Validation of Platelet Expression of FcɣRIIa as a Precision Tool

FcÉRIIa 的血小板表达作为精密工具的验证

• 批准号: 10682562
• 负责人: Jeanne Ohrnberger
• 金额: $ 68.79万
• 依托单位: PROLOCOR INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682562
• 关键词: Address; Age; Agonist; Agreement; American; American Heart Association; Antibodies; Assessment tool; Binding; Biological Assay; Biological Markers; Blood Platelets; CLIA certified; Cardiovascular system; Caring; Cessation of life; Clinical; Collaborations; Detection; Diabetes Mellitus; Diagnostic Reagent Kits; Ensure; Event; Feedback; Flow Cytometry; Formaldehyde; Future; Goals; Hemorrhage; Incidence; Individual; Instruction; Ischemia; Laboratories; Malignant Neoplasms; Measurement; Measures; Medicine; Methods; Myocardial Infarction; Observational Study; Patient Care; Patients; Performance; Pilot Projects; Platelet Activation; Platelet Function Tests; Reagent; Recurrence; Regression Analysis; Regulation; Reproducibility; Research Proposals; Residual state; Risk; Risk Assessment; Risk Management; Risk Reduction; Sampling; Sensitivity and Specificity; Site; Small Business Innovation Research Grant; Specificity; Stroke; Surface; System; Testing; Validation; Variant; Vascularization; acute coronary syndrome; cardiovascular risk factor; clinical risk; commercial prototype; coronary event; cost; design; diagnostic tool; experimental study; hazard; individual variation; individualized medicine; laboratory experience; novel; performance tests; phase III trial; precision medicine; prognostic; prospective; response; thrombotic; tool; trial design; uptake

ABSTRACT The American Heart Association estimates that, in 2022, about 720,000 Americans will have a first coronary event and 335,000 will have a recurrent event, of which, approximately 87% are ischemic (thrombotic). Anti- thrombotic therapy reduces the risk of recurrent ischemic events at the cost of a greater incidence of bleeding complications. Patients at low thrombotic/ischemic risk should benefit from shortened treatment whereas patients at high thrombotic/ischemic risk should derive greater absolute benefit from longer term treatment with more powerful antiplatelet therapy. Currently available tools such as clinical risk scores and platelet function testing are inadequate to effectively individualize cardiovascular care, and effective precision medicine strategies to enable clinicians to target patients with high residual risk are lacking. Platelet function tests effectively identify patients at risk but failed when used in trials designed to guide treatment. Key weaknesses of platelet function tests include that they demonstrate substantial intra-individual variability, are influenced by both assay conditions as well as the treatment of the patient, and that they measure platelet reactivity in response to a select agonist or group of agonists. To address this gap in patient care, Prolocor identified a biomarker, FcγRIIa, on the surface of platelets. When platelets activate, FcγRIIa amplifies platelet activation. Thus, increased platelet FcγRIIa increases platelet reactivity and leverages the prognostic implications of platelet function tests. Compared to currently available platelet function tests, expression of FcγRIIa shows less intra-individual variability, is substantially less sensitive to perturbations related to assay conditions, and predicts increased platelet reactivity in response to a variety of agonists. In a preliminary study of 197 patients, Cox regression analysis demonstrated that platelet expression of FcγRIIa was the sole covariate (hazard ratio 3.9, p=0.035) associated with an increased risk of heart attack, stroke, and death when age, diabetes, and prior revascularization were included as covariates. Thus, quantifying platelet FcγRIIa expression is a novel method to identify cardiovascular risk and should serve as a powerful precision medicine tool. Prolocor has since refined the assay by developing antibodies that bind to FcyRIIa on the surface of platelets that have been fixed with formaldehyde. Initial analytic testing has demonstrated excellent precision (coefficient of variation of repeated tests <5%). The Proposed SBIR is designed to provide comprehensive analytic validation of the assay in accordance with FDA Quality System Regulation, demonstrating that the measurement of platelet FcɣRIIa expression is accurate, precise, and reproducible. The analytic validation will be paired with clinical validation provided by prospective observational studies in acute coronary syndrome, stroke and cancer. The combination of the analytic and clinical validation will enable Prolocor to submit an FDA application for the Prolocor diagnostic tool, and allow for the uptake of FcγRIIa to the field of cardiovascular medicine as a diagnostic tool for assessing cardiovascular risk.

抽象的 美国心脏协会估计，到 2022 年，大约 72 万美国人将首次患有冠心病 事件，335,000 人会复发事件，其中约 87% 为缺血（血栓）事件。 血栓治疗可降低复发性缺血事件的风险，但代价是出血发生率更高 血栓/缺血风险低的患者应受益于缩短治疗时间，而患者则应受益。 处于高血栓形成/缺血风险的患者应该从长期治疗中获得更大的绝对益处 目前可用的工具，如临床风险评分和血小板功能测试。 不足以有效地个体化心血管护理，并且有效的精准医学策略 缺乏能够针对高残留风险患者进行有效识别的血小板功能测试。 处于危险中但在旨在指导血小板功能的试验中失败的患者。 测试表明，它们表现出显着的个体内部变异性，并受到两种测定条件的影响 以及患者的治疗，并测量血小板对选定激动剂的反应性 为了解决患者护理方面的这一空白，Prolocor 在表面发现了一种生物标志物 FcγRIIa。 当血小板活化时，FcγRIIa 会放大血小板活化，从而增加血小板 FcγRIIa。 与相比，增加血小板反应性并利用血小板功能测试的预后意义。 目前可用的血小板功能测试，FcγRIIa的表达显示个体内变异性较小，是 对与测定条件相关的扰动显着降低敏感度，并预测血小板反应性增加 在对 197 名患者进行的初步研究中，Cox 回归分析表明。 FcγRIIa 的血小板表达是与 当年龄、糖尿病和既往血运重建纳入考虑时，心脏病发作、中风和死亡的风险增加 因此，量化血小板 FcγRIIa 表达是一种识别心血管风险和风险的新方法。 Prolocor 应该作为一种强大的精准医学工具，通过开发改进了该检测方法。 与甲醛固定的血小板表面的 FcγRIIa 结合的抗体。 测试显示出出色的精度（重复测试的变异系数<5%）。 旨在根据 FDA 质量体系提供全面的分析验证 调节，证明血小板FcɣRIIa表达的测量准确、精确、 分析验证将与前瞻性观察提供的临床验证相结合。 急性冠状动脉综合征、中风和癌症的研究结合了分析和临床验证。 将使 Prolocor 能够向 FDA 提交 Prolocor 诊断工具的申请，并允许采用 FcγRIIa在心血管医学领域作为评估心血管风险的诊断工具。