Engineering of macrophage phagocytosis for cancer and stem cell immunotherapy

用于癌症和干细胞免疫治疗的巨噬细胞吞噬工程

基本信息

  • 批准号:
    8840913
  • 负责人:
  • 金额:
    $ 33.46万
  • 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:
    2014-05-01 至 2019-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Macrophages are phagocytic cells that recognize and 'eat' foreign cellular microbes, as well as dying cells and aberrant cells such as cancers. They display a variety of receptors by which they recognize 'eat me' and 'don't eat me' signals on their target cells. Macrophages inspect migrating hematopoietic stem cells (HSC) as they pass through the sinusoids. Macrophages also inspect cancer cells, which express pro-phagocytic 'eat me' signals to ensure that aberrant cells are ingested in a process termed programmed cell removal. However, successful cancer cells evade programmed cell removal by expressing CD47, a dominant 'don't eat me' signal that is a ligand for SIRP¿, an inhibitory receptor expressed on macrophages. Ligation of SIRP¿ by CD47 blocks macrophages from phagocytosing the tumor cells. The CD47/SIRP¿ axis represents a toggle switch that can be blocked or stimulated for different therapeutic goals. Blocking binding of CD47 to SIRP¿ promotes phagocytosis of cancer cells. Conversely, the CD47/SIRP¿ interaction is a critical determinant of engraftment success in hematopoietic cell transplantation (HCT): CD47 expression levels on HSC correlate with their relative engraftability. Unfortunately, bone marrow HSC express low levels of CD47, accounting for their relative inefficiency in transplantation. Thus, depending on the clinical scenario, the SIRP¿/CD47 system offers an exciting new axis for both anti-tumor and transplant therapy. However, effective utilization of the soluble ectodomains of either SIRP¿ or CD47 as agonists, or antagonists is limited by the low affinity of the wild-type CD47/SIRP¿ interaction. We wish to execute a structure-based engineering approach to creating high-affinity SIRP¿ and CD47 ectodomains as therapeutics for cancer and HCT. We propose to combine the expertise of the Garcia lab in structural biology, protein engineering and immune intervention, with the strengths of the Weissman and Shizuru labs in in vivo cancer, and hematopoietic cell transplantation biology, to target the CD47/SIRP¿ axis. For Aim #1, we have engineered high-affinity SIRP¿ monomers, that prevent the interaction between endogenous CD47 and SIRP¿, and dramatically synergize with clinically-established therapeutic monoclonal antibodies in stimulating phagocytosis of tumor cells in vivo. This "1-2" punch of target sensitization to macrophages followed by cytolysis by anti-tumor mAb is a completely novel strategy. For Aim #2, we are engineering high-affinity CD47 variants that activate SIRP¿ inhibitory signaling and decrease macrophage activation, thus enhancing HSC engraftment. Finally, in Aim #3 we wish to reconstitute and molecularly characterize the cell surface 'don't eat me' complex composed of CD47 and SIRP¿ with putative alternative ligands including thrombospondin and integrins in order to fully understand the therapeutic potential of this system for modulating macrophage phagocytosis. We anticipate these studies will yield novel classes of biotherapeutics with applications in many types of human cancers, and for transplant therapy.
描述(由申请人提供):巨噬细胞是一种吞噬细胞,可以识别并“吃掉”外来细胞微生物,以及垂死细胞和异常细胞(如癌症)。它们显示出多种受体,通过这些受体,它们可以识别“吃我”和“不要吃我”的信号

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(0)

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Kenan Christopher GARCIA其他文献

Kenan Christopher GARCIA的其他文献

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{{ truncateString('Kenan Christopher GARCIA', 18)}}的其他基金

A Global Map of Interactions Among Human Cell Surface Proteins and Secreted Ligands
人类细胞表面蛋白和分泌配体之间相互作用的全局图
  • 批准号:
    10710033
  • 财政年份:
    2022
  • 资助金额:
    $ 33.46万
  • 项目类别:
A Global Map of Interactions Among Human Cell Surface Proteins and Secreted Ligands
人类细胞表面蛋白和分泌配体之间相互作用的全局图
  • 批准号:
    10478763
  • 财政年份:
    2022
  • 资助金额:
    $ 33.46万
  • 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
  • 批准号:
    10176894
  • 财政年份:
    2018
  • 资助金额:
    $ 33.46万
  • 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
  • 批准号:
    9761520
  • 财政年份:
    2018
  • 资助金额:
    $ 33.46万
  • 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
  • 批准号:
    10197113
  • 财政年份:
    2018
  • 资助金额:
    $ 33.46万
  • 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
  • 批准号:
    10447202
  • 财政年份:
    2018
  • 资助金额:
    $ 33.46万
  • 项目类别:
Viral GPCR recognition of chemokines and engineered ligands
病毒 GPCR 识别趋化因子和工程配体
  • 批准号:
    9298587
  • 财政年份:
    2016
  • 资助金额:
    $ 33.46万
  • 项目类别:
Viral GPCR recognition of chemokines and engineered ligands
病毒 GPCR 识别趋化因子和工程配体
  • 批准号:
    9143553
  • 财政年份:
    2016
  • 资助金额:
    $ 33.46万
  • 项目类别:
Novel Interferons and small molecule enhancers of the interferon pathway
新型干扰素和干扰素途径的小分子增强剂
  • 批准号:
    8643869
  • 财政年份:
    2014
  • 资助金额:
    $ 33.46万
  • 项目类别:
Engineering of macrophage phagocytosis for cancer and stem cell immunotherapy
用于癌症和干细胞免疫治疗的巨噬细胞吞噬工程
  • 批准号:
    8687302
  • 财政年份:
    2014
  • 资助金额:
    $ 33.46万
  • 项目类别:

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