Trehalose Glycopolymers to Enhance both Pharmacokinetics and Stability of Therapeutic Proteins

海藻糖糖聚合物可增强治疗性蛋白质的药代动力学和稳定性

基本信息

  • 批准号:
    9245687
  • 负责人:
  • 金额:
    $ 33.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2020-01-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The long-term objective of the proposed research is to establish preclinical efficacy of a platform technology for the stabilization of proteins therapeutics. Inherent instability of protein therapeutics is a large hindrance and in some cases a barrier to their use. We have developed polymers that contain the sugar trehalose in the side chains. The materials stabilize biologics to high temperatures, room temperature, refrigeration, freezing, lyophilization, and even to electron beam sterilization dosages. Furthermore, we have evidence that the polymer confers favorable pharmacokinetic properties to proteins similar to the widely utilized polymer in medicine, poly (ethylene glycol) or PEG. We propose that trehalose glycopolymers will have comparable pharmacokinetic properties to PEG and yet be significantly better than PEG with regard to stabilization ability. This is important for patient health, quality of life, and to reduce costs. We plan to demonstrate this with three important therapeutics: insulin and granulocyte colony-stimulating factor (G-CSF) and hyaluronidase (HAse). These representative proteins have different sizes and degrees of glycosylation and are important to stabilize. Yet, if this research is successful, the polymers may be broadly applicable to many other therapeutics. To reach our major objectives, three specific aims are proposed. First, we will prepare polymer-insulin conjugates and determine bioactivity before and after subjection to heat stress. It is hypothesized that trehalose glycopolymer-protein will be comparable to PEG-protein with regard bioactivity, yet exhibit superior stability to heat compared to the PEG conjugate and unmodified protein. To test this, conjugates will be synthesized and subjected to increases in temperature. The protein integrity will be studied biochemically to evaluate size, aggregation state and folding. The bioactivities will then be determined with standard in vitro assays and in vivo assays in mice for insulin, G-CSF and HAse. Second, we will study pharmacokinetic properties and immune response of polymer conjugates. The hypothesis is that conjugated trehalose glycopolymers will prolong the blood half-life of proteins similar to PEG and will be non antigenic. To determine this, standard pharmacokinetic and immunogenicity studies will be undertaken and compared to the analogous PEGylated versions. Third, we will investigate biodistribution and toxicity of conjugates. It is hypothesized that conjugated trehalose glycopolymers will be nontoxic in vivo and will be distributed and eliminated from mice similarly to PEG. This will be ascertained by biodistribution studies utilizing positron emission tomography and gamma counting. The acute and chronic toxicity will be studied in mice by hematological analysis, biochemical parameters, and histological evaluation. These studies are critical to evaluate if trehalose glycopolymers are safe and can be explored further to enhance the life-times of proteins both inside and outside of the body. Studies to identify polymers that can replace PEG in conjugates are important and are part of our long-term goal to replace PEG in protein conjugates.
 描述(申请人提供):拟议研究的长期目标是建立一种稳定蛋白质疗法的平台技术的临床前疗效。蛋白质疗法固有的不稳定性是其使用的一大障碍,在某些情况下甚至是一种障碍。我们已经开发出侧链中含有糖的海藻糖的聚合物。该材料将生物制剂稳定到高温、室温、冷藏、冷冻、冷冻干燥,甚至电子束灭菌剂量。此外,我们有证据表明,这种聚合物对蛋白质具有良好的药代动力学特性,类似于在医学上广泛使用的聚合物,聚乙二醇或聚乙二醇组分。我们认为,海藻糖糖共聚物将具有与聚乙二醇类似的药代动力学特性,但在稳定能力方面明显优于聚乙二醇。这对患者的健康、生活质量和降低成本都很重要。我们计划用三种重要的疗法来证明这一点:胰岛素和粒细胞集落刺激因子(G-CSF)和透明质酸酶(Hase)。这些具有代表性的蛋白质具有不同的大小和糖基化程度,对稳定很重要。然而,如果这项研究成功,这种聚合物可能会得到广泛的应用 很多其他的治疗方法。为了达到我们的主要目标,我们提出了三个具体目标。首先,我们将制备聚合物-胰岛素偶联物,并测定受热应激前后的生物活性。假设海藻糖糖共聚物蛋白在生物活性方面与聚乙二醇蛋白相当,但与聚乙二醇偶联物和未修饰蛋白相比具有更好的热稳定性。为了测试这一点,将合成偶联物,并对其进行升温。将对蛋白质的完整性进行生化研究,以评估其大小、聚集状态和折叠。然后将用标准的体外试验和小鼠体内胰岛素、G-CSF和Hase的测定来确定其生物活性。其次,我们将研究聚合物结合物的药代动力学特性和免疫反应。假说是,共轭海藻糖糖聚合物将延长与聚乙二醇半衰期相似的蛋白质的血液半衰期,并且不具抗原性。为了确定这一点,将进行标准的药代动力学和免疫原性研究,并与类似的聚乙二醇化版本进行比较。第三,我们将调查结合物的生物分布和毒性。假设共轭海藻糖糖共聚物在体内是无毒的,并将类似于聚乙二醇组分在小鼠体内的分布和消除。这将通过利用正电子发射断层扫描和伽马计数进行的生物分布研究来确定。将通过血液学分析、生化参数和组织学评估来研究其急性和慢性毒性。这些研究对于评估海藻糖糖共聚物是否安全至关重要,并可以进一步探索以延长蛋白质在体内和体外的寿命。研究确定可以在结合物中取代聚乙二醇酯的聚合物是重要的,也是我们在蛋白质结合物中取代聚乙二醇酯的长期目标的一部分。

