Next-generation separation technologies for the advanced manufacturing of oncolytic viruses

用于溶瘤病毒先进制造的下一代分离技术

• 批准号: RGPIN-2019-06828
• 负责人: Latulippe, David
• 金额: $ 2.4万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747155
• 关键词: Next; generation; separation; technologies; advanced

Oncolytic viruses (OVs) are a special class of bio-therapeutic molecules being developed for the treatment of cancer. Given the recent approval of the first OV product (for advanced melanoma) by the US FDA, the excitement and expectations are at an all time high.  Currently over 40 clinical trials are being conducted worldwide and bio-therapeutic companies are making major investments in expanding and accelerating their pipeline of OV products. Canada is a major player in the OV field given our national network of world-class researchers (BioCanRx), who are discovering new OVs and novel ways to deliver OVs into cancer cells, and growing industry sector.  The commercial success of OV-based therapies is critically dependent on the development of large-scale OV manufacturing process that can achieve the activity and purity requirements established by regulatory agencies (e.g. Health Canada, FDA) while also being cost-effective. Given recent advances in 'upstream' OV manufacturing capacity, the accompanying 'downstream' separation processes are the major 'bottleneck' in OV manufacturing. The long-term vision of my research program is build the know-how, train the HQP, and develop the technologies to fix this problem.  In the short term, 4 PhD and 13 undergraduate students will carry out three interconnected projects to develop separation technologies that solve the critical 'technology gaps' that currently exist in large-scale OV manufacturing - they include: 1) Rational design of membrane chromatography processes for the production of OVs 2) Simultaneous purification, stabilization, and sterilization of OVs via diafiltration membrane process 3) Aptamer affinity chromatography process for the single-step purification of OVs The technologies will be developed for different OV candidates, however a significant focus will be on Maraba rhabdovirus given its potential use in the treatment of non-small cell lung cancer, the leading cause of cancer-related deaths in North America. Because bio-therapeutic manufacturers are reluctant to adopt new separation processes without extensive experimental validation, each project will include an assessment of process reproducibility and the development of theoretical frameworks. McMaster is the ideal venue to conduct this research given its world-class user facilities (Biointerfaces Institute, Centre for Microbial Chemical Biology) with state-of-the-art equipment. Most importantly, McMaster is also home to the Fitzhenry Manufacturing Facility (FMF), one of only two GMP suites in Canada with experience in producing pharmaceutical-grade OV products. While the FMF does not have the capacity to be used for commercial-scale production, it will allow for my team to demonstrate the 'proof-of-concept' at pilot-scale manufacturing. To my knowledge, there is no other group in Canada that has our expertise in separation processes plus this combination of infrastructure and equipment to execute a study of this kind.

溶瘤病毒（OV）是一类正在开发用于治疗癌症的特殊生物治疗分子。鉴于美国FDA最近批准了第一个OV产品（用于晚期黑色素瘤），兴奋和期望值达到了历史最高水平。目前全球正在进行40多项临床试验，生物治疗公司正在进行重大投资，以扩大和加速其OV产品线。加拿大是OV领域的主要参与者，因为我们的世界级研究人员（BioCanRx）的国家网络正在发现新的OV和将OV输送到癌细胞中的新方法，并正在发展工业部门。 基于OV的治疗的商业成功关键取决于大规模OV制造工艺的开发，该工艺可以实现监管机构（例如加拿大卫生部，FDA）制定的活性和纯度要求，同时还具有成本效益。鉴于“上游”OV制造能力的最新进展，伴随的“下游”分离工艺是OV制造中的主要“瓶颈”。我的研究计划的长期愿景是建立专有技术，培训HQP，并开发解决这个问题的技术。在短期内，4名博士生和13名本科生将开展三个相互关联的项目，以开发解决目前大规模OV制造中存在的关键“技术差距”的分离技术-它们包括：1）用于生产OV的膜层析工艺的合理设计2）通过渗滤膜工艺同时纯化、稳定化和灭菌OV 3）用于单步纯化OV的适体亲和层析工艺将针对不同的OV候选物开发技术，然而，由于马拉巴弹状病毒在治疗非小细胞肺癌（北美癌症相关死亡的主要原因）中的潜在用途，其将是重要的焦点。由于生物治疗制造商不愿意在没有广泛实验验证的情况下采用新的分离工艺，因此每个项目都将包括对工艺再现性的评估和理论框架的开发。麦克马斯特是进行这项研究的理想场所，因为它拥有世界一流的用户设施（生物界面研究所，微生物化学生物学中心）和最先进的设备。最重要的是，麦克马斯特也是Fitzhenry生产设施（FMF）的所在地，这是加拿大仅有的两个GMP套件之一，具有生产医药级OV产品的经验。虽然FMF不具备用于商业规模生产的能力，但它将允许我的团队在中试规模生产中展示“概念验证”。据我所知，在加拿大没有任何其他团体拥有我们在分离过程方面的专门知识，加上这种基础设施和设备的组合来执行这种研究。