necessary for the subject's welfare may be administered at the discretion of the Investigator. In the event that the site has a situation requiring further clarification, the Medical Monitor should be contacted.

[0113] Acceptable contraceptive methods considered highly effective (e.g., with low failure rates (i.e., less than 1% per year)) when used consistently and correctly include oral / injectable / insertive / implantable / transdermal contraceptives, co-investigational drugs and study condoms with diaphragms, condoms with spermicide, diaphragms with spermicide, intrauterine hormone-releasing systems or IUDs, or sexual abstinence.

[0114] Prohibited Therapies New initiation of investigational compounds or concomitant treatment with other asthma therapies is not permitted during the study. Use of systemic corticosteroids, biologic agents, immunosuppressants, and inhaled anticholinergics is not permitted. Leukotriene inhibitors are not permitted to be added to a subject's treatment regimen after being screened for the study. Subjects receiving a leukotriene inhibitor as part of their pre-therapy at screening (Visit 1) may continue to receive the leukotriene inhibitor over the course of study participation.

[0115] Treatment after the end of the study Subjects will be treated according to standard clinical practice after completing study participation.

[0116] Example 1.4 - Test Procedure Exam period Antibody A and placebo treatments will be administered at Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 (Day 56). Subjects may not receive treatment after Day 56. The treatment period is considered to be 84 days, with each dose of study drug considered to be 28 days of treatment. The overall study duration is approximately 135 days, including screening and a 30-day stable dose run-in period.

[0117] Medical history evaluation Medical and surgical history will be recorded at screening. All significant medical history findings that have been present or active within the 5 years prior to screening will be entered into the eCRF. Medical history findings that have not been present within the 5 years prior to screening will be recorded if the investigator deems them clinically relevant to the conduct of the study.

[0118] Additionally, the subject's overall NEA history will be captured at screening, including but not limited to, approximate date of diagnosis and prior treatment, including approximate start and end dates.

[0119] Efficacy evaluation Efficacy responses will be assessed by the procedures listed below at the time points described in the Evaluation Schedule (Table 1).

[0120] Asthma-related events The proportion of patients experiencing any of the following asthma-related events and the time to an asthma-related event will be determined: Six or more additional SABA reliever puffs (compared to baseline) in a 24-hour period on two consecutive days, or Baseline SABA use was determined by average use during the 7 days prior to Visit 2. an increase in ICS dose of ≥4 times the baseline dose, or Baseline ICS dose is defined as the dose a subject received during the 30-day run-in period. A decrease in peak flow of 30% or more (compared to baseline) on two consecutive days of treatment, or Baseline peak flow will be determined by averaging measurements over the 7 days prior to Visit 2. an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days, or Hospitalization or emergency department visit due to asthma exacerbation.

[0121] Time to event is measured in days, using the first day of the event to indicate the date of occurrence of the overall asthma-related event.

[0122] Patients who meet any of the above criteria for an asthma-related event will be allowed to resume background (pre-study) therapy. If background therapy is resumed, the patient must be withdrawn from the study.

[0123] Forced expiratory volume in 1 second (FEV1) FEV1 is the volume of air that can be forcefully exhaled from the lungs in the first second, measured in liters by spirometer and reported as a percentage of the expected volume.

[0124] Exhaled nitric oxide (FeNO) The FeNO test measures the level of nitric oxide in exhaled breath. The FeNO test is performed by exhaling into a tube attached to a handheld monitor.

[0125] Peak Flow Meter The peak flow meter measures the extent to which the lungs can expel air. Subjects will measure their peak flow daily with a device provided by the sponsor and record the results in a diary.

[0126] Asthma Control Questionnaire (ACQ) This is a brief questionnaire designed to measure the adequacy of asthma control and change in asthma control. The ACQ includes multidimensional constructs assessing symptoms (5 items, self-administered), rescue bronchodilator use (1 item, self-administered), and FEV1 (1 item, completed by study staff). Scores range from 0 (completely controlled) to 6 (severely uncontrolled). (Juniper EF, Svensson K, Mork AC, Stahl E. Respir. Med. 2005;99(5):553-558).

