Prevalence and characteristics of anti-PEG antibodies in humans

人类抗 PEG 抗体的流行率和特征

基本信息

  • 批准号:
    8622684
  • 负责人:
  • 金额:
    $ 18.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-30 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

Abstract Poly(ethylene glycol) (PEG), due to its ability to resist protein adsorption and reduce RES clearance, has been widely used to extend the circulation times and improve efficacy of protein- and nanoparticle- based therapeutics. However, because of constant exposure to PEG in everyday products including detergents (soap, shampoo, toothpaste, etc.), food products and fertilizers, a substantial proportion of the population has likely developed some degree of anti-PEG immunity. Recent animal studies show that antibodies that specifically recognize PEG can be generated in vivo, leading to accelerated blood clearance of PEGylated therapeutics and nanoparticles and thereby reduced efficacy. Although pre-existing anti-PEG immunity likely compromises the effectiveness of many PEGylated therapeutics, little is understood about anti-PEG immunity in humans. In this proposal, we seek to apply the latest advances in immunology and molecular biology to characterize anti-PEG antibodies in humans. In Aim 1, we will measure the prevalence and concentrations of anti-PEG IgG and IgM among blood samples received at the blood bank at the UNC Hospital. We will also evaluate serum anti-PEG antibody levels in a small number of patients before and at various time points post dosing with PEGylated therapeutics. In Aim 2, we will (A) isolate and immortalize human B cells producing anti-PEG antibodies, (B) characterize their binding affinity to PEG (kon, koff, KD), (C) sequence the DNA of high affinity binding monoclonal antibodies (mAb), and (D) obtain crystal structures to reveal how the amino acid orientation of the Fab binding arm specifically recognizes the ethylene oxide backbone of PEG. In Aim 3, using human mAb from Aim 2 cloned to a mouse IgG backbone, we will evaluate (A) how precise levels of anti-PEG IgG, at concentrations reflecting the range found in humans (from Aim 1), influence the bio- distribution and circulation kinetics of PEGylated particles in mice. (B) We will also determine whether pre- injection of free PEG, at various doses and times prior to injection of PEGylated particles, may restore native distribution and circulation characteristics by saturating serum anti-PEG IgG. These studies will contribute valuable resources for future studies in the field (fully human anti-PEG mAb and corresponding multiplex assays), provide important structural insights into how antibodies can specifically recognize PEG and potentially other polymers, and facilitate the development of next generation PEG-like polymers that can avoid binding by anti-PEG antibodies.
摘要 聚(乙二醇)(PEG),由于其抵抗蛋白质吸附和减少RES清除的能力,已被 广泛用于延长循环时间和提高基于蛋白质和纳米颗粒的 治疗学然而,由于日常产品(包括洗涤剂)中的PEG持续暴露, (soap洗发水、牙膏等),食品和化肥,很大一部分人口 可能产生了一定程度的抗PEG免疫力最近的动物研究表明, 可以在体内产生特异性识别PEG,导致PEG化的PEG的加速血液清除 治疗剂和纳米颗粒,从而降低功效。尽管先前存在的抗PEG免疫可能 损害了许多聚乙二醇化治疗剂的有效性,关于抗PEG免疫的了解很少 在人类身上。在这项提案中,我们寻求将免疫学和分子生物学的最新进展应用于 表征人体中的抗PEG抗体。在目标1中,我们将测量 抗-PEG IgG和IgM的血液样本中收到的血库中的血液样本在血液中的血液我们还将 在治疗前和治疗后不同时间点评价少数患者的血清抗PEG抗体水平 给药PEG化治疗剂。在目标2中,我们将(A)分离并永生化产生人B细胞, 抗PEG抗体,(B)表征它们对PEG的结合亲和力(kon,koff,KD),(C)对高表达的DNA进行测序, 亲和结合单克隆抗体(mAb),和(D)获得晶体结构以揭示氨基酸如何与单克隆抗体(mAb)结合。 Fab结合臂的方向特异性识别PEG的环氧乙烷主链。在目标3中, 使用来自克隆到小鼠IgG骨架的Aim 2的人mAb,我们将评估(A) 抗PEG IgG在反映人体中发现的浓度范围(来自目标1)时,影响生物学特性。 PEG化颗粒在小鼠中的分布和循环动力学。(B)我们还将确定是否预先- 在注射PEG化颗粒之前以各种剂量和时间注射游离PEG,可以恢复天然的PEG化颗粒。 分布和循环特性的饱和血清抗PEG IgG。这些研究将有助于 该领域未来研究的宝贵资源(全人源抗PEG mAb和相应的多重 分析),提供了关于抗体如何特异性识别PEG的重要结构见解, 潜在的其他聚合物,并促进下一代PEG样聚合物的开发, 通过抗PEG抗体结合。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Samuel Lai其他文献

