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

 描述(申请人提供)：在过去的十年里，89Zr标记的抗体已经成为非常有希望用于癌症PET成像的试剂。然而，目前用于制造这些放射性药物的方法阻碍了它们发挥其最大的临床潜力。具体地说，合成这些结构的关键一步 是89Zr4+螯合剂去铁胺(DFO)的胺反应性双功能变体与抗体的赖氨酸结合物的偶联。然而，由于抗体的赖氨酸残基分布在其整个结构中，因此不可能控制偶联反应的分子位置或抗体上附着的螯合剂的数量。这种缺乏位点特异性的结果导致了定义不明确的、具有次佳免疫反应性和体内行为的异质结构。为了解决这些问题，我们开发了一种化学酶策略，用于定位抗体的放射性标记。这种方法可重复地产生均一的、定义明确的、稳定的和高度免疫活性的89Zr标记抗体，已被证明在体内表现出与目前临床使用的随机标记构建物相当-而且往往更好-的性能。这项合作方案描述了89Zr-SSDT的合成、临床前验证和人类首例临床翻译，89Zr-SSDT是一种用于HER2阳性转移性乳腺癌PET成像的定点标记的89Zr-DFO-曲妥珠单抗放射免疫结合物。这项工作的中心假设是，与目前临床使用的非部位特异性标记的89Zr-DFO-trastuzumab构建物相比，定位标记的89Zr-SSDT放射免疫结合物作为转移性乳腺癌的PET显像剂将表现出更好的性能。具体目标1，在获奖期的1-2年期间执行，将专注于在乳腺癌小鼠模型中合成、体外表征和体内研究两种不同的89Zr-SSDT结构，目的是确定最有希望用于临床翻译的单一89Zr-SSDT。具体目标2将在授权期的2-3年内执行，将集中于对89Zr-SSDT的体内毒理学和药理学的研究，以及准备和提交FDA临床试验的调查性新药申请。具体目标3的目标是在授权期的第3-5年执行，这将是89Zr-SSDT用于HER2阳性转移性乳腺癌的PET成像的首个人体临床试验。这项有20名患者参加的试验将集中于对89Zr-SSDT AS的临床安全性和有效性的评估。 以及相对于目前临床使用的非特异性放射性标记的89Zr-DFO-曲妥珠单抗的体内性能的测定。最终，我们相信，这项临床试验可能会对临床癌症治疗产生巨大影响，在短期内使乳腺癌患者能够进行更安全、更敏感和更有效的PET成像，并在长期帮助开创一个同质、定点标记的放射免疫结合物成为治疗标准的时代。

 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.