[0127] Standardized Asthma Quality of Life Questionnaire for ages 12 and older (AQLQ(S)+12) The AQLQ(S)+12 is a modified version of the standardized AQLQ developed to measure functional impairment experienced by adults aged 17 years and older. The AQLQ(S)+12 is validated for patients aged 12 to 70 years and includes 32 questions across four domains: symptoms, activity limitations, emotional functioning, and environmental stimuli (Juniper et al. Thorax. 1992;47(2):76-83., Wyrwich et al. Qual Life Res. 2011;20(6):903-912).

[0128] Subjects are asked to recall their experiences over the past two weeks and rate each question on a 7-point scale (7 = not limited at all, 1 = completely limited). The AQLQ+12 composite score is derived as the average of the 32 questions. Thus, the total score ranges from 1 (indicating "complete impairment") to 7 (indicating "no impairment").

[0129] Asthma symptom diary The asthma symptom diary is a six-item daily measure of asthma symptom severity that assesses three core categories: respiratory symptoms (dyspnea, wheezing, shortness of breath), chest symptoms (chest tightness, chest pain), and cough. The asthma symptom diary is intended to be completed twice daily and consists of a morning diary (completed upon waking and addressing nighttime asthma symptoms) and an evening diary (completed before bed and addressing daytime asthma symptoms). During each time frame, subjects are required to rate six symptoms at their worst using an 11-point numeric rating scale ranging from 0 ("none") to 10 ("the worst you can imagine"). (United States Food and Drug Administration.Clinical Outcome Assessments(COA)Qualification Program DDT COA #000006: Asthma Daytime Symptom Diary(ADSD)and Asthma Nighttime Symptom Diary(ANSD)(available at https: / / www.fda.gov / drugs / clinical-outcome-assessment-coa-qualification-program / ddt-coa-000006-asthma-daily-symptom-diary-adsd)).

[0130] European Quality of Life-Five Dimensions, Five Levels Questionnaire (EQ-5D-5L) The EQ-5D-5L consists of the EQ-5D descriptor system and the EQ visual analogue scale (EQ VAS). The descriptor system is composed of five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, slight problem, moderate problem, serious problem, and severe problem. The EQ VAS records subjects' self-assessed health status on a vertical VAS, with endpoints labeled "best health you can imagine" and "worst health you can imagine" (EuroQol, Group. EQ-5D-5L:About.2017 (available at https: / / euroqol.org / eq-5d-instruments / eq-5d-5l-about / EuroQol,2017)).

[0131] Patient's global impression of change / severity The Patient Global Impression of Change or Severity (PGI-C, PGI-S) scales are global indices that can be used to assess the severity of a specific condition (single-state scales) from the patient's perspective. The PGI-C is a single-question scale that asks the patient to rate the overall state of a specific condition on a 7-point scale. The PGI-S is a single-question scale that asks the patient to rate the current state of their specific condition on a 7-point scale.

[0132] Clinician's global impression of improvement / severity The Clinician's Global Impression of Improvement / Severity (CGI-I, CGI-S) are global indices that can be used to assess the severity of a specific condition (single-state scale) from the clinician's perspective. The CGI-I is a single-question scale that asks clinicians to assess the overall state of a patient's specific condition on a 7-point scale since the start of a research study. The CGI-S is a single-question scale that asks clinicians to assess the current state of a patient's specific condition on a 7-point scale.

[0133] Use of short-acting beta-agonists The number of short-acting beta-agonist inhalations / puffs is assessed by reviewing a diary maintained by the subject.

[0134] safety Safety and tolerability assessments include evaluation of the frequency and severity of AEs and changes in clinical laboratory values, vital signs, and physical examination findings.

[0135] Laboratory tests performed Specimens for the following clinical tests will be collected at the time points specified in the assessment schedule (Table 1).

[0136] Hematology tests include hemoglobin, hematocrit, red blood cell count, red blood cell indices, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, platelet count (or estimated), and white blood cell count with differential.

