Mechanism and engineering of IgG-based monoclonal antibody/receptor interactions

基于 IgG 的单克隆抗体/受体相互作用的机制和工程

基本信息

  • 批准号:
    9300976
  • 负责人:
  • 金额:
    $ 28.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The fragment crystallizable (Fc) region links the dual pathogen identification and destruction properties of immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fc¿ receptors (FcgRs) on immune cells. Asparagine-linked (N)-glycan attached to Fc is required for productive engagement of the low-affinity FcgRs, though it is not known how the Fc N-glycan contributes to FcγR binding because the N-glycan does not directly contact the FcgRs. It has been suggested that the N-glycan provides optimal spacing of two Fc domains, stabilizing the Fc quaternary structure to bind the FCγR. Evidence from our laboratory points to a different hypothesis. We determined that Fc N-glycan motion, increased by Fc amino acid mutations far from the FcγR binding site, negatively correlated with Fc¿RIIIa affinity. Only a single region of Fc, the CE polypeptide loop that contains the site of N-glycosylation, was perturbed as a result of these Fc mutations. This result led to the proposal that the N-glycan affects FcγR affinity by pre-organizing the CE loop, and not by optimizing Fc domain orientation. Here we will directly test our hypothesis by measuring the structure and motion of the CE loop, in multiple forms stabilized through glycan or protein engineering, using solution nuclear magnetic resonance spectroscopy. The knowledge of CE loop structure and motion will be applied to redesign the Fc polypeptide to generate aglycosylated Fc variants that maintain high affinity for FcgRs. The molecular details of immune system activation that will emerge from these studies will be important to understand the process of multiple diseases and will be critical to enhance therapeutic monoclonal antibody function through engineering to treat cancer, transplant and autoimmune disease patients.


项目成果

期刊论文数量(0)
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Adam Wesley Barb其他文献

Adam Wesley Barb的其他文献

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{{ truncateString('Adam Wesley Barb', 18)}}的其他基金

Composition and structure of antibody receptors at the surface of primary human cells during immune activation
免疫激活过程中人体原代细胞表面抗体受体的组成和结构
  • 批准号:
    10189510
  • 财政年份:
    2020
  • 资助金额:
    $ 28.74万
  • 项目类别:
Composition and structure of antibody receptors at the surface of primary human cells during immune activation
免疫激活过程中人体原代细胞表面抗体受体的组成和结构
  • 批准号:
    10622590
  • 财政年份:
    2020
  • 资助金额:
    $ 28.74万
  • 项目类别:
Composition and structure of antibody receptors at the surface of primary human cells during immune activation
免疫激活过程中人体原代细胞表面抗体受体的组成和结构
  • 批准号:
    10410438
  • 财政年份:
    2020
  • 资助金额:
    $ 28.74万
  • 项目类别:
Mechanism and engineering of IgG-based monoclonal antibody/receptor interactions
基于 IgG 的单克隆抗体/受体相互作用的机制和工程
  • 批准号:
    9920805
  • 财政年份:
    2015
  • 资助金额:
    $ 28.74万
  • 项目类别:
NMR Studies on the Role of the Essential IgG N-Glycan in Immune System Activation
必需 IgG N-聚糖在免疫系统激活中作用的 NMR 研究
  • 批准号:
    8606158
  • 财政年份:
    2013
  • 资助金额:
    $ 28.74万
  • 项目类别:
NMR Studies on the Role of the Essential IgG N-Glycan in Immune System Activation
必需 IgG N-聚糖在免疫系统激活中作用的 NMR 研究
  • 批准号:
    8280530
  • 财政年份:
    2013
  • 资助金额:
    $ 28.74万
  • 项目类别:
NMR Studies on the Structure and Dynamics of Glycan-Mediated IgG Interactions
聚糖介导的 IgG 相互作用的结构和动力学的 NMR 研究
  • 批准号:
    8221012
  • 财政年份:
    2010
  • 资助金额:
    $ 28.74万
  • 项目类别:
NMR Studies on the Structure and Dynamics of Glycan-Mediated IgG Interactions
聚糖介导的 IgG 相互作用的结构和动力学的 NMR 研究
  • 批准号:
    8232940
  • 财政年份:
    2010
  • 资助金额:
    $ 28.74万
  • 项目类别:
NMR Studies on the Structure and Dynamics of Glycan-Mediated IgG Interactions
聚糖介导的 IgG 相互作用的结构和动力学的 NMR 研究
  • 批准号:
    7803424
  • 财政年份:
    2010
  • 资助金额:
    $ 28.74万
  • 项目类别:

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