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，在2022年，约有72万美国人将拥有第一个冠状动脉 事件和335,000将发生反复发生的事件，其中约87％是缺血性（血栓形成）。反对- 血小板疗法降低了复发性缺血事件的风险，以更大的出血事件为代价 并发症。低血栓形成/缺血风险的患者应受益于缩短治疗，而患者应受益 在高血栓形成/缺血风险下，应该从长期治疗中获得更大的绝对益处 强大的抗血小板疗法。当前可用的工具，例如临床风险分数和血小板功能测试 不足以有效地个性化心血管护理和有效的精确医学策略 使临床医生能够瞄准具有高剩余风险的患者。血小板功能测试有效识别 有风险的患者，但在旨在指导治疗的试验中使用时失败。血小板功能的关键弱点 测试包括它们表现出实质性的个体内变异性，受两种测定条件的影响 以及对患者的治疗，并且它们响应某些激动剂的响应测量血小板反应性 或一组激动剂。为了解决患者护理中的这一差距，Prolocor在表面上鉴定出生物标志物FcγRIIA 血小板。血小板激活时，FcγRIIA放大器血小板激活。这是血小板FcγRIIA的增加 增加血小板反应性并利用血小板功能测试的预后意义。相比 当前可用的血小板功能测试，FcγRIIA的表达显示出个体内的变异性较小，是 对与测定条件相关的扰动的敏感性大大降低，并预测了血小板反应性的增加 响应各种激动剂。在对197例患者的初步研究中，Cox回归分析表明 FcγRIIA的血小板表达是唯一的协变量（危险比3.9，p = 0.035） 包括年龄，糖尿病和先前的血运重建时，心脏病发作，中风和死亡的风险增加 作为协变量。那就是量化血小板FcγRIIA表达是一种识别心血管风险和的新方法 应该用作强大的精密药品工具。此后，Prolocor通过开发来完善测定 与甲醛固定的血小板表面上结合的抗体。初始分析 测试表现出极好的精度（重复测试的变化系数<5％）。拟议的Sbir 旨在根据FDA质量系统对测定法进行全面的分析验证 调节，表明血小板FCɣRIIA表达的测量是准确，精确和 可再现。分析验证将与前瞻性观察性提供的临床验证配对 急性冠状动脉综合征，中风和癌症研究。分析和临床验证的组合 将使Prolocor能够提交FDA申请，以供Prolocor诊断工具，并允许吸收 FCγRIIA至心血管医学领域，作为评估心血管风险的诊断工具。