[0137] Serum chemistry tests included sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatine, creatinine phosphokinase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, calcium, magnesium, phosphorus, lactate dehydrogenase, uric acid, total protein, albumin, C-reactive protein, total cholesterol, high-density lipoprotein, LDL, and triglycerides.

[0138] For women of childbearing potential, perform a serum / urine pregnancy test.

[0139] Urinalysis includes dipstick measurements of pH, specific gravity, protein, blood, glucose, and ketones.

[0140] Other tests include anti-drug antibodies (ADA), serum:soluble LIGHT, inflammatory proteins, immunophenotype, sputum:soluble LIGHT, and plasma antibody A pharmacokinetics.

[0141] Fasting is not required for test-specific laboratory samples.

[0142] Laboratory specimens are collected and analyzed in laboratories specified in the testing laboratory manual(s) or guidelines.

[0143] Blood collection volume The blood collection volumes for this study are shown in Table 2. [Table 2]

[0144] Evaluation of laboratory values Normal ranges for central test values ​​in this study will be provided to each site as part of the test manual. For locally performed evaluations, normal ranges for local laboratory values ​​will be provided to the sponsor's designee. They will be considered reference ranges determined at the specific site.

[0145] If a laboratory value is outside the reference range, it is not necessarily clinically relevant. The investigator must evaluate the out-of-range value and record their assessment of clinical relevance in the subject's source documentation.

[0146] Any laboratory value that, in the opinion of the investigator, indicates a clinically relevant or pathological change during or after the end of treatment should be discussed with the medical monitor and, if appropriate, reported as an AE and followed up.

[0147] All measurements described in this section are accepted standard methods.

[0148] Laboratory Tests: Vital Signs Vital signs, including systolic and diastolic blood pressure, temperature, pulse rate, respiratory rate, height, and weight, will be collected as indicated in the assessment schedule (see Table 1).

[0149] Pre-dose vital signs must be taken within 60 minutes prior to dosing. Post-dose vital signs must be taken at least 60 minutes after dosing and before discharge. Additional blood pressure and pulse rate measurements may be performed as determined by the investigator to ensure adequate monitoring of subject safety and accurate recording of vital signs. Any changes from baseline that are deemed clinically important by the investigator will be recorded as an AE.

[0150] Clinical Test: Electrocardiogram At the time indicated on the assessment schedule, a standard 12-lead ECG will be performed after the subject has been supine for approximately 5 minutes (see Table 1). All ECG recordings will be identified by subject number, date, and time of recording, and a copy will be included with the subject's source documentation.

[0151] Any ECG values ​​that, in the opinion of the investigator, indicate clinically relevant or pathological changes during or after the end of treatment will be discussed with the medical monitor and reported as AEs and followed up.

[0152] Clinical Test: Physical Examination A complete physical examination, including measurements of height and weight, will be performed by a licensed physician, physician assistant, or nurse at Visits 1 through 9 / ET (see Table 1). Clinically significant physical examination findings will be reported and tracked as AEs. Height will be measured only at Visit 1.

[0153] Clinical Testing: Adverse Events The investigator is responsible for detecting and documenting events that meet the criteria and definitions of AEs or SAEs described below. At each visit, subjects will be given a period to spontaneously report any problems since their last visit or evaluation.

[0154] Any clinically relevant observation made during each visit will be considered an AE. AEs will be collected from the time of informed consent until the final study visit.

[0155] Immunogenicity analysis Blood samples for ADA analysis will be collected at the time points indicated in the assessment schedule (see Table 1). Visit 2 samples should be collected pre-dose. Additionally, ADA samples will be collected if an immunologically related AE is reported. ADA samples will be processed according to the methods and instructions described in the laboratory manual(s) and guidance(s). ADA sample analysis will be performed according to standard operating procedures (SOPs) using validated methods by laboratories defined in the laboratory manual(s) and guidance(s). Assay and analysis details are described in the method validation and bioanalytical information.

[0156] Pharmacokinetics, Pharmacodynamics and Biomarker Assessment Blood samples will be collected for evaluation of PK, PD activity and mechanism of action of Antibody A in the NEA.

