{"id":{"repo_id":"houston","oai_identifier":"oai:uh-ir.tdl.org:10657/18344"},"canonical_url":"https://search.dev.ndltd.org/etd/houston/oai:uh-ir.tdl.org:10657/18344","repository":{"repo_id":"houston","name":"University of Houston","base_url":"https://uh-ir.tdl.org/server/oai/request"},"display":{"title":"A Novel Interleukin-15 Receptor Antagonist for the Treatment of Rheumatoid Arthritis","abstract":"Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States, causing debilitating joint inflammation, pain, and potential disability. Current treatment options, including methotrexate and biologics like adalimumab, have limited efficacy, leaving a substantial number of patients without adequate relief. Interleukin-15 (IL-15), a cytokine pivotal in RA pathogenesis, promotes inflammatory responses and is elevated in RA patients, highlighting it as a compelling therapeutic target. This study explores the potential of IFRA3Q1, a novel peptoid antagonist, designed to inhibit IL-15 by selectively binding to its receptor, IL-15Rα. Peptoids offer several advantages over peptides, such as increased stability, enhanced bioavailability, and reduced immunogenicity, making IFRA3Q1 a promising therapeutic candidate. The primary objectives of this research are to validate IFRA3Q1’s efficacy in reducing RA symptoms in preclinical models and to thoroughly evaluate its pharmacokinetic properties and safety profile. In Aim 1, we evaluated the therapeutic efficacy of IFRA3Q1 using the collagen antibody-induced arthritis (CAIA) model in BALB/c mice. Mice are treated with IFRA3Q1 following arthritis induction, and IFRA3Q1 treatment significantly reduced clinical arthritis scores, paw swelling, and histopathological markers of inflammation and joint damage in CAIA mice. Immune profiling via flow cytometry revealed that IFRA3Q1 decreased immune cell populations, including natural killer (NK) cells, natural killer T (NKT) cells, and memory CD8+ T cells, while also diminishing pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ. Immunofluorescence analysis further confirmed reduced infiltration of CD3+ T cells and CD19+ B cells into joint tissues, highlighting the compound’s immunomodulatory effects. In Aim 2, we investigate the plasma stability of IFRA3Q1 and further evaluate the pharmacokinetic properties and toxicity profile of IFRA3Q1 in mouse model. High-performance liquid chromatography (HPLC) and LC-MS/MS analyses successfully identified IFRA3Q1 in both mice and human plasma, confirming its molecular integrity and recovery. Plasma recovery studies demonstrated the critical role of formic acid (FA) in enhancing analyte detection, with 0.5% FA providing optimal recovery by disrupting plasma protein binding. Plasma stability studies further confirmed that IFRA3Q1 remains stable under physiological conditions in both mice and human plasma over 72h periods. Additionally, systemic toxicity evaluations indicated that IFRA3Q1 was well-tolerated in treated mice, with stable body weight and no adverse effects observed. This research demonstrates that IFRA3Q1 effectively mitigates inflammation, preserves joint integrity, and offers a favorable pharmacological profile, positioning it as a promising therapeutic candidate for RA. These findings pave the way for further preclinical development and potential clinical translation of IFRA3Q1 as a novel IL-15-targeted therapy for autoimmune diseases.","abstract_html":"Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States, causing debilitating joint inflammation, pain, and potential disability. Current treatment options, including methotrexate and biologics like adalimumab, have limited efficacy, leaving a substantial number of patients without adequate relief. Interleukin-15 (IL-15), a cytokine pivotal in RA pathogenesis, promotes inflammatory responses and is elevated in RA patients, highlighting it as a compelling therapeutic target. This study explores the potential of IFRA3Q1, a novel peptoid antagonist, designed to inhibit IL-15 by selectively binding to its receptor, IL-15Rα. Peptoids offer several advantages over peptides, such as increased stability, enhanced bioavailability, and reduced immunogenicity, making IFRA3Q1 a promising therapeutic candidate. The primary objectives of this research are to validate IFRA3Q1’s efficacy in reducing RA symptoms in preclinical models and to thoroughly evaluate its pharmacokinetic properties and safety profile. In Aim 1, we evaluated the therapeutic efficacy of IFRA3Q1 using the collagen antibody-induced arthritis (CAIA) model in BALB/c mice. Mice are treated with IFRA3Q1 following arthritis induction, and IFRA3Q1 treatment significantly reduced clinical arthritis scores, paw swelling, and histopathological markers of inflammation and joint damage in CAIA mice. Immune profiling via flow cytometry revealed that IFRA3Q1 decreased immune cell populations, including natural killer (NK) cells, natural killer T (NKT) cells, and memory CD8+ T cells, while also diminishing pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ. Immunofluorescence analysis further confirmed reduced infiltration of CD3+ T cells and CD19+ B cells into joint tissues, highlighting the compound’s