Transgenic Plant Technology for Producing Therapeutic Recombinant Antibodies

描述（由申请人提供）：迫切需要开发新的，具有成本效益的制造工艺来生产商业治疗性抗体，以降低高昂的制造费用并解决有限制造能力的潜力。本申请的长期目标是利用转基因植物开发新的制造工艺，以显著降低前期资本投资和加工成本，缩短产品开发周期，并提供具有优越安全性的产品。利用在第一阶段提案资助下开发的高产转基因生菜表达系统可以最好地实现这些目标。在这个第二阶段计划中，生产模型抗体的转基因生菜将用于评估该过程的可扩展性和大规模中试生产的产品质量。在标准哺乳动物细胞培养中产生的相同模型抗体将用于所有比较。该模型抗体是一种完全人源化的IgG1？抗组织因子抗体（hOAT），目前正处于临床前开发的抗癌治疗药物。这项研究计划的具体目标是：1)在温室环境下使用水培生产产生200公斤转基因hOAT生菜生物量；2)建立可扩展的蛋白质纯化方法，从转基因生菜中获得高纯度的hOAT；3)通过体外和体内测试评估植物源性hOAT的批对批一致性，进一步确定其与哺乳动物细胞产生的hOAT的可比性。使用转基因生菜表达方法的生产和资金成本较低，产品开发周期缩短，灵活性和可扩展性更强，安全性更高，为该平台制造治疗和诊断抗体产品提供了重要的价值和吸引力。商品成本的降低将使抗体疗法得到更广泛的应用，特别是在经济欠发达的市场。快速发展的转基因生菜能够产生大量的功能性重组抗体，非常适合生物防御应用，在生物防御应用中，需要大量的治疗性蛋白质来应对不断变化的威胁。使用hOAT作为模型蛋白将提供原理证明，证明有利的生产经济性，并确认抗体的功能/功效。它还可能导致一种植物源抗体进入临床研究，以对抗癌症适应症。7. 本提案的目标是开发一种新颖的，具有成本效益的生产工艺，以商业化生产转基因生菜的治疗性抗体。这些产品的成本较低，安全性较好，因此能够更广泛地使用抗体疗法，特别是在经济欠发达的市场和用于生物防御目的。本研究中使用的生菜产生的模型抗体也可以推进到抗癌的临床开发中。

DESCRIPTION (provided by applicant): There is an urgent need to develop novel, cost-effective manufacturing processes to produce therapeutic antibodies commercially in order to reduce the high manufacturing expenses as well as to address the potential for limited manufacturing capacity. The long-term objectives of this application are to develop novel manufacturing processes using transgenic plants to significantly lower the up-front capital investment and processing costs, shorten the product development cycle, and provide products with superior safety profiles. These objectives are best achieved by utilizing the high-yield transgenic lettuce expression system developed under the funding of the Phase I proposal. In this Phase II plan, transgenic lettuce producing a model antibody will be used to evaluate the scalability of the process and quality of the product from a larger scale pilot production. The same model antibody produced in standard mammalian cell culture will be used for all of comparisons. This model antibody is a fully humanized IgG1? anti-tissue factor antibody (hOAT) that is currently in pre-clinical development as an anti-cancer therapeutic. The specific aims of this research proposal are to: 1) generate 200-kg of transgenic hOAT lettuce biomass using hydroponic production in a greenhouse setting; 2) establish a scalable protein purification method to generate highly purified hOAT from transgenic lettuce; and 3) evaluate lot-to-lot consistency of the plant-derived hOAT using in-vitro and in-vivo testing and further establish its comparability to mammalian cell-produced hOAT. The lower production and capital costs, shortened product development cycle, greater flexibility and scalability, and improved safety of using transgenic lettuce expression methods provides significant value and appeal to this platform for manufacturing therapeutic and diagnostic antibody products. The lower cost of goods would enable wider spread use of antibody therapeutics, particularly in less economically developed markets. The rapidly develop transgenic lettuce capable of producing kilogram quantities of functional recombinant antibody is well suited for biodefense applications where stockpiles of therapeutic proteins are needed to address numerous and continuously changing threats. The use of hOAT as model protein will provide proof-of-principle, demonstrate favorable production economics and confirm antibody functionality/efficacy. It could also lead to the advance of a plant-derived antibody into clinical studies against cancer indications. 7. Project Narrative The goal of this proposal is to develop a novel, cost-effective manufacturing process to commercially produce therapeutic antibodies using transgenic lettuce. The lower cost of goods and better safety profiles of these products would enable broader use of antibody therapeutics, particularly in less economically developed markets and for biodefense purposes. The lettuce-produced model antibody used in this study could also be advanced into clinical development against cancer.