项目成果

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Heather D Maynard其他文献

Heather D Maynard的其他文献

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{{ truncateString('Heather D Maynard', 18)}}的其他基金

Stabilization of Glucagon by Trehalose Gylcopolymer Nanogels
海藻糖乙二醇聚合物纳米凝胶对胰高血糖素的稳定性
  • 批准号:
    10558471
  • 财政年份:
    2021
  • 资助金额:
    $ 33.13万
  • 项目类别:
Stabilization of Glucagon by Trehalose Gylcopolymer Nanogels
海藻糖乙二醇聚合物纳米凝胶对胰高血糖素的稳定性
  • 批准号:
    10372210
  • 财政年份:
    2021
  • 资助金额:
    $ 33.13万
  • 项目类别:
Chemistry Biology Interface Training Program
化学生物学界面培训计划
  • 批准号:
    10163884
  • 财政年份:
    2020
  • 资助金额:
    $ 33.13万
  • 项目类别:
Chemistry Biology Interface Training Program
化学生物学界面培训计划
  • 批准号:
    10413950
  • 财政年份:
    2020
  • 资助金额:
    $ 33.13万
  • 项目类别:
Trehalose Glycopolymers to Enhance both Pharmacokinetics and Stability of Therapeutic Proteins
海藻糖糖聚合物可增强治疗性蛋白质的药代动力学和稳定性
  • 批准号:
    9113714
  • 财政年份:
    2016
  • 资助金额:
    $ 33.13万
  • 项目类别:
2014 Drug Carriers in Medicine and Biology Gordon Research Conference and Gordon
2014年医学和生物学药物载体戈登研究会议和戈登
  • 批准号:
    8717902
  • 财政年份:
    2014
  • 资助金额:
    $ 33.13万
  • 项目类别:
Stable and Active bFGF-Polymer Conjugates for Wound Healing
用于伤口愈合的稳定且活性强的 bFGF-聚合物缀合物
  • 批准号:
    8246214
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:
Stable and Active bFGF-Polymer Conjugates for Wound Healing
用于伤口愈合的稳定且活性强的 bFGF-聚合物缀合物
  • 批准号:
    8588251
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:
Stable and Active bFGF-Polymer Conjugates for Wound Healing
用于伤口愈合的稳定且活性强的 bFGF-聚合物缀合物
  • 批准号:
    8776294
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:
Stable and Active bFGF-Polymer Conjugates for Wound Healing
用于伤口愈合的稳定且活性强的 bFGF-聚合物缀合物
  • 批准号:
    8398914
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:

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