immunomodulatory effects. In Aim 2, we investigate the plasma stability of IFRA3Q1 and further evaluate the pharmacokinetic properties and toxicity profile of IFRA3Q1 in mouse model. High-performance liquid chromatography (HPLC) and LC-MS/MS analyses successfully identified IFRA3Q1 in both mice and human plasma, confirming its molecular integrity and recovery. Plasma recovery studies demonstrated the critical role of formic acid (FA) in enhancing analyte detection, with 0.5% FA providing optimal recovery by disrupting plasma protein binding. Plasma stability studies further confirmed that IFRA3Q1 remains stable under physiological conditions in both mice and human plasma over 72h periods. Additionally, systemic toxicity evaluations indicated that IFRA3Q1 was well-tolerated in treated mice, with stable body weight and no adverse effects observed. This research demonstrates that IFRA3Q1 effectively mitigates inflammation, preserves joint integrity, and offers a favorable pharmacological profile, positioning it as a promising therapeutic candidate for RA. These findings pave the way for further preclinical development and potential clinical translation of IFRA3Q1 as a novel IL-15-targeted therapy for autoimmune diseases.","abstract_has_math":false,"creators":["Jiang, Guoyi"],"institution":"University of Houston","degree_name":"Doctor of Philosophy","degree_level":null,"degree_discipline":"Pharmaceutics","degree_department":null,"school":null,"contributors":[],"advisors":["Guo, Bin"],"committee_chairs":[],"committee_members":["An, Ran","Udugamasooriya, Gomika","Cuny, Greg","Peng, Weiyi"],"year":2024,"date_issued":"2024-12","date_published":"2024-12","updated_at":"2026-07-24T02:31:59Z","subjects":["Drug Development","Immunology","Pharmacology","Peptoid Chemistry","Therapeutics","Autoimmune Diseases","Cytokine Biology","Biomarkers and Precision Medicine","Inflammation and Immunopathology","Preclinical Research","Molecular Biology","Joint Biology and Tissue Analysis","High-Performance Liquid Chromatography (HPLC)","Flow Cytometry and Cellular Analysis","Pharmacokinetics and Drug Stability"],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10657/18344","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Guo, Bin"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["An, Ran","Udugamasooriya, Gomika","Cuny, Greg","Peng, Weiyi"]},{"key":"dc:creator","label":"Author","values":["Jiang, Guoyi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-01-28T17:12:13Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-12"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutics"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Houston"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Drug Development","Immunology","Pharmacology","Peptoid Chemistry","Therapeutics","Autoimmune Diseases","Cytokine Biology","Biomarkers and Precision Medicine","Inflammation and Immunopathology","Preclinical Research","Molecular Biology","Joint Biology and Tissue Analysis","High-Performance Liquid Chromatography (HPLC)","Flow Cytometry and Cellular Analysis","Pharmacokinetics and Drug Stability"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10657/18344"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States, causing debilitating joint inflammation, pain, and potential disability. Current treatment options, including methotrexate and biologics like adalimumab, have limited efficacy, leaving a substantial number of patients without adequate relief. Interleukin-15 (IL-15), a cytokine pivotal in RA pathogenesis, promotes inflammatory responses and is elevated in RA patients, highlighting it as a compelling therapeutic target. This study explores the potential of IFRA3Q1, a novel peptoid antagonist, designed to inhibit IL-15 by selectively binding to its receptor, IL-15Rα. Peptoids offer several advantages over peptides, such as increased stability, enhanced bioavailability, and reduced immunogenicity, making IFRA3Q1 a promising therapeutic candidate. The primary objectives of this research are to validate IFRA3Q1’s efficacy in reducing RA symptoms in preclinical models and to thoroughly evaluate its pharmacokinetic properties and safety profile. In Aim 1, we evaluated the therapeutic efficacy of IFRA3Q1 using the collagen antibody-induced arthritis (CAIA) model in BALB/c mice. Mice are treated with IFRA3Q1 following arthritis induction, and IFRA3Q1 treatment significantly reduced clinical arthritis scores, paw swelling, and histopathological markers of inflammation and joint damage in CAIA mice. Immune profiling via flow cytometry revealed that IFRA3Q1 decreased immune cell populations, including natural killer (NK) cells, natural killer T (NKT) cells, and memory CD8+ T cells, while also diminishing pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ. Immunofluorescence analysis further confirmed reduced infiltration of CD3+ T cells and CD19+ B cells into joint tissues, highlighting the compound’s immunomodulatory effects. In Aim 2, we investigate the plasma stability of IFRA3Q1 and further evaluate the pharmacokinetic properties and toxicity profile of IFRA3Q1 in mouse model. High-performance liquid chromatography (HPLC) and LC-MS/MS analyses