ANTI-PDZ DOMAIN ANTIBODIES ENHANCE THE EFFICACY OF RADIOTHERAPY

抗 PDZ 结构域抗体增强放射治疗的疗效

基本信息

  • 批准号:
    9198674
  • 负责人:
  • 金额:
    $ 21.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-19 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

Poor prognosis cancers including cancers of the lung and glioblastoma show robust overexpresion of Tax Interacting Protein-1 (TIP1). The proposed research is a novel approach to cancer drug development in which we target this chaperone protein that binds to signal transduction proteins that enhance cell viability following cytotoxic therapy. Stress responses in cancer cells are exaggerated over that of normal tissues. Examples are signal transduction pathways that include GRP78, PKC, PLC, Rho and others. Mechanisms by which these proteins dock on the plasma membrane in response to ionizing radiation include motor and scaffold proteins. One scaffold protein that caps the carboxyl terminus of plasma membrane-associated signaling proteins, TIP1 is overexpressed in cancer and translocates to the surface of the cell membrane of cancer cells following exposure to ionizing radiation. The functional domain of TIP1 is the PDZ binding domain which binds enzymes that regulate cell viability such as PLC, PKC, GPCR and Rho. Our preliminary data show that gene silencing of TIP1 and blocking antibodies that bind to the PDZ domain of TIP1 enhance radiation-induced cytotoxicity in cancer but not normal tissues. Anti-PDZ-domain antibodies injected into mice bearing irradiated lung cancer bind specifically to cancer and substantially enhance tumor growth delay over that of controls. We will study antibodies that enhance cytotoxity and improve tumor control. One mechanism by which the anti-PDZ domain antibodies enhance the efficacy of radiotherapy is through interruption of cell viability signal transduction pathways and subsequent programmed cell death specifically in cancer. We will compare antibody fragment (scFv) to whole IgG antibodies that bind to the PDZ domain of TIP1 and determine which antibodies achieve cancer specific binding and enhancement of the efficacy of radiotherapy in cancer without normal tissue toxicity. We will determine the lead human anti-TIP1 antibody fragment that achieves cancer specific binding and cytotoxicity in cancer cells. Our preliminary data show that assays which measure the interaction between anti-TIP1 antibodies and radiation include the clonogenic, and apoptosis assays. We will compare our lead antibodies that are specific to the PDZ domain on TIP1 to determine which is the most cancer specific and cytotoxic. We will determine the efficacy of anti-TIP1/PDZ IgG compared to anti-TIP1/PDZ scFv antibodies in mouse models of cancer. We will determine the role of immune effector cells in the cancer response to anti-TIP1 antibodies. We Hypothesize that IgG could further enhance the efficacy of radiotherapy by activating immune effector cells. We will study mouse models that lack Fc receptors and do not activate antibody mediated cancer cytotoxicity. These mouse models will allow us to determine whether the efficacy of the anti-TIP1 antibodies is a direct effect on cancer cells or whether immune effector cell activation contributes to the therapeutic effect.
包括肺癌和胶质母细胞瘤在内的预后不良的癌症显示出Tax的强烈过度表达 相互作用蛋白-1(TIP 1)。这项研究是癌症药物开发的新方法, 我们靶向这种伴侣蛋白,它与信号转导蛋白结合,增强细胞活力, 细胞毒疗法癌细胞中的应激反应比正常组织中的应激反应更夸张。实例是 信号转导途径包括GRP 78、PKC、PLC、Rho等。这些机制 响应电离辐射而停靠在质膜上的蛋白质包括马达蛋白和支架蛋白。 一种覆盖质膜相关信号蛋白TIP 1羧基末端的支架蛋白 在癌症中过表达,并在癌细胞死亡后易位至癌细胞膜表面。 暴露于电离辐射。TIP 1的功能结构域是结合酶的PDZ结合结构域 调节细胞活力的蛋白质如PLC、PKC、GPCR和Rho。我们的初步数据表明, TIP 1和与TIP 1的PDZ结构域结合的阻断抗体增强辐射诱导的细胞毒性, 癌细胞而不是正常组织。抗PDZ结构域抗体注射到携带放射性肺癌的小鼠中 与癌症特异性结合,并且与对照相比显著增强肿瘤生长延迟。我们将研究 增强细胞毒性和改善肿瘤控制的抗体。抗PDZ结构域的一种机制是 抗体增强放射治疗的疗效是通过中断细胞活力信号转导 途径和随后的程序性细胞死亡,特别是在癌症中。我们将比较抗体片段 在一些实施方案中,将抗体(scFv)与结合TIP 1的PDZ结构域的完整IgG抗体结合,并确定哪些抗体实现了与TIP 1的PDZ结构域的结合。 癌症特异性结合和增强无正常组织的癌症中的放射治疗的功效 毒性我们将确定实现癌症特异性结合的前导人抗TIP 1抗体片段, 对癌细胞的细胞毒性。我们的初步数据表明,测量抗TIP 1抗体与抗TIP 2抗体之间相互作用的测定法, 抗体和辐射包括克隆形成和凋亡测定。我们将比较我们的主要抗体, 特异于TIP 1上的PDZ结构域,以确定哪一个是最具癌症特异性和细胞毒性的。我们将确定 抗TIP 1/PDZ IgG与抗TIP 1/PDZ scFv抗体相比在小鼠癌症模型中的功效。我们将 确定免疫效应细胞在癌症对抗TIP 1抗体的反应中的作用。我们假设IgG 可以通过激活免疫效应细胞进一步增强放射治疗的功效。我们将研究小鼠模型 其缺乏Fc受体并且不激活抗体介导的癌细胞毒性。这些小鼠模型将使我们能够 为了确定抗TIP 1抗体的功效是否是对癌细胞的直接作用,或者是否是免疫抑制剂, 效应细胞活化有助于治疗效果。

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 }}

Sriram Devanathan其他文献

Sriram Devanathan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('Sriram Devanathan', 18)}}的其他基金

PEGYLATED PEPTIDES LIGANDS TARGETING RADIATION-INDUCIBLE RECEPTORS ON CANCER
靶向癌症辐射诱导受体的聚乙二醇化肽配体
  • 批准号:
    9038604
  • 财政年份:
    2016
  • 资助金额:
    $ 21.69万
  • 项目类别:

相似海外基金

University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
  • 批准号:
    10073243
  • 财政年份:
    2024
  • 资助金额:
    $ 21.69万
  • 项目类别:
    Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
  • 批准号:
    10752129
  • 财政年份:
    2024
  • 资助金额:
    $ 21.69万
  • 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
  • 批准号:
    2339201
  • 财政年份:
    2024
  • 资助金额:
    $ 21.69万
  • 项目类别:
    Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
    MR/Y008693/1
  • 财政年份:
    2024
  • 资助金额:
    $ 21.69万
  • 项目类别:
    Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
  • 批准号:
    10076445
  • 财政年份:
    2023
  • 资助金额:
    $ 21.69万
  • 项目类别:
    Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
  • 批准号:
    23K14783
  • 财政年份:
    2023
  • 资助金额:
    $ 21.69万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
  • 批准号:
    23KJ0394
  • 财政年份:
    2023
  • 资助金额:
    $ 21.69万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
  • 批准号:
    10639161
  • 财政年份:
    2023
  • 资助金额:
    $ 21.69万
  • 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
  • 批准号:
    10752441
  • 财政年份:
    2023
  • 资助金额:
    $ 21.69万
  • 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
  • 批准号:
    10867639
  • 财政年份:
    2023
  • 资助金额:
    $ 21.69万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了