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

开发 POEGMA-Aptamer 快速起效抗凝剂，消除抗 PEG 抗体的抗原性

• 批准号: 9409437
• 负责人: Ashutosh Chilkoti
• 金额: $ 27.71万
• 依托单位: GATEWAY BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409437
• 关键词: Allergic Reaction; American; Angioplasty; Antibodies; Anticoagulants; Antidotes; Argatroban; Benchmarking; Biological Assay; Blood Circulation; Clinical; Clinical Trials; Coagulation Process; Coronary Artery Bypass; Development; Dialysis procedure; Disadvantaged; Drug Design; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Epitopes; Equilibrium; Event; FDA approved; Goals; Hemorrhage; Heparin; In Vitro; Individual; Intravenous infusion procedures; Length; Lepirudin; Link; Modality; Molecular Weight; Mus; Oligonucleotides; Operative Surgical Procedures; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Polymers; Prevalence; Procedures; Radial; Research; Side; Site; Small Business Technology Transfer Research; Source; Structure; Technology; Testing; Therapeutic; Titrations; Toxic effect; Treatment Efficacy; Variant; Vertebral column; aptamer; base; bivalirudin; clinically significant; combat; consumer product; ethylene glycol; immunogenicity; improved; improved outcome; in vitro testing; in vivo; innovation; novel; percutaneous coronary intervention; phase 2 study; response; therapeutic protein

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.

抽象的 该STTR提案的目的是重新重新重新质量钉住钉子 通过应用新颖的“钉” Poegma聚合物刷来发作抗凝剂（ROA） 能够消除抗PEG抗原性的技术。该提议的重要性 最初的III期临床试验的早期终止强调了原始的临床试验 PEG-APTAMER共轭物，患有严重的过敏反应 高水平的抗PEG抗体。这项停止的临床试验证明了 循环抗PEG抗体的影响是由于患病率而越来越多 在天真地静脉治疗的个体中发现的抗PEG 建议在常用消费产品中存在的免费钉子可能是一种 这些干扰抗PEG抗体的来源。我们的“类似钉”的Poegma聚合物刷 已经显示技术会召集传统钉的相同的PD/PK优势 共轭，同时消除抗PEG抗原性。我们已经表明 Poegma，它分解了发现的重复乙二醇单元的长序列 在PEG中，呈现了较短的寡醇（乙二醇）序列，不相互作用 抗PEG抗体。我们希望将Poegma技术应用于 此处描述的基于apatamer的ROA将允许进行有效的疗法 与先前存在的抗PEG抗体的有害相互作用。重新进行 此APATMER ROA代表了Poegma技术的有用应用，因为 是可以快速逆转的抗凝剂的临床需求。现在， 每年约有1200万美国人需要静脉注入高度 潜在的，快速发作抗凝剂以执行高度的临床程序 促血栓性，包括经皮冠状动脉干预（PCI，“血管成形术”）， 冠状动脉搭桥移植（CABG）手术和其他手术以及透析。 当前FDA批准的ROA的重大灾难 - 未折射肝素 （UFH），Lepirudin，Bivalirudin和Argatroban促使努力识别ROAS 消除了与这些ROA相关的毒性和药物引起的出血。 这里描述的PEG-APTAMER序列与完整的解毒剂一起 能够滴定和迅速逆转抗凝活性的序列一直是 在第1阶段，第2阶段和3阶段临床试验中评估> 2,000名患者，相位 2个研究表明，这种apatmer抗抗物对可以减少缺血性事件，并且 与肝素相比，PCI患者的限制出血。基于这些承诺结果，我们 提议消除具有负面抗PEG相互作用的潜力 阻止了这种曾经有希望的PEG-APTAMER疗法的发展 开发一个poegma-aptamer共轭。