Glycan biomarker panels in liquid biopsies for predicting treatment response in lupus nephritis

液体活检中的聚糖生物标志物组用于预测狼疮性肾炎的治疗反应

• 批准号: 10601270
• 负责人: Stephen Castellino
• 金额: $ 27.54万
• 依托单位: GLYCOPATH, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601270
• 关键词: Address; Affect; Amines; Anti-Inflammatory Agents; Antibodies; Antigen-Antibody Complex; Asparagine; Autoimmune Diseases; Biological Assay; Biological Markers; Cells; Chronic; Clinic; Clinical; Collaborations; Data; Diagnostic; Disease; End stage renal failure; Glomerulonephritis; Glycoproteins; IgG1; IgG2; IgG3; IgG4; Immune Complex Diseases; Immunoglobulin G; Immunoglobulins; Immunosuppression; In complete remission; Inflammatory Response; Joints; Kidney Transplantation; Legal patent; Licensing; Link; Lung Transplantation; Lupus Nephritis; Mediating; Metadata; Methods; Modification; Monitor; Nephrology; Organ; Outcome; Parents; Patients; Peptide N-glycohydrolase F; Peripheral; Phase; Physicians; Plasma; Polysaccharides; Prediction of Response to Therapy; Property; Publishing; Reporting; Sampling; Serum; Slide; Small Business Technology Transfer Research; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spottings; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tissues; Treatment Protocols; Urine; biobank; biomarker panel; clinical translation; cohort; follow-up; glycosylation; immunoregulation; liquid biopsy; mycophenolate mofetil; patient subsets; predicting response; profiles in patients; response; standard care; standard of care; sugar; treatment response

Lupus nephritis (LN), an immune complex-mediated glomerulonephritis, affects up to two-thirds of patients with systemic lupus erythematosus. Despite standard treatment protocols, progression of the most aggressive forms of LN (class III and IV) to end-stage renal failure remains high. Thus, there is a need for biomarkers of therapeutic response that would allow physicians to make better-informed treatment decisions for LN patients. To address this, our proposal builds upon ongoing collaborations between a clinical nephrology group at MUSC with an extensive LN biorepository of control and treatment samples with clinical metadata and GlycoPath Inc., a diagnostic company developing unique glycosylation targeted liquid biopsy assays. GlycoPath has recently patented, licensed and published a streamlined antibody capture slide array approach, GlycoTyper, to directly profile N-glycans of captured serum and plasma glycoproteins including imm unoglobulin G (IgG) subtypes. An adaption of the GlycoTyper platform has also been developed to rapidly obtain total glycan profiles of biofluids like serum and urine. Using this approach, several cohorts of patient matched serum and urine from control and LN subjects have been evaluated for N-linked glycan constituents. A distinct panel of LN associated N- glycans have already been identified and serve as the basis for the proposed studies. Because we can use glycan panels to distinguish control from LN conditions, we hypothesize that this assay can be applied to monitor treatment response in biofluids from subjects treated with standard-of-care therapies like mycophenolate mofetil (MMF). In this Phase I STTR application, we propose to establish the technical merit and feasibility of Glycotyper-LNTx for monitoring LN treatment responses. Aim 1 will validate N-glycan profiles in urine samples from LN subjects for MMF treatment response at time zero, 3 months and 12 months of treatment. Aim 2 will identify IgG specific N-glycan profiles in patient matched serum and urine samples with follow up application in a LN treatment response cohort. This study will establish and validate a LN specific liquid biopsy glycan biomarker assay for use in monitoring disease status and therapeutic response.

狼疮性肾炎 (LN) 是一种免疫复合物介导的肾小球肾炎，影响多达三分之二的患者 系统性红斑狼疮患者。尽管有标准的治疗方案，但病情进展 大多数侵袭性形式的 LN（III 类和 IV 类）导致终末期肾衰竭的风险仍然很高。因此，有一个 需要治疗反应的生物标志物，使医生能够更好地了解情况 LN 患者的治疗决策。为了解决这个问题，我们的提案建立在持续合作的基础上 MUSC 的临床肾病学小组与广泛的 LN 控制和治疗生物存储库之间的合作 具有临床元数据的样本和 GlycoPath Inc.（一家开发独特的诊断公司） 糖基化靶向液体活检测定。 GlycoPath 最近获得了专利、许可并发布了 简化的抗体捕获载玻片阵列方法 GlycoTyper，可直接分析捕获的 N-聚糖 血清和血浆糖蛋白，包括免疫球蛋白 G (IgG) 亚型。的改编 GlycoTyper 平台也已开发用于快速获取血清等生物液体的总聚糖谱 和尿液。使用这种方法，几组患者的血清和尿液与对照和 LN 相匹配 已对受试者的 N 连接聚糖成分进行了评估。一组独特的 LN 相关 N- 聚糖已被鉴定并作为拟议研究的基础。因为我们可以 使用聚糖组来区分对照和 LN 条件，我们假设该测定可以 用于监测接受标准护理疗法治疗的受试者的生物体液中的治疗反应 如吗替麦考酚酯 (MMF)。在第一阶段 STTR 申请中，我们建议建立技术 Glycotyper-LNTx 用于监测 LN 治疗反应的优点和可行性。目标 1 将验证 N-聚糖 LN 受试者尿液样本中零时、3 个月和 12 个月时 MMF 治疗反应的概况 的治疗。目标 2 将鉴定患者匹配的血清和尿液样本中的 IgG 特异性 N-聚糖谱 在 LN 治疗反应队列中进行后续应用。本研究将建立并验证 LN 特定 液体活检聚糖生物标志物测定用于监测疾病状态和治疗反应。