Development of a POEGMA-Aptamer rapid onset anticoagulant that eliminates antigenicity to anti-PEG antibodies

摘要 该STTR提案的目的是重新配制一种有前途的PEG-适体， 通过应用新型“PEG样”POEGMA聚合物刷进行起效抗凝剂（罗阿） 消除抗PEG抗原性的技术。这项提议的重要性 最近的一项III期临床试验提前终止， PEG-适体偶联物，其中在患有以下疾病的个体中发生严重过敏反应： 高水平的抗PEG抗体。正如这次暂停的临床试验所证明的那样， 循环抗PEG抗体的影响是一个越来越多的关注，由于流行 在对聚乙二醇化治疗未经治疗的个体中发现的抗PEG-它已经被 建议，目前在常用的消费品中的游离PEG可能是一种 这些干扰抗PEG抗体的来源。我们的“PEG样”POEGMA聚合物刷 已显示该技术具有与传统PEG相同的PD/PK优势 缀合物，同时消除抗PEG抗原性。我们已经证明 POEGMA，它打破了长序列的重复乙二醇单位发现 在PEG中并呈现更短的寡聚（乙二醇）序列，不相互作用 抗PEG抗体我们期望POEGMA技术在 本文所述的基于适体的罗阿将允许有效的治疗， 遭受与预先存在的抗PEG抗体的有害相互作用。重新制定 这种适体罗阿代表了POEGMA技术的一种有用的应用，因为 是对可快速逆转的抗凝剂的未满足的临床需求。目前， 每年约有1200万美国人需要静脉输注高浓度的 强效、速效抗凝剂，用于执行高度 血栓形成前，包括经皮冠状动脉介入治疗（PCI，“血管成形术”）， 冠状动脉旁路移植术（CABG）手术和其他手术，以及透析。 目前FDA批准的ROA-普通肝素的显著缺点 (UFH)，lepirudin，bivalirudin和argatroban-促使人们努力识别ROA 其消除了与这些ROA相关的毒性和药物诱导的出血。的 此处描述的PEG-适体序列，连同互补解毒剂 能够滴定和快速逆转抗凝活性的序列，已被 在1期、2期和3期临床试验中对> 2，000名患者进行了评估， 2项研究表明，这种适体-解毒剂对可以减少缺血事件， 与肝素相比，限制PCI患者的出血。基于这些令人鼓舞的结果，我们 建议消除潜在的负面抗PEG相互作用， 阻止了这种曾经有前途的PEG-适体治疗剂的开发， 开发POEGMA-适体缀合物。

ABSTRACT The objective of this STTR proposal is to reformulate a promising PEG-aptamer rapid onset anticoagulant (ROA) by applying a novel “PEG-like” POEGMA polymer brush technology capable of eliminating anti-PEG antigenicity. The importance of this proposal is highlighted by the early termination of a recent Phase III clinical trial of the original PEG-aptamer conjugate in which severe allergic reactions occurred in individuals with high levels of pre-existing anti-PEG antibodies. As evidenced by this halted clinical trial, the effect of circulating anti-PEG antibodies is a growing concern due to the prevalence of anti-PEG found in individuals who are naive to PEGylated therapeutics—it has been suggested that the free PEGs present in commonly used consumer products are a likely source of these interfering anti-PEG antibodies. Our “PEG-like” POEGMA polymer brush technology has been shown to confer the same PD/PK advantages of traditional PEG conjugates, while simultaneously eliminating anti-PEG antigenicity. We have shown that POEGMA, which breaks up the long sequences of repeating ethylene glycol units found in PEG and presents much shorter oligo(ethylene glycol) sequences, does not interact with anti-PEG antibodies. We expect that the application of POEGMA technology to the aptamer based ROA described here will allow for an effective therapeutic that does not suffer from a harmful interaction with pre-existing anti-PEG antibodies. Reformulating this aptamer ROA represents a useful application of the POEGMA technology, as there is an unmet clinical need for anticoagulants that can be rapidly reversed. Currently, approximately 12 million Americans per year require intravenous infusion of a highly potent, rapid onset anticoagulant to perform clinical procedures that are highly prothrombotic, including percutaneous coronary intervention (PCI, “angioplasty”), coronary artery bypass graft (CABG) surgery and other surgeries, as well as dialysis. Significant disadvantages of current FDA-approved ROAs—unfractionated heparin (UFH), lepirudin, bivalirudin and argatroban—have prompted efforts to identify ROAs that eliminate the toxicity and drug induced bleeding associated with these ROAs. The PEG-aptamer sequence described here, together with the complementary antidote sequence capable of titrating and rapidly reversing anticoagulant activity, has been evaluated in >2,000 patients in Phase 1, Phase 2 and Phase 3 clinical trials, with phase 2 studies suggesting that this aptamer-antidote pair can reduce ischemic events and limit bleeding in PCI patients compared to heparin. Based on these promising results, we propose to eliminate the potential for the negative anti-PEG interactions that have stopped the development of this once promising PEG-aptamer therapeutic by developing a POEGMA-aptamer conjugate.