Developing a multivalent agent for long-lasting treatment of diabetic macular edema

项目摘要 DME是工作年龄人口失明的主要原因。抗VEGF剂是目前治疗的标准。 护理DME，但这些治疗远远不是最佳的：患者需要接受8-12玻璃体内注射，在第一次 并在其余生中继续定期随访和治疗。这些患者还必须花费大量的 时间管理糖尿病和其他合并症-最近的一项研究报告说，平均DME患者有约30个医疗保健 一年的访问天数。因此，他们很难平衡工作和疾病管理。因此 由于治疗不足，DME患者的真实结局明显差于对照试验的结果 和失访。迫切需要更持久的治疗方法。 药效的持续时间由3个关键因素决定：药物效力，其影响最低有效剂量 药物浓度（MEC）;药物半衰期（t1/2），决定代谢的速度;初始药物剂量， 决定了它能持续多久直到到达MEC。改善这些因素的益处得到验证：1）阿柏西普 利用二价实现比雷珠单抗更高的效价，并实现更长的持续时间（每两个月vs.每月）; 2)广泛的研究表明，增加药物的流体动力学半径（RH）成比例地延长其 玻璃体半衰期，并且正在开发多个程序来利用该原理; 3）Brolucizumab采用了许多 剂量高于批准的抗VEGF药物，并且在最近的湿性AMD III期试验中报告了更长的持续时间。 虽然这些项目证明了通过合理的生物工程来改善药物持续时间的可行性，但它们都解决了 一个因素，仅实现增量改善（约3个月持续时间）。同时改善这三个因素， 解锁戏剧性的改进，但极具挑战性。 该SBIR的目的是开发一种新型的治疗性适体的多价聚合物缀合物， 首次改善药物持续时间的所有3个因素，使DME的治疗显著更持久。与 最后，Aptitude团队在适体发现方面积累了丰富的经验。我们以前开发了 粒子展示方法显著提高了适体的性能。我们也取得了显著的成绩 初步研究以证明构建多价聚合物缀合物的可行性。此外，我们还 进一步改进以直接筛选具有上级稳定性和性能的完全修饰的适体 与之前的适配体相比。我们在适体发现方面的专业知识与我们合作者的专业知识相辅相成 DME临床前研究和临床试验。如果成功，这个项目有可能带来更有效的 为DME患者提供经济实惠的治疗。

PROJECT ABSTRACT DME is the leading cause of blindness in the working age population. The anti-VEGF agents are currently the standard of care for DME, but these treatments are far from optimal: patients need to receive 8-12 intravitreal injections in the first year and continue regular follow-up and treatment for the rest of their lives. These patients also have to spend significant time managing diabetes and other comorbidities – a recent study reported that an average DME patient has ~30 healthcare visit days a year. It is therefore extremely difficult for them to balance work and disease management. Consequently, the real-world outcomes of DME patients are significantly worse than the results from controlled trials due to under-treatment and loss to follow-up. Longer-lasting therapeutics are urgently needed. The duration of drug efficacy is determined by 3 key factors: drug potency, which affects the minimum effective concentration (MEC); drug half-life (t1/2), which determines how fast it is metabolized; initial drug dosage, which determines how long it can last until it reaches MEC. The benefits of improving these factors are validated: 1) Aflibercept leveraged bivalency to achieve higher potency than Ranibizumab and enabled a longer duration (bimonthly vs. monthly); 2) extensive studies have shown that increasing the hydrodynamic radius (RH) of a drug proportionally elongates its vitreous half-life, and multiple programs are being developed to leverage this principle; 3) Brolucizumab adopted a much higher dose than the approved anti-VEGF agents and reported a longer duration in the recent phase 3 trials in wet AMD. While these programs proved the feasibility to improve drug duration through rational bioengineering, they each tackles one factor and only achieved incremental improvement (~3-month duration). Simultaneously improving all 3 factors may unlock dramatic improvement but is extremely challenging. The purpose of this SBIR is to develop a novel multivalent polymer conjugate of therapeutic aptamers that simultaneously improve all 3 factors of drug duration for the first time, enabling significantly longer-lasting treatment for DME. To that end, the Aptitude team has accumulated extensive experience in aptamer discovery. We have previously developed the Particle Display method that significantly improves the aptamer performance. We have also performed significant preliminary studies to prove the feasibility of constructing multivalent polymer conjugates. Moreover, we have made further improvement to directly screen for fully modified aptamers that possess superior stability and performance compared to the previous aptamers. Our expertise in aptamer discovery is complemented by our collaborators' expertise in DME preclinical research and clinical trials. If successful, this project has the potential of bringing more efficacious and affordable treatment to DME patients.