Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications

利用 IgG1 的疏水性糖基口袋进行成像和药物输送应用

基本信息

  • 批准号:
    10298609
  • 负责人:
  • 金额:
    $ 30.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary: Due to the rapidly growing importance of antibody-mediated drug delivery, there is a critical need for simple and efficient site-specific conjugation techniques that do not require extensive antibody engineering efforts. Moreover, there is significant need to identify sites of conjugation that are protected from plasma enzymes and are useful for the attachment of hydrophobic payloads. The goal of this proposal is to optimize conjugation technology at the conserved Q295 residue in order to meet these challenges. In contrast to most sites of conjugation, the Q295 site is contained within a large hydrophobic cavity that is sterically shielded from plasma and is particularly amenable to the conjugation of large nonpolar payloads. Remarkably, the properties of this hydrophobic pocket are largely unexplored to-date and our preliminary research shows that there are significant untapped opportunities for exploiting the unique features of this site. The goal of this project is to demonstrate the broad utility of this site-specific conjugation technology through the preparation and evaluation of antibody conjugates for oncology, immunology, and imaging applications. We will accomplish this goal through the achievement of three aims. Aim#1 focuses on developing a thorough molecular understanding of the local environment around the Q295 residue and optimizing linkers that can place the payload within the associated hydrophobic pocket. The goal of this aim is to thoroughly understand the chemical properties of the hydrophobic pocket that surrounds the Q295 moiety. Aim#2 focuses on demonstrating the therapeutic utility of this technology through the preparation of ADCs that deliver a wide range of payloads – particularly focusing on payloads that have exhibited difficulties when attached through traditional (“stochastic”) conjugation approaches. Four particular payloads were selected: MMAE (due to its clinical relevance and known linker stability issues), Tubulysin (due to interest in payloads with low PGP efflux and also a labile ester functionality that has caused problems with traditional approaches), Thailanstatin A (due to its unique mechanism of action and to the labile functional groups in its structure), and Brequinar (due to its potency as an immunosuppressive agent and its very high hydrophobicity that has so-far prevented ADC delivery). The resulting B-cell targeting ADCs will be thoroughly evaluated for their pharmacokinetic profile and efficacy in a B-cell xenograft model. Aim#3 focuses on using the Q295 site for the development of Raman imaging probes that can be used for generating live-cell time lapse images. Importantly, there have been no reported attempts to use Raman imaging to study ADC trafficking. Traditional ADC conjugation methods cannot be employed for the attachment of the Raman tags due to their very high hydrophobicity. Successful achievement of these aims will provide the drug-delivery community with a valuable new tool for site-specific conjugation of problematic payloads and will establish new imaging techniques for the study of ADC trafficking and catabolism.
项目总结: 由于抗体介导的药物传递的重要性迅速增长,迫切需要一种简单和 高效的部位特异性结合技术,不需要广泛的抗体工程努力。此外, 很有必要确定不受血浆酶保护的结合部位,并对 疏水有效载荷的附着。这项提议的目标是在 保守Q295残基以应对这些挑战。与大多数结合位点不同,Q295位点是 包含在一个大的疏水空腔中,该空腔是立体屏蔽的,不受等离子体的影响 大型非极有效载荷的共轭。值得注意的是,这个疏水口袋的特性在很大程度上还没有被探索 到目前为止,我们的初步研究表明,有大量尚未开发的机会来开发独特的 本网站的特点。这个项目的目标是展示这种特定部位结合的广泛用途。 通过制备和评价用于肿瘤学、免疫学和成像的抗体结合物的技术 申请。我们将通过实现三个目标来实现这一目标。目标1专注于开发 深入了解Q295残基周围的局部环境,并优化连接子,以 将有效载荷放置在关联的疏水口袋中。这一目标的目的是彻底了解 Q295部分周围疏水口袋的化学性质。目标2侧重于演示 通过制备可提供各种有效载荷的ADC来实现这项技术的治疗效用- 特别关注在通过传统(“随机”)连接时表现出困难的有效载荷 共轭接近了。选择了四个特定的有效载荷:MMAE(由于其临床相关性和已知连接物 稳定性问题),Tubuysin(由于对具有低PGP外流的有效载荷的兴趣,以及具有 造成传统方法的问题),泰兰他汀A(由于其独特的作用机制和不稳定 其结构中的官能团)和Brequina(由于其作为免疫抑制剂的效力和非常高的 到目前为止阻碍ADC交付的疏水性)。最终得到的B细胞靶向ADC将得到彻底的评估 在B细胞异种移植模型中的药代动力学特征和疗效。目标#3重点介绍如何使用Q295站点 可用于产生活细胞时间推移图像的拉曼成像探针的开发。重要的是 目前还没有使用拉曼成像来研究ADC贩运的报道。传统ADC共轭 由于拉曼标签具有很高的疏水性,因此不能采用这种方法来粘贴。成功 这些目标的实现将为药物递送界提供一种有价值的新工具,用于特定地点 结合有问题的有效载荷,并将建立新的成像技术,以研究ADC贩运和 分解代谢。

项目成果

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Lawrence Tumey其他文献

Lawrence Tumey的其他文献

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{{ truncateString('Lawrence Tumey', 18)}}的其他基金

Legumain to the rescue: A new ADC linker strategy to address the limitations of cathepsin cleavage
Legumain 来拯救:一种新的 ADC 连接策略,解决组织蛋白酶切割的局限性
  • 批准号:
    10561636
  • 财政年份:
    2022
  • 资助金额:
    $ 30.85万
  • 项目类别:
Legumain to the rescue: A new ADC linker strategy to address the limitations of cathepsin cleavage
Legumain 来拯救:一种新的 ADC 连接策略,解决组织蛋白酶切割的局限性
  • 批准号:
    10342525
  • 财政年份:
    2022
  • 资助金额:
    $ 30.85万
  • 项目类别:
Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications
利用 IgG1 的疏水性糖基口袋进行成像和药物输送应用
  • 批准号:
    10627830
  • 财政年份:
    2021
  • 资助金额:
    $ 30.85万
  • 项目类别:
Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications
利用 IgG1 的疏水性糖基口袋进行成像和药物输送应用
  • 批准号:
    10619285
  • 财政年份:
    2021
  • 资助金额:
    $ 30.85万
  • 项目类别:
"Molecular whack-a-mole”: Targeting Transmembrane-TNFα for the Delivery of Anti-Inflammatory Drugs
“分子打地鼠”:靶向跨膜 TNFα 来输送抗炎药物
  • 批准号:
    10303479
  • 财政年份:
    2021
  • 资助金额:
    $ 30.85万
  • 项目类别:
Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications
利用 IgG1 的疏水性糖基口袋进行成像和药物输送应用
  • 批准号:
    10458034
  • 财政年份:
    2021
  • 资助金额:
    $ 30.85万
  • 项目类别:
"Molecular whack-a-mole”: Targeting Transmembrane-TNFα for the Delivery of Anti-Inflammatory Drugs
“分子打地鼠”:靶向跨膜 TNFα 来输送抗炎药物
  • 批准号:
    10430241
  • 财政年份:
    2021
  • 资助金额:
    $ 30.85万
  • 项目类别:

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