[0157] Blood samples are used to separate serum, which is then analyzed for circulating soluble LIGHT levels using a related immunoassay for measuring PD activity. In addition, for selected subsets of sites or subjects, sputum samples are analyzed for soluble LIGHT levels and gene expression. Biomarkers related to inflammation, such as (but not limited to) IL-6, IFN-γ, and TNF-α, can be assessed using a related immunoassay. As the rationale evolves, serum can also be used for novel biomarker analysis.

[0158] Blood samples collected for PBMC isolation can be used for comprehensive immunophenotyping of circulating immune cell subsets by flow cytometry or CyTOF to study the effects of AVTX-002 on these cell types. Additionally, transcriptome analysis can be performed within PBMCs as needed.

[0159] All of these exploratory biomarkers listed in Table 1 will be performed in the laboratories specified in the laboratory manual(s) and / or guidance(s).

[0160] Example 1.5 - Adverse Events An AE is defined as any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product, not necessarily causally related to the product. Thus, an AE can be any untoward, unintended sign (including new, clinically significant abnormal laboratory findings), symptom, or disease, whether or not related to the product, that is temporally related to the product. An AE is considered treatment-emergent if it occurs after the first dose of investigational drug and within 28 days of the last dose of the investigational drug. Additionally, an AE that occurs before administration of the investigational drug and increases in severity after initiation of dosing and within 28 days of the last dose of the investigational drug is also considered a treatment emergency.

[0161] All AEs will be collected from the time informed consent is signed through the end of the study (Day 98 / ET). This includes events that occur whether or not the study drug is administered. Note: Clinically significant observations recorded during the screening procedure (laboratories, physical exam, vital signs, etc.) should be entered as medical history. Only if a clinically significant observation is clearly related to the performance of the screening procedure should it be entered as an AE (e.g., hematoma due to blood being drawn for the screening lab). When possible, a diagnosis should be recorded rather than a list of symptoms. If no diagnosis is made, each symptom should be listed individually.

[0162] All AEs must be followed to closure, regardless of whether the subject is still participating in the study. Closure indicates that outcome is achieved or stabilization is achieved (the investigator does not anticipate any further improvement or worsening of the event). When appropriate, medical tests and investigations are performed to document the resolution of the event(s).

[0163] Lack of efficacy, including worsening of symptoms, disease progression, or lack of improvement, should not be recorded as an AE unless it meets the definition of an SAE criteria.

[0164] AEs that change in severity over time should be recorded once on the eCRF with the highest severity, with two exceptions. The first exception is a worsening of a non-NEA-related pretreatment event after initiation of study drug, which must be recorded as a new AE. For example, if a subject experiences mild intermittent headache before receiving study drug, but the headache intensity increases to moderate after the first dose of study drug, a new AE of moderate intermittent headache should be recorded on the source document and eCRF. The second exception is an AE that later begins as a non-serious event that meets the definition of an SAE, which should be entered once for the non-serious portion of the AE and then re-recorded as a new event with the start date of the day it became severe.

[0165] Severity of adverse events Medical assessment of the clinical severity of AEs is determined using the definitions outlined in the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (published November 27, 2017, by the US Department of Health and Human Services, National Institutes of Health, National Cancer Institute). Grade 1 is defined as mild, asymptomatic, or mild symptoms, or clinical or diagnostic observation only, or no intervention is indicated. Grade 2 is defined as moderate or minimal, local or noninvasive intervention is indicated, or age-appropriate instrumental activities of daily living (ADLs) are limited. Grade 3 is defined as severe or medically significant but not immediately life-threatening, or hospitalization or prolonged hospital stay is indicated, or disabling, or limiting self-care ADLs. Grade 4 is defined as life-threatening consequences or urgent intervention is indicated. Grade 5 is defined as death related to the AE.

[0166] The above grading guidelines should be used whenever possible. For AEs that cannot be graded using the CTCAE, severity should be graded using mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), and fatal (Grade 5).

[0167] For a complete description of CTCAE terminology and instrumental and self-care ADLs, please refer to the CTCAE document referenced above. It is important to distinguish between serious AEs and SAEs. Severity is a classification of intensity, while an SAE is an AE that meets the serious criteria.

