Engineered anti-PSCA antibodies for immunoPET and targeted therapy of pancreatic cancer

用于免疫PET和胰腺癌靶向治疗的工程化抗PSCA抗体

基本信息

  • 批准号:
    10544038
  • 负责人:
  • 金额:
    $ 71.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Pancreatic cancer remains among the most lethal of solid tumors, due to late diagnosis and a high probability of metastatic spread. Effective new systemic treatments are needed in order to improve outcomes in patients. Targeted radionuclide therapy has demonstrated effectiveness cancer therapy, notably with the success of 177Lu- dotatate in neuroendocrine tumors including those of the pancreas. Prostate Stem Cell Antigen (PSCA) is upregulated in 60-80% of pancreatic adenocarcinomas, making it a promising target for antibody-directed therapy. An engineered antibody fragment, the A2 scFv-Fc2 DM has been specifically designed for optimized delivery of therapeutic radionucides in pancreatic cancer. It is based on a humanized, high-affinity anti-PSCA antibody, and contains Fc mutations engineered to foster rapid blood clearance via the hepatobiliary route. As a result, radiation dose to key organs/tissues (bone marrow and kidney) is minimized, enabling effective delivery of an alpha- or beta-emitting radionuclide to tumors. In Aim 1, biodistribution studies will be undertaken in mouse models, in order to confirm the expected tumor targeting and hepatic clearance. Formal dose estimations will be made for the scFv-Fc2 DM radiolabeled with either 177Lu or 225Ac for therapy. Aim 2 will explore the potential efficacy of the anti-PSCA scFv-Fc2 DM in mouse models of pancreatic cancer, including subcutaneous xenografts of human pancreatic tumor cells, a syngeneic model of KPC-PSCA tumors in huPSCA knock-in mice, and patient-derived pancreatic tumor xenograft models. The relative efficacies and toxicities of the alpha-emitter 225Ac and beta-emitter 177Lu will be analyzed in order to prepare for future clinical therapy studies. In Aim 3, clinical production and conjugation of the anti-PSCA scFv-Fc2 DM will be performed, testing conducted, and an IND filed. Finally, in Aim 4 we will conduct a first-in-human imaging study using 64Cu-DOTA-anti-PSCA scFv- Fc2 DM in patients with advanced pancreatic cancer, to evaluate the targeting, and clearance properties and potential radiation dose delivery of this novel engineered antibody fragment. Results from this clinical immunoPET study will be central to guiding future development of a radioimmunotherapy agent that can be implemented in a theranostic approach to pancreatic cancer.
胰腺癌仍然是最致命的实体瘤之一,因为诊断较晚并且发生癌症的可能性很高。 转移性扩散。为了改善患者的预后,需要有效的新系统治疗。 靶向放射性核素治疗已证明癌症治疗的有效性,特别是 177Lu- dotatate 治疗神经内分泌肿瘤,包括胰腺肿瘤。前列腺干细胞抗原 (PSCA) 是 在 60-80% 的胰腺腺癌中表达上调,使其成为抗体导向的有希望的靶标 治疗。 A2 scFv-Fc2 DM 是一种工程化抗体片段,专为优化 在胰腺癌中输送治疗性放射性核素。它基于人源化、高亲和力的抗 PSCA 抗体,并含有 Fc 突变,旨在通过肝胆途径促进快速血液清除。作为一个 结果,对关键器官/组织(骨髓和肾脏)的辐射剂量降至最低,从而实现有效输送 α或β发射放射性核素对肿瘤的影响。在目标 1 中,将在小鼠中进行生物分布研究 模型,以确认预期的肿瘤靶向和肝脏清除。正式的剂量估计将是 用于用 177Lu 或 225Ac 放射性标记的 scFv-Fc2 DM 进行治疗。目标2将探索潜力 抗 PSCA scFv-Fc2 DM 在小鼠胰腺癌模型(包括皮下注射)中的功效 人胰腺肿瘤细胞的异种移植物,huPSCA 敲入小鼠中 KPC-PSCA 肿瘤的同基因模型, 和患者来源的胰腺肿瘤异种移植模型。 α发射体的相对功效和毒性 225Ac和β-发射体177Lu将被分析,以便为未来的临床治疗研究做好准备。在目标 3 中, 将进行抗 PSCA scFv-Fc2 DM 的临床生产和缀合,进行测试,并 IND 提交。最后,在目标 4 中,我们将使用 64Cu-DOTA-anti-PSCA scFv- 进行首次人体成像研究 Fc2 DM 在晚期胰腺癌患者中的作用,以评估靶向性和清除特性 这种新型工程抗体片段的潜在辐射剂量传递。本次临床结果 免疫PET研究对于指导放射免疫治疗剂的未来开发至关重要,该治疗剂可以 在胰腺癌的治疗诊断方法中实施。

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)

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 }}

Anna M Wu其他文献

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop
利用成像工具指导免疫治疗试验:美国国家癌症研究所癌症成像指导委员会研讨会总结
  • DOI:
    10.1016/s1470-2045(22)00742-2
  • 发表时间:
    2023-03-01
  • 期刊:
  • 影响因子:
    35.900
  • 作者:
    Lalitha K Shankar;Heiko Schöder;Elad Sharon;Jedd Wolchok;Michael V Knopp;Richard L Wahl;Benjamin M Ellingson;Nathan C Hall;Martin J Yaffe;Alexander J Towbin;Michael D Farwell;Daniel Pryma;Tina Young Poussaint;Chadwick L Wright;Lawrence Schwartz;Mukesh Harisinghani;Umar Mahmood;Anna M Wu;David Leung;Elisabeth G E de Vries;Steven A Reeves
  • 通讯作者:
    Steven A Reeves
Arming antibodies: prospects and challenges for immunoconjugates
武装抗体:免疫偶联物的前景与挑战
  • DOI:
    10.1038/nbt1141
  • 发表时间:
    2005-09-07
  • 期刊:
  • 影响因子:
    41.700
  • 作者:
    Anna M Wu;Peter D Senter
  • 通讯作者:
    Peter D Senter

