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The Clinical PET Imaging of Metastatic Breast Cancer with Site-Specifically Labeled 89Zr-Trastuzumab

使用位点特异性标记的 89Zr-曲妥珠单抗对转移性乳腺癌进行临床 PET 成像

基本信息

批准号：
9884743
负责人：
Jason S. Lewis
金额：
$ 68.4万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884743
关键词：
Acute Address Amines Antibodies Award Behavior Biodistribution Breast Cancer Model Breast Cancer Patient Chelating Agents Clinic Clinical Clinical Trials Collaborations Colorectal Cancer Coupling Data Deferoxamine Discipline of Nuclear Medicine Disease ERBB2 gene Exhibits Goals Human Image Immunoconjugates Impairment In Vitro Investigation Investigational New Drug Application Label Lead Leadership Location Lysine Malignant neoplasm of pancreas Metastatic breast cancer Methodology Methods Molecular Mus Patient imaging Patient-Focused Outcomes Patients Performance Pharmacology Study Pharmacology and Toxicology Polysaccharides Positron-Emission Tomography Preparation Procedures Production Radioimmunoconjugate Radiolabeled Radiopharmaceuticals Reaction Research Running Safety Series Signal Transduction Site Specificity Structure Technology Thinking Tissues Trastuzumab Validation Variant Work Xenograft procedure antibody conjugate antigen antibody binding base cancer care cancer imaging clinical care clinical translation design experimental study first-in-human imaging agent immunoreactivity improved in vivo malignant breast neoplasm mouse model novel pre-clinical preclinical evaluation prevent prostate cancer model public health relevance radiotracer research clinical testing standard of care sugar tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Over the past ten years, 89Zr-labeled antibodies have emerged as extremely promising agents for the PET imaging of cancer. However, the current methodology used to create these radiopharmaceuticals prevents them from reaching their maximum clinical potential. Specifically, a crucial step in the synthesis of these constructs is the coupling of an amine-reactive, bifunctional variant of the 89Zr4+ chelator desferrioxamine (DFO) to the lysine conjugates of the antibody. Yet because antibodies have lysine residues distributed throughout their structure, it is impossible to control the molecular location of the conjugation reaction or the number of chelators attached to the antibody. This lack of site-specificity results in poorly defined, heterogeneous constructs with suboptimal immunoreactivity and in vivo behavior. To address these issues, we have developed a chemoenzymatic strategy for the site-specific radiolabeling of antibodies. This approach reproducibly creates homogenous, well-defined, stable, and highly immunoreactive 89Zr-labeled antibodies that have been shown to exhibit in vivo performance comparable - and often superior - to the randomly-labeled constructs currently employed in the clinic. This collaborative proposal describes the synthesis, preclinical validation, and first-in-human clinical translation of 89Zr-SSDT, a site-specifically labeled 89Zr-DFO-trastuzumab radioimmunoconjugate for the PET imaging of HER2-positive metastatic breast cancer. The central hypothesis of this work is that a site-specifically labeled 89Zr-SSDT radioimmunoconjugate will exhibit improved performance as a PET imaging agent for metastatic breast cancer compared to the non-site- specifically labeled 89Zr-DFO-trastuzumab construct currently employed in the clinic. Specific Aim 1, executed during Years 1-2 of the award period, will be focused on the synthesis, in vitro characterization, and in vivo investigation of two, different 89Zr-SSDT constructs in murine models of breast cancer, with the aim of identifying the single most promising 89Zr-SSDT for clinical translation. Specific Aim 2, executed during Years 2-3 of the award period, will be centered on the study of the in vivo toxicology and pharmacology of 89Zr-SSDT as well as the preparation and submission of an FDA Investigational New Drug application for the clinical trial. The goal of Specific Aim 3, executed during Years 3-5 of the award period, will be the first-in-human clinical trial of 89Zr-SSDT for the PET imaging of HER2-positive metastatic breast cancer. This 20-patient trial will be focused on the evaluation of the clinical safety and efficacy of 89Zr-SSDT as well as the determination of its in vivo performance relative to the non-site-specifically radiolabeled 89Zr-DFO-trastuzumab currently employed in the clinic. Ultimately, we believe that this clinical trial could have a tremendous impact on clinical cancer care, in the near term enabling safer, more sensitive, and more effective PET imaging of breast cancer patients and in the long term helping to usher in an era in which homogenous, site-specifically labeled radioimmunoconjugates become the standard of care.