successfully identified IFRA3Q1 in both mice and human plasma, confirming its molecular integrity and recovery. Plasma recovery studies demonstrated the critical role of formic acid (FA) in enhancing analyte detection, with 0.5% FA providing optimal recovery by disrupting plasma protein binding. Plasma stability studies further confirmed that IFRA3Q1 remains stable under physiological conditions in both mice and human plasma over 72h periods. Additionally, systemic toxicity evaluations indicated that IFRA3Q1 was well-tolerated in treated mice, with stable body weight and no adverse effects observed. This research demonstrates that IFRA3Q1 effectively mitigates inflammation, preserves joint integrity, and offers a favorable pharmacological profile, positioning it as a promising therapeutic candidate for RA. These findings pave the way for further preclinical development and potential clinical translation of IFRA3Q1 as a novel IL-15-targeted therapy for autoimmune diseases."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["A Novel Interleukin-15 Receptor Antagonist for the Treatment of Rheumatoid Arthritis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Guo, Bin"],"dc:contributor.committeemember":["An, Ran","Udugamasooriya, Gomika","Cuny, Greg","Peng, Weiyi"],"dc:creator":["Jiang, Guoyi"],"dc:date.accessioned":["2025-01-28T17:12:13Z"],"dc:date.issued":["2024-12"],"dc:description.abstract":["Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States, causing debilitating joint inflammation, pain, and potential disability. Current treatment options, including methotrexate and biologics like adalimumab, have limited efficacy, leaving a substantial number of patients without adequate relief. Interleukin-15 (IL-15), a cytokine pivotal in RA pathogenesis, promotes inflammatory responses and is elevated in RA patients, highlighting it as a compelling therapeutic target. This study explores the potential of IFRA3Q1, a novel peptoid antagonist, designed to inhibit IL-15 by selectively binding to its receptor, IL-15Rα. Peptoids offer several advantages over peptides, such as increased stability, enhanced bioavailability, and reduced immunogenicity, making IFRA3Q1 a promising therapeutic candidate. The primary objectives of this research are to validate IFRA3Q1’s efficacy in reducing RA symptoms in preclinical models and to thoroughly evaluate its pharmacokinetic properties and safety profile. In Aim 1, we evaluated the therapeutic efficacy of IFRA3Q1 using the collagen antibody-induced arthritis (CAIA) model in BALB/c mice. Mice are treated with IFRA3Q1 following arthritis induction, and IFRA3Q1 treatment significantly reduced clinical arthritis scores, paw swelling, and histopathological markers of inflammation and joint damage in CAIA mice. Immune profiling via flow cytometry revealed that IFRA3Q1 decreased immune cell populations, including natural killer (NK) cells, natural killer T (NKT) cells, and memory CD8+ T cells, while also diminishing pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ. Immunofluorescence analysis further confirmed reduced infiltration of CD3+ T cells and CD19+ B cells into joint tissues, highlighting the compound’s immunomodulatory effects. In Aim 2, we investigate the plasma stability of IFRA3Q1 and further evaluate the pharmacokinetic properties and toxicity profile of IFRA3Q1 in mouse model. High-performance liquid chromatography (HPLC) and LC-MS/MS analyses successfully identified IFRA3Q1 in both mice and human plasma, confirming its molecular integrity and recovery. Plasma recovery studies demonstrated the critical role of formic acid (FA) in enhancing analyte detection, with 0.5% FA providing optimal recovery by disrupting plasma protein binding. Plasma stability studies further confirmed that IFRA3Q1 remains stable under physiological conditions in both mice and human plasma over 72h periods. Additionally, systemic toxicity evaluations indicated that IFRA3Q1 was well-tolerated in treated mice, with stable body weight and no adverse effects observed. This research demonstrates that IFRA3Q1 effectively mitigates inflammation, preserves joint integrity, and offers a favorable pharmacological profile, positioning it as a promising therapeutic candidate for RA. These findings pave the way for further preclinical development and potential clinical translation of IFRA3Q1 as a novel IL-15-targeted therapy for autoimmune diseases."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/10657/18344"],"dc:language.iso":["English"],"dc:subject":["Drug Development","Immunology","Pharmacology","Peptoid Chemistry","Therapeutics","Autoimmune Diseases","Cytokine Biology","Biomarkers and Precision Medicine","Inflammation and Immunopathology","Preclinical Research","Molecular Biology","Joint Biology and Tissue Analysis","High-Performance Liquid Chromatography (HPLC)","Flow Cytometry and Cellular Analysis","Pharmacokinetics and Drug Stability"],"dc:title":["A Novel Interleukin-15 Receptor Antagonist for the Treatment of Rheumatoid Arthritis"],"dc:type":["Thesis"],"thesis:degree_discipline":["Pharmaceutics"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["University of Houston"]},"updated_at":"2026-07-24T02:31:59Z"}