Anna M Wu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('Anna M Wu', 18)}}的其他基金

Engineered anti-PSCA antibodies for immunoPET and targeted therapy of pancreatic cancer
用于免疫PET和胰腺癌靶向治疗的工程化抗PSCA抗体
  • 批准号:
    10343450
  • 财政年份:
    2022
  • 资助金额:
    $ 71.49万
  • 项目类别:
(PQC4) Imaging CD8 T Cells In Tumor Immunotherapy By Immunopet
(PQC4) 在肿瘤免疫治疗中对 CD8 T 细胞进行成像 Immunopet
  • 批准号:
    8928583
  • 财政年份:
    2014
  • 资助金额:
    $ 71.49万
  • 项目类别:
In vivo imaging of T Cells using engineered antibodies and PET
使用工程抗体和 PET 对 T 细胞进行体内成像
  • 批准号:
    8786848
  • 财政年份:
    2014
  • 资助金额:
    $ 71.49万
  • 项目类别:
(PQC4) Imaging CD8 T Cells In Tumor Immunotherapy By Immunopet
(PQC4) 在肿瘤免疫治疗中对 CD8 T 细胞进行成像 Immunopet
  • 批准号:
    8791842
  • 财政年份:
    2014
  • 资助金额:
    $ 71.49万
  • 项目类别:
Cancer Molecular Imaging
癌症分子成像
  • 批准号:
    7944543
  • 财政年份:
    2009
  • 资助金额:
    $ 71.49万
  • 项目类别:
Imaging Core
成像核心
  • 批准号:
    7315097
  • 财政年份:
    2007
  • 资助金额:
    $ 71.49万
  • 项目类别:
Recombinant Carcinoembronic Antigen as PET Reporter Gene
重组癌胚抗原作为 PET 报告基因
  • 批准号:
    7039880
  • 财政年份:
    2005
  • 资助金额:
    $ 71.49万
  • 项目类别:
Biological Modification of Quantum Dots for in vivo Imaging
用于体内成像的量子点的生物修饰
  • 批准号:
    7067899
  • 财政年份:
    2005
  • 资助金额:
    $ 71.49万
  • 项目类别:
High-avidity multimeric cancer imaging agent
高亲合力多聚体癌症显像剂
  • 批准号:
    6829532
  • 财政年份:
    2004
  • 资助金额:
    $ 71.49万
  • 项目类别:
High-avidity multimeric cancer imaging agent
高亲合力多聚体癌症显像剂
  • 批准号:
    6931073
  • 财政年份:
    2004
  • 资助金额:
    $ 71.49万
  • 项目类别:

相似海外基金

Alpha particles combined with ATR inhibition to activate the immune system: mechanisms and pre-clinical translation
Alpha 粒子结合 ATR 抑制激活免疫系统:机制和临床前转化
  • 批准号:
    10636348
  • 财政年份:
    2023
  • 资助金额:
    $ 71.49万
  • 项目类别:
Long range detection of alpha particles.
阿尔法粒子的远距离检测。
  • 批准号:
    ST/W005050/1
  • 财政年份:
    2022
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Training Grant
Elucidation of unusual nano-effects on dissolution, aggregation and denaturation processes of alpha particles generated by fuel debris retrieval
阐明燃料碎片回收产生的α粒子溶解、聚集和变性过程中异常纳米效应
  • 批准号:
    EP/X022218/1
  • 财政年份:
    2022
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Research Grant
Integrated modelling of burning plasmas with a reduced transport model for alpha particles
燃烧等离子体的集成建模与α粒子的简化传输模型
  • 批准号:
    15K18311
  • 财政年份:
    2015
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
SHINE: Self-Consistent Resonant-Cyclotron Heating of Protons and Alpha Particles in the Solar Wind and Solar Corona
SHINE:太阳风和日冕中质子和阿尔法粒子的自洽共振回旋加热
  • 批准号:
    1358103
  • 财政年份:
    2014
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Continuing Grant
Basic Study to evaluate DNA Damage and Cell Survival with Alpha-Particles from Astatine-211
使用 Astatine-211 的 α 粒子评估 DNA 损伤和细胞存活的基础研究
  • 批准号:
    26461866
  • 财政年份:
    2014
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Study of the alpha cluster gas-like state in 12C via the measurement of the multiple decay alpha particles
通过多次衰变α粒子的测量研究12C中的α团簇气态
  • 批准号:
    24740139
  • 财政年份:
    2012
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Theoretical study on dynamics of 12C synthesis through radiative capture reactions of three alpha-particles
三种α粒子辐射捕获反应合成12C动力学的理论研究
  • 批准号:
    24540261
  • 财政年份:
    2012
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Analysis of ripple resonance diffusion of alpha particles in burning plasma
燃烧等离子体中α粒子的波纹共振扩散分析
  • 批准号:
    21560856
  • 财政年份:
    2009
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
NSWP: Kinetic Turbulence-Driven Solar Wind Model Through the Resonant Cyclotron Interaction - Protons and Alpha Particles
NSWP:通过共振回旋加速器相互作用的动力学湍流驱动的太阳风模型 - 质子和阿尔法粒子
  • 批准号:
    0719738
  • 财政年份:
    2007
  • 资助金额:
    $ 71.49万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了