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景的聚乙二醇适配子快速 新型聚乙二醇型聚乙二醇胺聚合物刷子的起效抗凝剂(ROA) 能够消除抗聚乙二醇抗原性的技术。这项提议的重要性 突出的是提前终止了最初的第三阶段临床试验 聚乙二醇适配子结合物，其中严重过敏反应发生在患有 高水平的预先存在的抗聚乙二醇化抗体。正如这项暂停的临床试验所证明的那样， 由于流行，循环中的抗聚乙二醇抗体的影响日益受到关注。 在对聚乙二醇化疗法天真的人身上发现的抗聚乙二醇酯-它已经被 表明常用消费产品中存在的免费挂钩很可能是 这些干扰性抗聚乙二醇单抗的来源。我们的聚乙二醇式POEGMA聚合物刷子 事实证明，这项技术具有与传统聚乙二醇组分相同的PD/PK优势 结合，同时消除抗聚乙二醇抗原性。我们已经证明了 POEGMA，它打破了发现的重复乙二醇单位的长序列 在聚乙二醇中，并呈现短得多的寡聚(乙二醇)序列，不相互作用 用抗聚乙二醇单抗。我们期待POEGMA技术在 这里描述的基于适体的ROA将允许有效的治疗，而不是 与预先存在的抗-聚乙二醇抗体发生有害的相互作用。重新制定 这一适配子ROA代表了POEGMA技术的有用应用，因为 临床上对抗凝剂的需求尚未得到满足，这种需求可以迅速逆转。目前， 每年大约有1200万美国人需要静脉输注一种高度 高效、快速起效的抗凝剂，用于执行高度敏感的临床操作 血栓形成，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(CABG)手术和其他手术，以及透析。 当前FDA批准的ROAS-普通肝素的显著缺点 (UFH)、来皮鲁丁、比伐卢定和阿加曲班--已促使人们努力确定ROA 消除与这些ROA相关的毒性和药物引起的出血。这个 这里描述的peg-适配子序列，以及互补解毒剂 能够滴定和快速逆转抗凝血剂活性的序列已经被 在1期、2期和3期临床试验中对2,000名患者进行评估， 2项研究表明，这种适配子-解毒剂对可以减少缺血事件和 与肝素相比，限制经皮冠状动脉介入治疗患者的出血。基于这些有希望的结果，我们 建议消除潜在的反聚乙二醇负相互作用 停止了这种曾经很有希望的聚乙二醇适配子治疗药物的开发 开发一种POEGMA-适体偶联物。

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.