Exploiting Siglec-6 for targeted anti-allergy drug delivery into human mast cells

利用 Siglec-6 将靶向抗过敏药物输送到人体肥大细胞中

基本信息

  • 批准号:
    10368109
  • 负责人:
  • 金额:
    $ 23.07万
  • 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:
    2021-03-08 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Allergic diseases are IgE-dependent, mast cell-mediated conditions that affect more than 50 million Americans. Severe allergic reactions result in anaphylaxis and can be potentially life threatening, sometimes requiring hospital visits in conjunction with emergency interventions such as the use of epinephrine autoinjectors. Various pharmacotherapies have been developed for the treatment of allergic rhinitis, atopic dermatitis, asthma and food allergy, but none are capable of directly regulating mast cell behavior in a way that truly prevents mast cell reactivity to allergens. A therapeutic strategy is therefore needed to 1) selectively target mast cells for delivery of 2) a potent drug that can directly prevent IgE-dependent mast cell secretion. Sialic acid binding immunoglobulin-like lectin 6 (Siglec-6) is a cell surface receptor that is highly and preferentially expressed on all types of mast cells. While its specific function and associated mechanism of signaling is largely unexplored, its homology to other mast cell Siglecs, like CD33, Siglec-7 and Siglec-8, makes it likely to be inhibitory in function. Separate from its canonical signaling function, engagement of Siglec-6 results in its endocytosis. This supports the hypothesis that Siglec-6 can be exploited for targeted drug delivery into mast cells. Development of a Siglec-6-targeted therapy requires an appropriate delivery vehicle. Previously, the Scott Lab has developed and tested a variety of stable, scalable and customizable drug carriers that each possess distinct structure-dependent advantages for controlled delivery. For example, spherical and filamentous nanocarriers can both transport lipophilic drugs, but their differences in aspect ratio result in distinct capacity for receptor-mediated endocytosis and signaling when targeting moieties are presented on their surfaces. In terms of therapeutic agents, Acalabrutinib (AcB) and other Bruton’s kinase inhibitors (BTKi) irreversibly bind and inhibit BTK to prevent IgE-mediated activation of mast cells via FcεRI, a key driver of anaphylaxis. The Bochner Lab has just demonstrated that pretreatment with AcB in a novel humanized mast cell mouse model of anaphylaxis has profound protective effects regarding anaphylaxis severity and improved survival. In parallel, BTKi completely shut off IgE receptor signaling in both human basophils and mast cells in vitro, with IC50’s in the low to mid nanomolar range. However, the pleiotropic nature of systemic BTKi treatment results in potentially serious side effects, and thus BTKi are not approved for use outside of cancer indications. To test the hypothesis that Siglec-6-mediated targeted delivery of AcB will result in specific inhibition of allergic mast cell activation, two Specific Aims will be achieved: (1) to optimize and characterize the binding kinetics, specificity, and inhibitory activity of Siglec-6/BTKi loaded micellar and filamentous nanocarriers; and (2) to compare the specificity and inhibitory effects of these nanocarriers in Siglec-6 mast cell knock-in mice and humanized mast cell mice. The overarching goal is to generate proof-of-concept data for a subsequent R01 application to more fully develop and test drug delivery systems that selectively deliver drugs into mast cells.
项目摘要 过敏性疾病是IgE依赖性、肥大细胞介导的疾病,影响超过5000万人 美国人严重的过敏反应会导致过敏反应,有时可能危及生命。 需要与紧急干预(例如使用肾上腺素自动注射器)相结合的医院就诊。 已经开发了各种药物疗法用于治疗过敏性鼻炎、特应性皮炎、哮喘和哮喘。 和食物过敏,但没有一个能够直接调节肥大细胞的行为,真正防止肥大细胞的方式, 细胞对过敏原的反应性因此,需要一种治疗策略来1)选择性地靶向肥大细胞用于递送 2)可直接阻止IgE依赖性肥大细胞分泌的有效药物。 唾液酸结合免疫球蛋白样凝集素6(Siglec-6)是一种细胞表面受体, 在所有类型的肥大细胞上优先表达。虽然它的具体功能和相关机制, 信号传导在很大程度上尚未探索,其与其他肥大细胞Siglec,如CD 33,Siglec-7和Siglec-8的同源性使得 它在功能上可能是抑制性。与其典型的信号传导功能分开,Siglec-6的参与导致 在其内吞作用中。这支持了Siglec-6可用于靶向药物递送至靶向细胞的假设。 肥大细胞Siglec-6靶向疗法的开发需要适当的递送载体。此前 斯科特实验室已经开发和测试了各种稳定的,可扩展的和可定制的药物载体, 对于控制输送具有明显的结构依赖性优势。例如,球形和丝状 纳米载体都可以运输亲脂性药物,但它们在纵横比上的差异导致了不同的运输能力。 受体介导的内吞作用和信号传导。 在治疗药物方面,Acalabrutinib(AcB)和其他布鲁顿激酶抑制剂(BTKi)不可逆 结合并抑制BTK,以防止IgE介导的肥大细胞通过FcεRI活化,Fc ε RI是过敏反应的关键驱动因素。的 Bochner实验室刚刚证明,在一种新的人源化肥大细胞小鼠模型中, 过敏反应对过敏反应的严重程度和提高生存率具有深远的保护作用。同时, BTKi在体外完全关闭人嗜碱性粒细胞和肥大细胞中的IgE受体信号传导, 低至中等纳摩尔范围。然而,全身BTKi治疗的多效性导致潜在的 严重的副作用,因此BTKi未被批准用于癌症适应症以外的用途。 为了检验Siglec-6介导的AcB靶向递送将导致特异性抑制AcB的假设, 过敏性肥大细胞活化,将实现两个特定目的:(1)优化和表征结合 负载Siglec-6/BTKi的胶束和丝状纳米载体的动力学、特异性和抑制活性;和(2) 比较这些纳米载体在Siglec-6肥大细胞敲入小鼠中的特异性和抑制作用, 人源化肥大细胞小鼠。总体目标是为后续R 01生成概念验证数据 本申请旨在更全面地开发和测试选择性地将药物递送到肥大细胞中的药物递送系统。

