PhenoDev: A novel Saccharomyces cerevisiae platform for high-yield protein secretion

重组治疗性蛋白和许多疫苗的制造成本都很高。目前最先进的蛋白质表达系统包括：*哺乳动物中国仓鼠卵巢(CHO)和HEK293系统。_限制：_细胞生长缓慢，昂贵的介质，高能源负担(例如，供应二氧化碳和加热细胞培养)，一次性技术带来的高环境负担，以及不太适合大规模生产。*龙沙的XS_E.Coli_系统。_局限性：_不能形成二硫键导致错误折叠的蛋白质聚集成不能分泌的不溶包涵体，需要细胞裂解和进一步加工才能产生功能蛋白质。*Validogen的Pichia Pastoris_系统。_限制：_转化需要有毒的热霉素；整合质粒阻碍菌株发展；复杂的IP/许可问题；糖化赖氨酸残基可能导致功能丧失和不必要的免疫原性；甲醇/氧气饲料造成大规模火灾风险。很少有毕氏酵母衍生的产品获得FDA或MHRA的批准。面包酵母(Saccharmyces Cerevisiae)在FDA批准的生物制品中有着长期、安全的记录，通常被认为是安全的(GRAS)，例如胰岛素，并且具有自然适应性和工业规模的条件，同时正确地生产具有生物活性的真核蛋白。尽管如此，目前还没有“开放”的商业表达系统可用。贝克的酵母系统通常只为内部使用而开发。产量往往低于最佳水平；开发时间缓慢，菌株不容易适应新产品。有机会优化下一代酿酒酵母蛋白表达平台并将其商业化，以获得更广泛的治疗市场。Phenotyeca正在开发基于酿酒酵母的重组蛋白高效表达平台‘PhenoDev’，以满足这一未得到满足的需求。为了实现全部市场潜力，PhenoDev必须通过解决这些疗法所需的蛋白酶和蛋白质折叠问题来优化蛋白质分泌。改进的PhenoDev平台将得到另一家英国中小企业Isgenica的验证，后者将受益于_E.Coli的替代品，以开发和生产他们想要销售的VHH抗体。

Recombinant therapeutic proteins and many vaccines are costly to manufacture. Current state-of-the-art protein expression systems include:* Mammalian Chinese Hamster Ovary (CHO) and HEK293 systems. _Limitations:_ Slow-growing cells, expensive media, high energy burden (e.g., for supplying CO2, and for heating the cell cultures), high environmental burden with disposable technologies, and less amenable to large-volume manufacture.* Lonza's XS _E. coli_ system. _Limitations:_ Inability to form disulphide bonds causes misfolded proteins to aggregate as insoluble inclusion bodies that are not secreted, requiring cell lysis and further processing to generate functional proteins.* Validogen's _Pichia pastoris_ system. _Limitations:_ Transformations require toxic zeomycin; integrated-plasmids hamper strain development; complex IP/licensing issues; glycated lysine residues can cause loss-of-function and unwanted immunogenicity; methanol/oxygen feeds pose a fire risk at scale. Few _Pichia_-derived products have received FDA or MHRA approval.Baker's yeast (_Saccharomyces cerevisiae_) has a long, safe track-record of FDA approve biologics and is generally regarded as safe (GRAS), e.g., insulins, and has natural adaptability industrial-scale conditions whilst correctly producing biologically active eukaryotic proteins. Despite this, no 'open' commercial expression systems are available. Baker's yeast systems are typically developed for in-house use only. Yields are frequently sub-optimal; development times are slow, and strains are not easily adapted to new products.There is an opportunity to optimise and commercialise the next-generation _S. cerevisiae_ protein expression platform for a broader therapeutics market. Phenotypeca are developing the _S. cerevisiae_-based platform 'PhenoDev' for high-yield expression of recombinant proteins to address this unmet need.To realise the full market potential, PhenoDev must be optimised for protein secretion by solving protease and protein folding issues these therapeutics require.The improved PhenoDev platform will be validated by another UK SME, Isogenica, who will benefit from an alternative to _E. coli_ for developing and producing VHH antibodies they want to sell.