Development of a novel production platform for complex recombinant biotherapeutic

描述(申请人提供)：重组蛋白生物制药的制造是一项复杂的、劳动和资本密集型的工作。目前人们普遍认为，使用哺乳动物细胞是生产大多数人类蛋白质的必要条件，这些蛋白质通常包含原核生物和单细胞真核生物不具有的广泛的翻译后修饰。尽管中国仓鼠卵巢细胞和幼年仓鼠肾脏细胞等哺乳动物细胞可以忠实地生物合成大多数人类蛋白质，但其效率远远低于细菌或酵母细胞。在目前市场上销售的重组蛋白中，凝血因子VIII的生产效率最低，在单位质量的基础上也是最昂贵的。其他昂贵且难以制造的生物药物包括其他凝血因子(如凝血因子IX和VIIa)、干扰素和基于激素的细胞因子。目前应用的目标是开发一种能够提高这些难以制造的重组生物制品的生产量和药价的技术。Expression Treateutics开发了一种新的幼年仓鼠肾脏来源(BHK)细胞系，命名为BHK-MS，可以在悬浮生物反应器条件下的血清和血液产物无限期培养和扩增。在目前的研究中，我们正在开发和验证悬浮适应的BHK-MS细胞系，以生产更好的凝血因子VIII和凝血因子IX，以及2)进行中试生产，并分析BHK-MS生物合成的重组因子VIII和凝血因子IX的生化和药学特性，这将作为一个模型，难以生产生物药物。 与公共健康相关：目前项目的长期商业目标是将一种基于悬浮细胞的生物制造平台商业化，旨在提高复杂、难以制造的生物制品的体积生产率。目前的低成品率制造工艺往往导致产品供应有限和产品成本高。Expression Treateutics已经开发出一种正在申请专利的细胞系，旨在高效地制造重组生物制品。本文提出的研究旨在为这一新型制造平台的效率和可扩展性以及严格的临床前验证和表征提供概念验证。

DESCRIPTION (provided by applicant): The manufacturing of recombinant protein-based biopharmaceuticals is a complex, labor and capital intensive endeavor. It currently is accepted that the use of mammalian cells is a requirement for the production of most human proteins, which typically contain extensive post-translational modifications that are not performed by prokaryotes and single-celled eukaryotes. Although mammalian cells such as Chinese hamster ovary cells and baby hamster kidney cells can faithfully biosynthesize most human proteins, the efficiency is dramatically lower than is achieved by bacterial or yeast cells. Of the recombinant proteins currently marketed, coagulation factor VIII is manufactured with the lowest efficiency and is by far the most expensive on a per unit mass basis. Other expensive and difficult to manufacture biopharmaceuticals include the other coagulation factors (e.g. factors IX and VIIa), interferon, and hormone-based cytokines. The goal of the current application is to develop a technology that can improve the production volume and pharmacy price of these difficult to manufacture recombinant biologics. Expression Therapeutics has developed a new baby hamster kidney-derived (BHK) cell line, designated BHK-MS, which can be cultured and expanded indefinitely in serum and blood product-free medium under suspension bioreactor conditions. In the current studies, we are 1) developing and validating the suspension adapted BHK-MS cell line for superior coagulation factor VIII and factor IX production, and 2) performing a pilot-scale manufacturing run and analyzing the biochemical and pharmaceutical characteristics of BHK-MS biosynthesized recombinant factor VIII and factor IX, which will serve as a model, difficult to manufacture biopharmaceuticals. PUBLIC HEALTH RELEVANCE: The long-term commercial objective of the current project is to commercialize a suspension cell-based biomanufacturing platform designed for improved volumetric productivity of complex, hard to manufacture biologics. Low-yield manufacturing processes currently in place often result in limited product availability and high-product costs. Expression Therapeutics has developed a patent-pending cell line designed for efficient manufacturing of recombinant biologics. The studies proposed herein are designed to provide proof-of-concept of the efficiency and scalability, as well as, rigorous preclinical validation and characterization of this novel manufacturing platform.