Maximising Efficiency of Liquid Phase Oligo Synthesis (MELOS)

最大限度提高液相寡核苷酸合成 (MELOS) 的效率

• 批准号: 10062179
• 金额: $ 233.95万
• 依托单位: EXACTMER LIMITED
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10062179
• 关键词: Maximising; Efficiency; Liquid; Phase; Oligo

Oligonucleotides (oligos) are sequences of nucleotides monomers which usually contain between 15-25 nucleotides/ nucleotide-analogues, they offer promising treatment for a wide range of medical conditions. There are now 15 oligo drugs which have been approved between the EMA and FDA. In recent years, an **increasing number of oligos in clinical trials** have shown excellent results for diseases with large patient populations. For example, Inclisiran, an oligo developed for the treatment of cardiovascular disease (thousands of patients), was approved in Europe in 2020 and is available on the NHS since 2021\. It is estimated Inclisiran will treat 300,000 patients in the UK in the next three years.While Solid Phase Synthesis (SPS) is the dominant manufacturing process to produce oligos it presents several limitations. The main challenges comprise: **the lack of scalability** (~10-20kg batch sizes maximum), the **high costs** (£800-£1000/g of oligos) and the **heavy environmental burden** associated with the process (~4300kg/kg PMI). This creates a critical need for sustainable, ton-per-annum-scale oligo production routes to enable oligos to deliver patient benefits in large populations.The Grand Challenge 'GC3' consortium (comprising Novartis, AstraZeneca, Alnylam, Exactmer, CPI) is developing Nanostar Sieving, a **breakthrough new technology based on Liquid Phase Synthesis** (LPS) to manufacture oligos. For oligo manufacture, this platform is positioned to provide ease of scaling under GMP conditions (100kg/batch), with high crude purity oligos (70-90%) and use of similar phosphoramidite monomer equivalents (1.5 equivalents/cycle). Maximising Efficiency of Liquid-phase Oligo Synthesis (MELOS) is a UK based collaboration between Exactmer, Queen Mary University of London (QMUL), CPI and AstraZeneca, seeking to build on the success of GC3\. This 24-month project will focus on **a step change in the process efficiency and sustainability of the Nanostar Sieving platform** for the synthesis of oligos on large scale. The current chemistry will be further developed by using Nanostar hubs and monomers with better membrane selectivities and higher solubilities. Further step changes include integration of a solvent recycling loop within the Nanostar Sieving process, seeking a **reduction of 40% in the total Process Mass Intensity** (PMI) compared to SPS technology. A solvent drying device will allow in-process water removal that will reduce required phosphoramidites equivalents to close to stoichiometric (i.e., <1.1 equivalents). In-line, real-time analysis will be implemented to monitor the quality of the recycled solvent. Furthermore, this work is required to ensure the **highest quality of product is obtained with minimal environmental impact, and at reduced costs**.

寡核苷酸（寡核苷酸）是通常包含15-25个核苷酸/核苷酸 - 分析的核苷酸单体序列，它们为多种医疗条件提供了有希望的治疗。现在，EMA和FDA之间已经批准了15种寡核药物。近年来，在临床试验中，越来越多的寡素**在患者群体较大的疾病中显示出极好的结果。例如，开发用于治疗心血管疾病（数千例患者）的Oligo，于2020年在欧洲批准，自2021年以来就在NHS上获得了批准。据估计，含糖兰将在未来三年内治疗30万名患者。虽然固相合成（SPS）是生产寡核酸的主要制造过程，但它提出了几个限制。主要挑战包括：**缺乏可扩展性**（〜10-20kg批量量最高），**高成本**（£800-£1000/g的寡寡核）和与该过程相关的**重型环境燃烧**（〜4300kg/kg PMI）。这至关重要的是，对可持续的，每吨位的寡核生产路线，以使寡核能在大量人群中带来患者的福利。对于Oligo生产，该平台定位在GMP条件下（100kg/批次），具有较高的粗纯度寡聚（70-90％），并使用相似的磷光素单体等效物（1.5等效物/循环）。液相寡核合成（MELOS）的效率最大化是英国伦敦皇后大学（QMUL），CPI和阿斯利康之间的一项基于英国的合作，试图以GC3 \的成功为基础。这个24个月的项目将重点介绍**纳米级筛分平台的过程效率和可持续性的步骤变化**大规模合成寡核酸的过程。通过使用具有更好的膜选择性和更高溶解度的纳米级枢纽和单体，将进一步开发当前的化学性质。进一步的变化包括将溶剂循环集成在纳米级筛分过程中，与SPS技术相比，在总过程质量强度**（PMI）中寻求降低40％。溶液干燥装置将允许在进程中去除水，从而减少所需的磷光素等效物以接近化学计量学（即，<1.1等效物）。在线实时分析将实施以监视回收解决方案的质量。此外，需要这项工作，以确保以最小的环境影响获得**最高质量的产品，并且成本降低**。