Glycoengineering of CHO cells to express recombinant alpha-1 antitrypsin

CHO细胞的糖工程表达重组α-1抗胰蛋白酶

基本信息

  • 批准号:
    10484110
  • 负责人:
  • 金额:
    $ 27.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-22 至 2024-09-21
  • 项目状态:
    已结题

项目摘要

ABSTRACT Alpha-1 antitrypsin (A1AT) is well-established as a biotherapeutic used for the treatment of alpha-1 antitrypsin deficiency, and shows promise for treating a variety of other diseases. However, A1AT augmentation therapy carries unnecessary risk since it relies upon the weekly transfusion of plasma-derived product, which presents supply chain and contaminant risks. This could be remedied with recombinant A1AT, if it adequately matches or improves upon the plasma-derived product, including its post-translational modifications and functional attributes. However, major hurdles to the development of recombinant A1AT exist, since post- translational modifications, such as glycosylation, impact drug activities and half-life, and it has remained challenging to match glycosylation of recombinant A1AT to the plasma derived isoforms. Here we developed a large panel of diverse GMP-ready glycoengineered CHO (geCHO) cell lines that allowed us to discover a host cell line, geCHO-L, that matches glycosylation of the plasma derived product. Here we will demonstrate our platform not only allows us to identify a CHO clone matches the glycosylation of the approved product, but that we can also match the function and half-life of the approved A1AT to enable the manufacturing of a recombinant A1AT to increase the safety and protect the supply of therapeutic A1AT. We further engineer the recombinant A1AT to obtain a product with improved activity and half-life as a candidate therapeutic for alpha-1 antitrypsin deficiency and other diseases.
摘要 α-1抗胰蛋白酶(A1 AT)是公认的用于治疗α-1 抗胰蛋白酶缺乏症,并显示出治疗各种其他疾病的前景。然而,A1 AT增强 治疗带有不必要的风险,因为它依赖于每周输注血浆衍生产品, 存在供应链和污染物风险。这可以用重组A1 AT来补救,如果它足够的话。 匹配或改进血浆衍生产品,包括其翻译后修饰, 功能属性然而,重组A1 AT的开发存在主要障碍,因为后 翻译修饰,如糖基化,影响药物活性和半衰期,它一直保持 使重组A1 AT的糖基化与血浆衍生的同种型匹配具有挑战性。在这里,我们开发了一个 大量不同的GMP就绪糖工程CHO(geCHO)细胞系,使我们能够发现宿主 细胞系geCHO-L,其与血浆衍生产品的糖基化相匹配。在这里,我们将展示我们的 该平台不仅允许我们识别与批准产品的糖基化相匹配的CHO克隆, 我们还可以匹配批准的A1 AT的功能和半衰期, A1 AT,以增加安全性和保护治疗A1 AT的供应。我们进一步改造重组体 A1 AT以获得具有改善的活性和半衰期的产物作为α-1抗胰蛋白酶的候选治疗剂 缺乏症和其他疾病。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Glycoengineered recombinant alpha1-antitrypsin results in comparable in vitro and in vivo activities to human plasma-derived protein.
糖基工程重组 α1-抗胰蛋白酶的体外和体内活性与人血浆衍生蛋白相当。
  • DOI:
    10.1101/2024.03.27.587088
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Rocamora,Frances;Schoffelen,Sanne;Arnsdorf,Johnny;Toth,EricA;Abdul,Yunus;Cleveland4th,ThomasE;Bjørn,SaraPetersen;Wu,MinaYingMin;McElvaney,NoelG;Voldborg,BjørnGunnarRude;Fuerst,ThomasR;Lewis,NathanE
  • 通讯作者:
    Lewis,NathanE
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Nathan Enoch Lewis其他文献

Nathan Enoch Lewis的其他文献

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{{ truncateString('Nathan Enoch Lewis', 18)}}的其他基金

ImmCellFIE: producing high-resolution snapshots of the functions of immune cells
ImmCellFIE:生成免疫细胞功能的高分辨率快照
  • 批准号:
    10199979
  • 财政年份:
    2020
  • 资助金额:
    $ 27.44万
  • 项目类别:
ImmCellFIE: producing high-resolution snapshots of the functions of immune cells
ImmCellFIE:生成免疫细胞功能的高分辨率快照
  • 批准号:
    10027185
  • 财政年份:
    2020
  • 资助金额:
    $ 27.44万
  • 项目类别:
Unraveling the mammalian secretory pathway through systems biology and algorithm development
通过系统生物学和算法开发揭示哺乳动物的分泌途径
  • 批准号:
    10826657
  • 财政年份:
    2016
  • 资助金额:
    $ 27.44万
  • 项目类别:
Unraveling the mammalian secretory pathway through systems biology and algorithm development
通过系统生物学和算法开发揭示哺乳动物的分泌途径
  • 批准号:
    10207258
  • 财政年份:
    2016
  • 资助金额:
    $ 27.44万
  • 项目类别:
Unraveling the mammalian secretory pathway through systems biology and algorithm development
通过系统生物学和算法开发揭示哺乳动物的分泌途径
  • 批准号:
    10413925
  • 财政年份:
    2016
  • 资助金额:
    $ 27.44万
  • 项目类别:
Unraveling the mammalian secretory pathway through systems biology and algorithm development
通过系统生物学和算法开发揭示哺乳动物的分泌途径
  • 批准号:
    10654737
  • 财政年份:
    2016
  • 资助金额:
    $ 27.44万
  • 项目类别:
Unraveling the mammalian secretory pathway through systems biology and algorithm development
通过系统生物学和算法开发揭示哺乳动物的分泌途径
  • 批准号:
    9142975
  • 财政年份:
    2016
  • 资助金额:
    $ 27.44万
  • 项目类别:
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