An in vitro diagnostic assay for the early and accurate detection of platelet-activating antibodies associated with Heparin-induced Thrombocytopenia

用于早期准确检测与肝素诱导的血小板减少症相关的血小板激活抗体的体外诊断测定

• 批准号: 10653274
• 负责人: Curtis Jones
• 金额: $ 122.03万
• 依托单位: RETHAM TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653274
• 关键词: Adverse reactions; Agreement; Amputation; Antibodies; Anticoagulants; Benchmarking; Benign; Binding; Biological Assay; Biometry; Blinded; Blood Platelets; COVID-19 complications; COVID-19 patient; COVID-19 vaccination; COVID-19 vaccine; Cessation of life; Characteristics; Clinical Research; Complex; Complication; Coupled; Critical Illness; Cryopreservation; Data; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic tests; Economic Burden; Enzyme-Linked Immunosorbent Assay; Evaluation; Exposure to; Family; Feedback; Freezing; Future; Goals; Healthcare Systems; Hemorrhage; Heparin; Hospital Costs; Hospitalization; Immune; Intellectual Property; Japan; Laboratories; Legal patent; Licensing; Life; Limb structure; Marketing; Methods; Monoclonal Antibodies; Outcome; PF4 Gene; Pathogenicity; Patient-Focused Outcomes; Patients; Performance; Phase; Physicians; Platelet Activating Factor; Platelet Activation; Predictive Value; Production; Research; Rest; Risk; Sampling; Serotonin; Shipping; Signal Transduction; Small Business Innovation Research Grant; Specificity; Stroke; Surface; Technology; Testing; Thrombocytopenia; Thrombosis; Thrombospondin 1; Vaccines; Validation; accurate diagnosis; antibody detection; clinically relevant; clinically significant; commercial application; commercialization; design; detection assay; detection limit; diagnostic assay; epidemiology study; experience; heparin-induced thrombocytopenia; hospital laboratories; in-vitro diagnostics; manufacture; member; novel; polyanion; prevent; prospective; prototype; thrombotic; usability; validation studies

PROJECT SUMMARY/ABSTRACT This phase II SBIR proposal is aimed at developing a highly accurate functional in vitro diagnostic (IVD) assay for the detection of pathogenic antibodies in Heparin-induced thrombocytopenia (HIT), an adverse reaction to heparin treatment. This assay is based on recent findings that Platelet Factor 4 (PF4)-treated platelets can be used for the sensitive and specific detection of clinically-significant HIT antibodies. HIT kills more than 5 patients every day in the US and is frequently suspected in heparin-treated hospitalized patients who may have a number of potential causes for thrombocytopenia. To assist with diagnosis and management, physicians rely on two families of HIT assays. The first, the PF4/Polyanion ELISA- based in vitro diagnostic (IVD) assays are sensitive but are highly non-specific such that the positive predictive value of these assays is poor at only 30-50%. The second, more accurate platelet activation-based (functional) assays such as the Serotonin release assay (SRA) are technically complex and are performed only at a few reference laboratories which can lead to a long turnaround times. As a result, frontline ELISAs are used to manage most HIT-suspected patients and many patients with false-positive ELISAs are inappropriately treated with alternative anticoagulants which are expensive and have a significantly worse bleeding profile. Retham’s goal is to revolutionize HIT diagnosis by replacing both the inaccurate ELISA and technically complex SRA with HITDx, a simple yet accurate functional IVD that can be performed in the hospital laboratory. HITDx is based on groundbreaking research that suggests that pathogenic platelet-activating HIT antibodies can bind and activate PF4-treated platelets in a heparin-independent manner. Clinical studies including a 409-patient, prospective, multicenter, blinded study demonstrate that this technology can be leveraged to provide accurate HIT diagnosis. During phase I, Retham Technologies demonstrated that PF4 treated, long term (12-months) stabilized platelets can be coupled to an ELISA-based endpoint for detection of a novel analyte, demonstrating that this technology can be adapted to an IVD assay. The foundational patents covering this technology have issued, and multiple additional patents are pending in various jurisdictions. In this SBIR Phase II proposal, Retham will develop, verify and assess the performance of a self-contained HIT IVD prototype using PF4- treated long-term stored platelets. The utility of HITDx for detection of antibodies that cause vaccine-induced thrombotic thrombocytopenia, a newly recognized complication of COVID-19 vaccines will be assessed in future studies. The project will be led by Curtis Jones who is inventor of this technology and spearheaded the development of novel methods to stabilize platelets. He will be supported by Dr. Padmanabhan, a leading HIT expert, QA/RA and biostatistics consultants, and expert Retham advisory board members. It is expected that this patient-impacting product will revolutionize HIT diagnosis by decentralizing functional testing and providing rapid, accurate results that will facilitate early and appropriate patient management.

项目总结/摘要 这一第二阶段SBIR提案旨在开发一种高度准确的功能性体外诊断方法， (IVD)检测肝素诱导的血小板减少症（HIT）中病原性抗体的试验， 肝素治疗的不良反应。该测定是基于最近的发现，即血小板因子4 （PF 4）处理的血小板可用于敏感和特异性检测临床显著的HIT 抗体的在美国，HIT每天导致5名以上患者死亡，在肝素治疗的患者中经常被怀疑。 可能有多种血小板减少症潜在原因的住院患者。协助 诊断和管理，医生依赖于两个家庭的HIT测定。第一，PF 4/聚阴离子ELISA- 基于体外诊断（IVD）的测定是敏感的，但高度非特异性， 这些测定的值很差，仅为30- 50%。第二，更准确的血小板活化基础（功能） 诸如血清素释放测定（SRA）的测定在技术上是复杂的， 参考实验室，这可能导致周转时间很长。因此，一线ELISA通常用于 管理大多数HIT疑似患者，许多ELISA假阳性患者治疗不当 与昂贵的并且具有明显更差的出血特征的替代抗凝剂一起使用。Retham's 我们的目标是通过取代不准确的ELISA和技术复杂的SRA来彻底改变HIT诊断 HITDx是一种简单而准确的功能性IVD，可在医院实验室进行。HITDx是 基于突破性的研究，表明致病性血小板激活HIT抗体可以结合 并以非肝素依赖性方式激活PF 4处理的血小板。临床研究包括409例患者， 前瞻性、多中心、盲法研究表明，该技术可用于提供准确的 HIT诊断。在第一阶段，Retham Technologies证明PF 4治疗的长期（12个月） 稳定的血小板可以与基于ELISA的终点偶联，用于检测新的分析物，证明 该技术可适用于体外诊断试验。涵盖这项技术的基础专利有 已发布，并且多个其他专利正在各个司法管辖区申请。在SBIR第二阶段提案中， Retham将使用PF 4开发、验证和评估独立HIT IVD原型的性能， 长期储存的血小板。HITDx用于检测引起疫苗诱导的抗体的效用 血栓性血小板减少症，一种新认识到的COVID-19疫苗并发症，将在 未来的研究。该项目将由Curtis Jones领导，他是这项技术的发明者， 开发稳定血小板的新方法。他将得到Padmanabhan博士的支持， 专家、QA/RA和生物统计学顾问以及Retham咨询委员会专家成员。预计在 这种影响患者的产品将通过分散功能测试和提供 快速，准确的结果，这将有助于早期和适当的病人管理。