Samuel Lai的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Samuel Lai', 18)}}的其他基金

Engineering Siglec15/TGF-beta targeted bispecific antibodies that modulate the tumor microenvironment and enhances T-cell immunotherapy against pancreatic cancer
工程化 Siglec15/TGF-β 靶向双特异性抗体可调节肿瘤微环境并增强针对胰腺癌的 T 细胞免疫治疗
  • 批准号:
    10651442
  • 财政年份:
    2023
  • 资助金额:
    $ 18.83万
  • 项目类别:
Engineered “muco-trapping” antibodies for inhaled therapy of parainfluenza and human metapneumovirus infections
用于副流感和人类偏肺病毒感染吸入治疗的工程化“粘膜捕获”抗体
  • 批准号:
    10587723
  • 财政年份:
    2022
  • 资助金额:
    $ 18.83万
  • 项目类别:
Engineered “muco-trapping” antibodies for inhaled therapy of parainfluenza and human metapneumovirus infections
用于副流感和人类偏肺病毒感染吸入治疗的工程化“粘膜捕获”抗体
  • 批准号:
    10707403
  • 财政年份:
    2022
  • 资助金额:
    $ 18.83万
  • 项目类别:
Engineering bispecific antibodies for non-hormonal contraception
用于非激素避孕的双特异性抗体工程
  • 批准号:
    10428467
  • 财政年份:
    2020
  • 资助金额:
    $ 18.83万
  • 项目类别:
Engineering bispecific antibodies for non-hormonal contraception
用于非激素避孕的双特异性抗体工程
  • 批准号:
    10618849
  • 财政年份:
    2020
  • 资助金额:
    $ 18.83万
  • 项目类别:
Overcoming anti-PEG immunity to restore prolonged circulation and efficacy of PEGylated therapeutics
克服抗 PEG 免疫,恢复 PEG 化治疗的延长循环和功效
  • 批准号:
    10181024
  • 财政年份:
    2018
  • 资助金额:
    $ 18.83万
  • 项目类别:
Artificial neural networks for high performance, fully automated particle tracking analysis even at low signal-to-noise regimes
人工神经网络即使在低信噪比条件下也能实现高性能、全自动粒子跟踪分析
  • 批准号:
    9347679
  • 财政年份:
    2017
  • 资助金额:
    $ 18.83万
  • 项目类别:
Optimizing Plantibodies for Trapping HIV and HSV in Cervicovaginal Mucus
优化 Plantibodies 以捕获宫颈阴道粘液中的 HIV 和 HSV
  • 批准号:
    8803845
  • 财政年份:
    2014
  • 资助金额:
    $ 18.83万
  • 项目类别:
Optimizing Plantibodies for Trapping HIV and HSV in Cervicovaginal Mucus
优化 Plantibodies 以捕获宫颈阴道粘液中的 HIV 和 HSV
  • 批准号:
    8515320
  • 财政年份:
    2013
  • 资助金额:
    $ 18.83万
  • 项目类别:
Trapping HIV in mucus with IgG antibodies
用 IgG 抗体将 HIV 捕获在粘液中
  • 批准号:
    8208988
  • 财政年份:
    2011
  • 资助金额:
    $ 18.83万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 18.83万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了