[0168] Related Category Classification The investigator must assess each AE for a relationship to the investigational drug. The investigator should determine, in their medical judgment, whether there is a reasonable possibility that the event could be caused by the investigational drug. If there is no valid reason to suggest a relationship, the AE should be classified as "unrelated." Otherwise, the AE should be classified according to the following guidelines. The causality assessment must be documented in the source document and eCRF (Table 3). [Table 3]

[0169] Outcome at last observation Outcome at last observation will be classified as recovered / resolved, recovered / resolved with sequelae, recovering / resolving, not recovered / not resolved, fatal, or unknown.

[0170] Reporting of serious adverse events Initial and follow-up SAE reports must be completed by the investigator or designee and sent to the CRO within 24 hours of initial knowledge of the SAE. The investigator or designee must complete, sign, and date the appropriate SAE form and verify the accuracy of the information against corresponding source documentation. This information shall be sent to the CRO Pharmacovigilance Department.

[0171] Definition of serious adverse events An SAE is any untoward medical occurrence, at any dose, whether or not considered related to the investigational drug: that results in death, is life-threatening, requires hospitalization or extension of an existing hospitalization, results in persistent or significant impairment / incapacity, is a congenital abnormality, or is a significant medical event.

[0172] Note that the term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event, not an event that, if more severe, might have hypothetically caused death.

[0173] Note that a patient hospitalization is defined as a 24-hour or overnight stay in the hospital. Voluntary hospitalization to treat a condition present before exposure to the study drug or hospitalization for diagnostic evaluation of an AE does not qualify the condition or event as an SAE. Furthermore, an overnight hospital stay due solely to transportation, organizational, or accommodation issues and without a medical context need not be considered an SAE.

[0174] Note that a congenital anomaly in an infant born to a mother exposed to an investigational drug during pregnancy is an SAE, except that a newly diagnosed pregnancy in a subject who has been receiving an investigational drug is not considered an SAE unless the pregnancy is suspected to have resulted from an interaction of the investigational drug with a contraceptive method.

[0175] It is noted that medical and scientific judgment should be used in determining whether it is appropriate to consider other serious circumstances, such as significant medical events that may not be immediately life-threatening or result in death or hospitalization, but which may endanger the subject or require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are allergic bronchospasm, blood disorders or seizures that do not result in hospitalization, or intensive care in the emergency room or at home in the development of drug addiction or substance abuse.

[0176] Timeframe for collecting serious adverse events All SAEs, regardless of study relatedness, will be collected from the time the subject signs the informed consent through the end of the study / early termination visit. The investigator or designee must promptly report all SAEs to the CRO within 24 hours of first becoming aware of the event.

[0177] Any SAE(s) that occur during the study but are not discovered by the site until the study is completed must be reported to the CRO within 24 hours of first knowledge of the event, regardless of its relationship to the study.

[0178] Date of onset and resolution of serious adverse events The date of onset of an SAE is defined as the date the event met the severity criterion. The date of resolution is the date outcome or stabilization is achieved (i.e., the investigator does not expect further improvement or worsening of the event).

[0179] Any sign or symptom experienced by the subject after signing the informed consent form and assent form (if applicable), or up to the date of onset of the SAE, or after the date of resolution of the SAE must be recorded as an AE.

[0180] Fatal outcome Fatal should be selected as the outcome only when the AE results in death. If more than one AE may be associated with the subject's death, the outcome of death must be indicated for each such AE.

[0181] Any AE resulting in subject death will be checked as fatal and the date of death will be recorded as the resolution date. AEs resulting in death should be reported as SAEs within 24 hours if not already reported as such. In the event of subject death, data should be collected on whether death occurred after discontinuation of treatment and, if so, the reason for discontinuation of treatment.

[0182] For other AEs that were ongoing at the time of death and did not contribute to the subject's death, the outcome should be considered as not resolved, and the resolution date was not recorded.