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)

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Bruce S Bochner其他文献

Bruce S Bochner的其他文献

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{{ truncateString('Bruce S Bochner', 18)}}的其他基金

Exploiting Siglec-6 for targeted anti-allergy drug delivery into human mast cells
利用 Siglec-6 将靶向抗过敏药物输送到人体肥大细胞中
  • 批准号:
    10194041
  • 财政年份:
    2021
  • 资助金额:
    $ 23.07万
  • 项目类别:
Using siglecs and their ligands to treat allergic diseases SALTAD
使用siglecs及其配体治疗过敏性疾病SALTAD
  • 批准号:
    10331722
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Defining Siglec-6 and Siglec-8 function on effector cells of allergic diseases
定义 Siglec-6 和 Siglec-8 对过敏性疾病效应细胞的功能
  • 批准号:
    10097994
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Core A Admin
核心A管理员
  • 批准号:
    10331723
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Core A Admin
核心A管理员
  • 批准号:
    10097991
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Using siglecs and their ligands to treat allergic diseases SALTAD
使用siglecs及其配体治疗过敏性疾病SALTAD
  • 批准号:
    10097976
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Defining Siglec-6 and Siglec-8 function on effector cells of allergic diseases
定义 Siglec-6 和 Siglec-8 对过敏性疾病效应细胞的功能
  • 批准号:
    10331725
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Human mast cell and tissue acquisition core
人类肥大细胞和组织采集核心
  • 批准号:
    10331724
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Human mast cell and tissue acquisition core
人类肥大细胞和组织采集核心
  • 批准号:
    10097992
  • 财政年份:
    2018
  • 资助金额:
    $ 23.07万
  • 项目类别:
Northwestern University Allergy and Immunology Research (NUAIR) Program
西北大学过敏与免疫学研究 (NUAIR) 项目
  • 批准号:
    10207416
  • 财政年份:
    2010
  • 资助金额:
    $ 23.07万
  • 项目类别:
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