Structural Surfaceomics: A Strategy for Immunotherapy Target Discovery

结构表面组学:免疫治疗靶点发现的策略

基本信息

  • 批准号:
    10290239
  • 负责人:
  • 金额:
    $ 20.32万
  • 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:
    2021-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Engineered cellular therapies, such as CAR-T cells, hold great promise as “living drugs”. However, the application of this approach beyond B-cell origin malignancies has been hampered by a lack of tumor-specific cell surface antigen targets. Current methods to identify new targets rely largely on expression patterns from RNA-seq data. However, the limitations of this transcriptome-based strategy have rapidly become apparent. We were struck by the recent serendipitous discovery of a tumor- specific surface antigen in the blood cancer multiple myeloma, amenable to CAR-T targeting, defined not by its expression but by its structural conformation compared to normal hematopoietic cells. The central hypothesis of this proposal is that many additional conformation-specific tumor antigens likely exist, across cancers, but currently there is no technology yet available to detect them. Here we aim to develop such a technology, combining our expertise in cell surface proteomics with crosslinking mass spectrometry, which we call “structural surfaceomics”. While this approach could be applied to any cancer, here we first explore acute myeloid leukemia (AML), a hematologic malignancy with poor clinical outcomes and a lack of highly-specific cell surface targets. In preliminary data, utilizing an initial version of the structural surfaceomics technology, we have already identified a novel conformation-specific antigen in AML that may be a promising therapeutic target. Here, we propose two Specific Aims: 1) Further development of the structural surfaceomics approach. Our preliminary protocol is restricted to highly-expressed surface antigens with sufficient lysine crosslinks to report on structural changes. To broaden applicability, we first aim to implement recently-described XL-MS strategies that can achieve much higher proteomic coverage. We will further assess the performance of our method using biochemical control of specific surface antigens, as well as profile additional AML lines for novel target discovery. 2) Development of novel CAR-T's targeting a conformation-specific AML antigen. We will generate CAR-T compatible binders both using a standard scFv approach, based on an existing murine antibody, as well as fully in vitro-selected nanobodies via yeast display. Our lab has recently demonstrated the latter strategy as a promising approach for cellular therapy in acute leukemia (Nix et al., in revision for Cancer Discovery). We will perform initial in vitro and in vivo validation of these cellular therapies. Overall, we anticipate developing an approach to identify an entirely new class of immunotherapy targets. Furthermore, we aim to demonstrate that our approach can nominate a promising cellular therapeutic candidate specific for AML. In future work, beyond this pilot funding, we anticipate applying structural surfaceomics to broader profiling of malignancies, as well as more complete preclinical validation of our AML conformation-targeting CAR-T's.
项目总结/摘要 工程细胞疗法,如CAR-T细胞,作为“活药物”有很大的希望。然而,在这方面, 这种方法在B细胞来源的恶性肿瘤之外的应用受到缺乏 肿瘤特异性细胞表面抗原靶标。目前识别新靶点的方法主要依赖于 来自RNA-seq数据的表达模式。然而,这种基于转录组的策略的局限性 迅速变得明显。我们被最近偶然发现的肿瘤所震惊- 血液癌症多发性骨髓瘤中的特异性表面抗原,适合CAR-T靶向,定义 不是通过其表达,而是通过其与正常造血细胞相比的结构构象。的 这一建议的中心假设是,许多额外的构象特异性肿瘤抗原可能 存在于各种癌症中,但目前还没有技术可以检测它们。我们的目标是 将我们在细胞表面蛋白质组学方面的专业知识与交联技术相结合, 我们称之为“结构表面组学”虽然这种方法可以应用于 对于任何癌症,在这里我们首先探讨急性髓系白血病(AML),这是一种恶性血液病,预后较差。 临床结果和缺乏高度特异性的细胞表面靶点。在初步数据中,利用 结构表面组学技术的初始版本,我们已经确定了一种新的 在AML中的构象特异性抗原,可能是一个有前途的治疗靶点。在此,我们建议 两个具体目标:1)进一步发展结构表面组学方法。我们的初步 该方案仅限于具有足够赖氨酸交联的高表达表面抗原, 结构变化。为了扩大适用性,我们首先旨在实现最近描述的XL-MS 可以实现更高的蛋白质组覆盖率的策略。我们将进一步评估 我们的方法使用特定表面抗原的生化控制,以及额外的AML谱 用于新目标发现的线路。2)靶向构象特异性配体的新型CAR-T的开发 AML抗原。我们将使用标准scFv方法产生CAR-T相容性结合物, 基于现有的鼠抗体,以及通过酵母展示的完全体外选择的纳米抗体。 我们的实验室最近证明了后一种策略是一种有前途的细胞治疗方法, 急性白血病(Nix等人,在癌症发现的修订版中)。我们将在体外和体内进行初步研究 这些细胞疗法的有效性。总的来说,我们期望开发一种方法来识别 全新的免疫治疗靶点此外,我们的目标是证明我们的方法 可以提名一个有前途的细胞治疗候选人的AML特异性。在今后的工作中, 试点资金,我们预计将结构表面组学应用于更广泛的恶性肿瘤分析, 以及我们的AML构象靶向CAR-T的更完整的临床前验证。