[0183] pregnancy All women of childbearing potential participating in this study, and men with female partners of childbearing potential, should be counseled about the need to use highly effective contraception throughout the study and for 28 days after the final dose of study drug, as well as the importance of avoiding pregnancy while participating in the study. Highly effective contraception is defined as a method that, when used consistently and correctly, has a low failure rate (i.e., less than 1% per year), such as oral, injectable, insertive, implantable, or transdermal contraceptives, diaphragm condoms, spermicide-coated condoms, spermicide-coated diaphragms, intrauterine hormone-releasing systems, or IUDs, or sexual abstinence. Contraception is not required for women who have undergone one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy, and for men who have undergone vasectomy, if at least 6 weeks have passed since their sterilization procedure. Contraception is not required if women are postmenopausal (spontaneous amenorrhea for 12 consecutive months and age 51 or older).

[0184] Women and men with female partners should be instructed to contact the investigator or study staff immediately if pregnancy occurs or is suspected.

[0185] Pregnancy testing will be performed on all women according to the assessment schedule (Table 1). Women who are found to be pregnant at screening will be excluded from the study and will be considered a screening failure. Women who are found to be pregnant after receiving study drug will be required to discontinue the study, and an end-of-study assessment will be performed as soon as possible after learning of their pregnancy.

[0186] Investigators must report pregnancies for females (study participants or female partners of male study participants) who become pregnant during study drug treatment or within 28 days after study drug discontinuation (permission must be obtained from the pregnant female partner of a male subject to track the pregnancy and report the outcome). Pregnancies must be reported to the CRO within 24 hours of learning of the pregnancy using the Pregnancy Data Collection Form via email address similar to SAE reporting. Investigators should contact the designated individual(s) to be notified of the pregnancy and record the pregnancy-related information on the pregnancy form / other provided by the sponsor or designee.

[0187] The investigator is also responsible for following the pregnancy until delivery or termination. These findings must be reported on the Pregnancy Data Collection Form and forwarded to the designated individual(s). An event meets the criteria for an SAE only if it results in spontaneous abortion or congenital anomaly.

[0188] Reporting to regulatory authorities, institutional review boards / ethics committees and sites The sponsor or its designee is responsible for notifying relevant unanticipated SAEs to the relevant regulatory authorities and, if applicable, the US Central Institutional Review Board (IRB).

[0189] In addition, sponsors and CROs are responsible for notifying participating sites of all relevant unanticipated SAEs that occur during all interventional studies throughout the development program.

[0190] Investigators are responsible for notifying the local IRB, local ethics committee, or relevant local regulatory authority, as appropriate, of all SAEs that occur at the investigational site.

[0191] Example 1.8 - Statistics The sample size in this study will be approximately 80, with 40 subjects randomized in a 1:1 ratio per treatment group.

[0192] Sample size estimation was based on the estimated proportion of patients in the two treatment groups expected to experience asthma-related events as defined by the primary endpoint. In a study using another product, a rate of 6% was observed in the active group and 44% in the placebo group (Wenzel et al., N Engl J Med, June 2013;368(26):2455-66). Using these estimates, a study with 40 subjects per group would have a power of greater than 95%. To account for potential variations from the cited study, sample size estimation was assessed assuming a 5% type I error and a range of 30%-50% for the placebo group and 5%-8% for the active group. In the 20 such scenarios considered, power was slightly below 80% only when the difference between treatments was less than 23%. In the majority of cases examined, power exceeded 90%.

[0193] Re-estimation of sample size may be performed once a sufficient number of subjects have been enrolled to provide meaningful data, details of which will be described in the statistical analysis plan.

[0194] The study includes the following subject populations: randomized analysis set, safety analysis set, and total analysis set. The randomized analysis set includes all subjects randomized in the study. Subjects are classified according to their randomized treatment group. The randomized analysis set will be used for all disposition, protocol deviation, and demographic and other baseline characteristic analyses. The safety analysis set includes all subjects randomized in the study and who receive at least one dose of study drug. Subjects are classified according to their actual treatment group. The safety analysis set will be used for all exposure and safety analyses and immunogenicity analyses. The total analysis set includes all subjects who receive at least one dose of study drug and have a baseline and at least one post-baseline efficacy assessment. Subjects are classified according to their randomized treatment group. The total analysis set will be used for all efficacy and pharmacodynamic analyses.