描述（由申请人提供）：在过去的十年中，89 Zr标记的抗体已经成为非常有前途的癌症PET成像试剂。然而，目前用于生产这些放射性药物的方法阻止了它们达到最大的临床潜力。具体来说，合成这些结构的关键步骤是89 Zr 4+螯合剂去铁胺（DFO）的胺反应性双功能变体与抗体的赖氨酸缀合物的偶联。然而，由于抗体具有分布在其整个结构中的赖氨酸残基，因此不可能控制缀合反应的分子位置或附着于抗体的螯合剂的数量。这种位点特异性的缺乏导致定义不明确的异质构建体具有次优的免疫反应性和体内行为。为了解决这些问题，我们已经开发了一种化学酶策略，用于抗体的位点特异性放射性标记。这种方法可重复地产生同质的、明确定义的、稳定的和高度免疫反应性的89 Zr标记的抗体，其已显示出与目前临床中使用的随机标记的构建体相当的并且通常上级的体内性能。该合作提案描述了89 Zr-SSDT的合成、临床前验证和首次人体临床翻译，89 Zr-SSDT是一种位点特异性标记的89 Zr-DFO-曲妥珠单抗放射免疫偶联物，用于HER 2阳性转移性乳腺癌的PET成像。这项工作的中心假设是，位点特异性标记的89 Zr-SSDT放射免疫缀合物与目前临床上使用的非位点特异性标记的89 Zr-DFO-曲妥珠单抗构建体相比，作为转移性乳腺癌的PET成像剂将表现出改善的性能。具体目标1，在奖励期的第1-2年期间执行，将专注于两种不同的89 Zr-SSDT构建体在乳腺癌小鼠模型中的合成，体外表征和体内研究，目的是确定最有前途的89 Zr-SSDT用于临床转化。具体目标2，在奖励期的第2-3年执行，将集中在89 Zr-SSDT的体内毒理学和药理学研究以及临床试验的FDA研究新药申请的准备和提交。在奖励期的第3-5年执行的具体目标3的目标将是89 Zr-SSDT用于HER 2阳性转移性乳腺癌PET成像的首次人体临床试验。这项20名患者的试验将重点评估89 Zr-SSDT的临床安全性和有效性，以及确定其相对于目前临床上使用的非位点特异性放射性标记的89 Zr-DFO-曲妥珠单抗的体内性能。最终，我们相信这项临床试验可能对临床癌症护理产生巨大影响，在短期内使乳腺癌患者的PET成像更安全，更灵敏，更有效，从长远来看，有助于开创一个时代，在这个时代中，同质的，位点特异性标记的放射免疫缀合物成为护理标准。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Click Here for Better Chemistry.

DOI：
10.1056/nejmcibr2213596
发表时间：
2022-12-15
期刊：
NEW ENGLAND JOURNAL OF MEDICINE
影响因子：
158.5
作者：
Zeglis, Brian M.;Lewis, Jason S.
通讯作者：
Lewis, Jason S.

A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89.

DOI：
10.1021/acs.inorgchem.0c01629
发表时间：
2020-08-17
期刊：
Inorganic chemistry
影响因子：
4.6
作者：
Sarbisheh EK;Salih AK;Raheem SJ;Lewis JS;Price EW
通讯作者：
Price EW

Clinical Potential of Human Epidermal Growth Factor Receptor 2 and Human Epidermal Growth Factor Receptor 3 Imaging in Breast Cancer.

DOI：
10.1016/j.cpet.2018.02.010
发表时间：
2018-07
期刊：
PET clinics
影响因子：
2.6
作者：
Henry KE;Ulaner GA;Lewis JS
通讯作者：
Lewis JS

A brief overview of metal complexes as nuclear imaging agents.

作为核显像剂的金属配合物的简要概述。

DOI：
10.1039/c9dt03039e
发表时间：
2019
期刊：
Dalton transactions (Cambridge, England : 2003)
影响因子：
0
作者：
MacPherson,DouglasS;Fung,Kimberly;Cook,BrendonE;Francesconi,LynnC;Zeglis,BrianM
通讯作者：
Zeglis,BrianM

Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CT.

使用 HER2 靶向 89Zr-帕妥珠单抗 PET/CT 鉴定 HER2 阴性原发性乳腺癌患者的 HER2 阳性转移灶。

DOI：
10.1148/radiol.2020192828
发表时间：
2020
期刊：
Radiology
影响因子：
19.7
作者：
Ulaner,GaryA;Carrasquillo,JorgeA;Riedl,ChristopherC;Yeh,Randy;Hatzoglou,Vaios;Ross,DaraS;Jhaveri,Komal;Chandarlapaty,Sarat;Hyman,DavidM;Zeglis,BrianM;Lyashchenko,SergeK;Lewis,JasonS
通讯作者：
Lewis,JasonS