项目成果

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Arun P. Wiita其他文献

Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia
针对 CLL-1 的细胞免疫疗法用于幼年型粒单核细胞白血病
  • DOI:
    10.1038/s41467-025-59040-6
  • 发表时间:
    2025-04-23
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Juwita Werner;Alex G. Lee;Chujing Zhang;Sydney Abelson;Sherin Xirenayi;Jose Rivera;Khadija Yousuf;Hanna Shin;Bonell Patiño-Escobar;Stefanie Bachl;Kamal Mandal;Abhilash Barpanda;Emilio Ramos;Adila Izgutdina;Sibapriya Chaudhuri;William C. Temple;Shubhmita Bhatnagar;Jackson K. Dardis;Julia Meyer;Carolina Morales;Soheil Meshinchi;Mignon L. Loh;Benjamin Braun;Sarah K. Tasian;Arun P. Wiita;Elliot Stieglitz
  • 通讯作者:
    Elliot Stieglitz
Bladder cancer variants share aggressive features including a CA125+ cell state and targetable TM4SF1 expression
膀胱癌变异体具有侵袭性特征,包括 CA125+细胞状态和可靶向的 TM4SF1 表达
  • DOI:
    10.1038/s41467-025-59888-8
  • 发表时间:
    2025-06-17
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Heiko Yang;Hanbing Song;Elizabeth Yip;Timothy Gilpatrick;Kevin Chang;Paul Allegakoen;Kevin L. Lu;Keliana Hui;Julia H. Pham;Corynn Kasap;Vipul Kumar;Janae Gayle;Bradley A. Stohr;Chien-Kuang Cornelia Ding;Arun P. Wiita;Maxwell V. Meng;Jonathan Chou;Sima P. Porten;Franklin W. Huang
  • 通讯作者:
    Franklin W. Huang
Time-resolved proteomics vs. ribosome profiling reveals translation dynamics under stress
时间分辨蛋白质组学与核糖体分析揭示了压力下的翻译动态
  • DOI:
    10.1101/087486
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Tzu;Hector H. Huang;Diamond Wheeler;James A. Wells;Yun S. Song;Arun P. Wiita
  • 通讯作者:
    Arun P. Wiita
Tumour-wide RNA splicing aberrations generate actionable public neoantigens
肿瘤范围的 RNA 剪接异常产生可操作的公共新抗原
  • DOI:
    10.1038/s41586-024-08552-0
  • 发表时间:
    2025-02-19
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Darwin W. Kwok;Nicholas O. Stevers;Iñaki Etxeberria;Takahide Nejo;Maggie Colton Cove;Lee H. Chen;Jangham Jung;Kaori Okada;Senthilnath Lakshmanachetty;Marco Gallus;Abhilash Barpanda;Chibo Hong;Gary K. L. Chan;Jerry Liu;Samuel H. Wu;Emilio Ramos;Akane Yamamichi;Payal B. Watchmaker;Hirokazu Ogino;Atsuro Saijo;Aidan Du;Nadia R. Grishanina;James Woo;Aaron Diaz;Shawn L. Hervey-Jumper;Susan M. Chang;Joanna J. Phillips;Arun P. Wiita;Christopher A. Klebanoff;Joseph F. Costello;Hideho Okada
  • 通讯作者:
    Hideho Okada
DNA methyltransferase inhibitors upregulate CD38 protein expression and enhance daratumumab efficacy in multiple myeloma
DNA 甲基转移酶抑制剂上调多发性骨髓瘤中 CD38 蛋白表达并增强达雷木单抗疗效
  • DOI:
    10.1038/s41375-019-0587-5
  • 发表时间:
    2019-10-08
  • 期刊:
  • 影响因子:
    13.400
  • 作者:
    Priya Choudhry;Margarette C. Mariano;Huimin Geng;Thomas G. Martin;Jeffrey L. Wolf;Sandy W. Wong;Nina Shah;Arun P. Wiita
  • 通讯作者:
    Arun P. Wiita

