Validation of Platelet Expression of FcɣRIIa as a Precision Tool

摘要 美国心脏协会估计，到2022年，大约72万名美国人将首次患上冠状动脉 335,000人将发生复发事件，其中约87%为缺血性(血栓形成)。反- 血栓治疗降低了再发缺血性事件的风险，但代价是出血发生率更高 并发症。血栓形成/缺血风险较低的患者应该从缩短治疗中受益，而患者 血栓形成/缺血风险较高的患者应从长期治疗中获得更大的绝对好处 强大的抗血小板治疗。目前可用的工具，如临床风险评分和血小板功能测试 不足以有效地使心血管护理个体化，以及有效的精准医学战略来 缺乏使临床医生能够针对高残留风险患者的能力。血小板功能测试可有效识别 有风险的患者，但在用于指导治疗的试验中失败。血小板功能的主要弱点 测试包括，它们显示出很大的个体内变异性，受两种检测条件的影响 以及患者的治疗，他们测量对选定的激动剂的反应的血小板反应 或一组激动剂。为了解决患者护理方面的这一差距，普罗克公司在表面上确定了一种生物标记物Fcγria 对血小板的影响。当血小板激活时，FcγRIIA放大了血小板的激活。因此，升高的血小板Fcγ放射免疫分析 增加血小板的反应性，并利用血小板功能测试的预后意义。与.相比 目前可用的血小板功能测试，FcγRia的表达显示个体内变异性较小，是 对与分析条件相关的扰动的敏感度大大降低，并预测血小板反应性增加 对多种激动剂的反应。在对197名患者的初步研究中，COX回归分析表明 FcγRIIA的血小板表达是与AN相关的唯一协变量(风险比3.9p=0.035)。 当计入年龄、糖尿病和既往血管重建时，心脏病发作、中风和死亡的风险增加。 作为协变量。因此，定量检测血小板FcγRIIA的表达是一种识别心血管危险和 应该作为一种强大的精准医疗工具。自那以后，普罗科尔通过开发出 与甲醛固定的血小板表面的FcyRIIa结合的抗体。初始分析 测试表明，该方法具有很高的精密度(重复测试的变异系数为5%)。建议的SBIR 旨在根据FDA质量体系提供全面的分析验证 调节，表明测定血小板FcɣRIIA的表达是准确、精确和 可重现的。分析验证将与前瞻性观察提供的临床验证配对 研究急性冠脉综合征、中风和癌症。分析验证与临床验证相结合 将使ProLocor能够向FDA提交ProLocor诊断工具的申请，并允许采用 FcγRIIA将心血管医学领域作为评估心血管风险的诊断工具。

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.