[0195] This section presents a summary of the planned statistical analyses. Additional details regarding data handling, analysis methods, and presentation of results will be described in the Statistical Analysis Plan (SAP) for this study. The SAP will be finalized before the database is locked.

[0196] All efficacy, safety, PD, and ADA variables will be summarized using descriptive statistics. For continuous data, descriptive statistics include the number of subjects (n), mean, standard deviation, median, minimum, and maximum. Summary of change from baseline variables will include only subjects with both the baseline value and the corresponding value at the time point of interest. For categorical data, descriptive statistics will include frequencies and percentages. A listing of all study data collected will be provided.

[0197] Study drug and study disposition for all subjects randomized in this study will be summarized by treatment group and completion / discontinuation status. Subjects who discontinue study drug and / or the study early will be summarized by treatment group and reason for discontinuation. The number of subjects in each analysis set will also be summarized by treatment group.

[0198] All subject data will be reviewed for the occurrence of protocol deviations. Prior to database lock, all protocol deviations will be reviewed and classified with respect to their potential to affect study outcomes. Protocol deviations will be summarized by treatment group.

[0199] Demographic and other baseline characteristics will be summarized by treatment group using descriptive statistics.

[0200] All previous and concomitant medications will be coded using the WHO Drug Dictionary. Previous and concomitant medications will be summarized by treatment group using descriptive statistics.

[0201] Exposure to study drug will be summarized by treatment group using descriptive statistics.

[0202] Safety analyses will be performed using data from the safety analysis set. Safety variables include TEAEs, clinical laboratory values, vital signs, and ECG results. No formal inferential analyses will be performed for any safety variables unless otherwise stated.

[0203] Verbatim terms for adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The overall incidence of subjects with at least one AE will be summarized by treatment group. The incidence of TEAEs will be summarized by treatment group, system organ class (SOC), and preferred preferred term (PT). Each subject will be counted only once per SOC and preferred term. An AE was considered treatment-emergent if it occurred after the first dose of study drug and within 28 days after the subject's last dose of study drug.

[0204] For all continuous laboratory variables, descriptive statistics of all reported values ​​and changes from baseline will be summarized by treatment group and visit.

[0205] For all continuous vital signs, descriptive statistics of all reported values ​​and changes from baseline will be summarized by treatment group and visit.

[0206] For the primary variable, comparison of the proportion of subjects with asthma-related events is via the Wald Z test (corrected for continuity). Summary statistics are provided via a 2x2 table showing the presence or absence of events in each treatment group. The test statistic, its associated p-value, and the 95% confidence interval for the treatment difference are also provided.

[0207] All other efficacy variables will be summarized using descriptive statistics. For continuous data, descriptive statistics include the number of subjects (n), mean, standard deviation, median, minimum, and maximum. For summaries of changes from baseline variables, only subjects with both the baseline value and the corresponding value at the time point of interest will be included. For categorical data, descriptive statistics include frequencies and percentages.

[0208] Further details regarding all statistical analyses can be found in the study Statistical Analysis Plan (SAP).

[0209] For all PK, PD and biomarker variables, descriptive statistics will be presented by treatment group and time point.

[0210] For all immunogenicity variables, descriptive statistics are presented by treatment group and time point.

[0211] Table 4 below provides the sequences referred to in this application. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

Table 4-5

Claims

1. 1. A medicament for use in a method for treating asthma, including non-eosinophilic asthma (NEA), comprising an anti-LIGHT antibody, wherein the medicament is administered to a human subject in need thereof in an effective amount of the anti-LIGHT antibody.

2. The anti-LIGHT antibody comprises the following set of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 amino acid sequences: (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 2. The agent of claim 1, comprising: (i) a heavy chain and a light chain that together comprise one of SEQ ID NOs: 52, 53, 54, 55, 56, and 57.

