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

溶瘤病毒（OVs）是一类特殊的生物治疗分子，正在开发用于治疗癌症。鉴于最近美国FDA批准了首个OV产品（用于晚期黑色素瘤），人们的兴奋和期望达到了前所未有的高度。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，以扩大和加速其体外循环产品的管道。加拿大是OV领域的主要参与者，因为我们拥有世界级的研究人员网络（BioCanRx），他们正在发现新的OV和将OV输送到癌细胞的新方法，以及不断发展的行业。基于OV的疗法的商业成功在很大程度上取决于大规模OV制造工艺的发展，该工艺既能达到监管机构（如加拿大卫生部、FDA）规定的活性和纯度要求，又具有成本效益。鉴于“上游”外挂制造能力的最新进展，伴随的“下游”分离过程是外挂制造的主要“瓶颈”。我的研究计划的长期愿景是建立专门知识，培训HQP，并开发技术来解决这个问题。在短期内，4名博士和13名本科生将开展三个相互关联的项目，开发分离技术，解决目前大规模OV制造中存在的关键“技术差距”，包括：1)合理设计膜层析工艺生产OVs 2)通过滤膜工艺同时纯化、稳定和灭菌OVs 3)单步纯化OVs的适体亲和层析工艺这些技术将针对不同的OVs候选物开发，但鉴于其在治疗非小细胞肺癌方面的潜在应用，重点将放在Maraba横纹肌病毒上。是北美癌症相关死亡的主要原因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，每个项目都将包括对工艺可重复性的评估和理论框架的发展。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（生物接口研究所，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制造工厂（FMF）的所在地，这是加拿大仅有的两个GMP套件之一，具有生产制药级OV产品的经验。虽然FMF不具备用于商业规模生产的能力，但它将使我的团队能够在中试规模生产中展示“概念验证”。据我所知，在加拿大没有其他团队拥有我们在分离过程方面的专业知识，以及这样的基础设施和设备组合来执行这种研究。

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.