Arun P. Wiita的其他文献

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{{ truncateString('Arun P. Wiita', 18)}}的其他基金

ClinTAD: A Tool for Improving Clinical CNV Interpretation
ClinTAD:改善临床 CNV 解读的工具
  • 批准号:
    10461112
  • 财政年份:
    2021
  • 资助金额:
    $ 20.32万
  • 项目类别:
Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy
利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效
  • 批准号:
    10308238
  • 财政年份:
    2021
  • 资助金额:
    $ 20.32万
  • 项目类别:
Structural Surfaceomics: A Strategy for Immunotherapy Target Discovery
结构表面组学:免疫治疗靶点发现的策略
  • 批准号:
    10434121
  • 财政年份:
    2021
  • 资助金额:
    $ 20.32万
  • 项目类别:
ClinTAD: A Tool for Improving Clinical CNV Interpretation
ClinTAD:改善临床 CNV 解读的工具
  • 批准号:
    10286951
  • 财政年份:
    2021
  • 资助金额:
    $ 20.32万
  • 项目类别:
Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy
利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效
  • 批准号:
    10341162
  • 财政年份:
    2018
  • 资助金额:
    $ 20.32万
  • 项目类别:
Exploiting myeloma proteome remodeling to extend proteasome inhibitor efficacy
利用骨髓瘤蛋白质组重塑来延长蛋白酶体抑制剂的功效
  • 批准号:
    10524110
  • 财政年份:
    2018
  • 资助金额:
    $ 20.32万
  • 项目类别:
In vivo monitoring of oxidative protein folding through time-resolved quantitative mass spectrometry
通过时间分辨定量质谱法体内监测氧化蛋白折叠
  • 批准号:
    9167306
  • 财政年份:
    2016
  • 资助金额:
    $ 20.32万
  • 项目类别:
Global Assessment of Myeloma Response to Chemotherapy
骨髓瘤化疗反应的整体评估
  • 批准号:
    8819976
  • 财政年份:
    2014
  • 资助金额:
    $ 20.32万
  • 项目类别:
Global Assessment of Myeloma Response to Chemotherapy
骨髓瘤化疗反应的整体评估
  • 批准号:
    8928081
  • 财政年份:
    2014
  • 资助金额:
    $ 20.32万
  • 项目类别:
Global Assessment of Myeloma Response to Chemotherapy
骨髓瘤化疗反应的整体评估
  • 批准号:
    9337420
  • 财政年份:
    2014
  • 资助金额:
    $ 20.32万
  • 项目类别:

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通过上调 HOX 基因靶向急性白血病中的 Menin
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