3. A drug for use in a method for treating asthma, including non-eosinophilic asthma (NEA), comprising an anti-LIGHT antibody, characterized in that the drug is administered to a human subject in need of such treatment in an effective amount of the anti-LIGHT antibody, wherein the anti-LIGHT antibody comprises a heavy chain comprising a heavy chain variable region (VH) comprising complementarity determining region 1 (CDR-H1) comprising the amino acid sequence of SEQ ID NO:2, CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, and CDR-H3 comprising the amino acid sequence of SEQ ID NO:4, and a light chain comprising a light chain variable region (VL) comprising CDR-L1 comprising the amino acid sequence of SEQ ID NO:5, CDR-L2 comprising the amino acid sequence of SEQ ID NO:6, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:

7.

4. 4. The method of claim 3, wherein the subject has poorly controlled asthma as determined by an Asthma Control Questionnaire (ACQ) score of 1.5 or greater.

5. 4. The method of claim 3, wherein the subject has asthma that is poorly controlled with long-acting beta agonists (LABAs) and inhaled corticosteroids (ICS).

6. 6. The method of claim 5, wherein the LABA is salmeterol.

7. 7. The method of claim 5 or 6, wherein the ICS is fluticasone.

8. 4. The method of claim 3, wherein the subject has experienced an asthma exacerbation within 25 months prior to administration of the first dose of the anti-LIGHT antibody.

9. The method of claim 3, wherein the subject has a blood eosinophil count of less than 300 cells / μL.

10. The method of claim 3, wherein the subject has a blood eosinophil count of less than 150 cells / μL.

11. 4. The method of claim 3, wherein the subject is receiving a LABA at the time of administration of the first dose of the anti-LIGHT antibody, and the LABA is discontinued about 14 days after administration of the first dose of the anti-LIGHT antibody.

12. 4. The method of claim 3, wherein the subject is experiencing ICS upon administration of a first dose of the anti-LIGHT antibody, and the ICS is reduced by 50% about 28 days after administration of the first dose of the anti-LIGHT antibody.

13. 13. The method of claim 12, wherein the ICS is discontinued about 42 days after administration of the first dose of the anti-LIGHT antibody.

14. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of 3 to 12 mg / kg, 3 to 11 mg / kg, 3 to 10 mg / kg, 3 to 9 mg / kg, 3 to 8 mg / kg, 3 to 7 mg / kg, 3 to 6 mg / kg, 3 to 5 mg / kg, or 3 to 4 mg / kg.

15. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of 6 mg / kg.

16. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of 8 mg / kg.

17. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, or 100-200 mg.

18. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of about 600 mg.

19. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered about every 14 days, about every 21 days, about every 28 days, about every 35 days, about every 42 days, about every 49 days, about every 56 days, or monthly.

20. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered about every 28 days.

21. The method of claim 3, wherein the anti-LIGHT antibody is administered monthly.

22. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of 600 mg every 28 days.

23. 4. The method of claim 3, wherein the anti-LIGHT antibody is administered at a dose of 600 mg monthly.

24. 23. The method of claim 22, wherein at least three doses of the anti-LIGHT antibody are administered.

25. 23. The method of claim 22, wherein the anti-LIGHT antibody is administered subcutaneously.

26. 23. The method of claim 22, wherein the anti-LIGHT antibody is administered intravenously.

27. The method of claim 3, wherein the subject is an adult.

28. The method of claim 3 , wherein the subject is a pediatric subject.

29. The agent of claim 3 , wherein the anti-LIGHT antibody comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO:

84.

30. 30. The agent of claim 29, wherein the anti-LIGHT antibody comprises a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:

85.

31. The agent of claim 3 , wherein the anti-LIGHT antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

8.

32. 32. The agent of claim 31 , wherein the anti-LIGHT antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:

9.

33. 4. The method of claim 3, wherein the method further comprises assaying total LIGHT before, during, or after administration of the anti-LIGHT antibody.

34. 25. The method of claim 24, wherein the subject has elevated total LIGHT.

35. The method of claim 3, wherein administration of the anti-LIGHT antibody reduces total LIGHT in the subject.

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