Clinical Trials for Imaging and Therapy

项目3摘要 所有用于癌症治疗的静脉注射的治疗剂所需的剂量都远远超过所需的剂量。 如果所有给药都被放置在肿瘤内；这些升高的剂量会导致血液中的高水平 最大限度地提高血液到组织的浓度梯度，使药物被动地穿过血管壁 进入肿瘤。很多次，尽管接近最大耐受量，但只有很小一部分的治疗性药物 药物可以到达药物最有效的内部肿瘤。克服形成的限制性障碍 通过阻止治疗剂渗透到实体肿瘤的肿瘤血管内皮细胞，我们 探索空泡泵送系统实现抗体药物精确输送的临床应用 结合物(ADC)和放射免疫疗法直接进入原发和转移性肿瘤。初步数据 支持我们方法的临床翻译，这将通过严格的临床前研究进一步探索 在项目1和2中的测试开发。这项努力的一部分将是将主要的CAVEOLA人性化- 靶向抗体。在项目3中，临床翻译将通过建立一个显著的缺失来逐步完成 人源化形式的靶向抗体(HAnnA1)与成像放射性核素的结合和毒性 随后以hAnnA1-ADC的形式进行新的化疗。该项目的具体目标是： 1)临床前评估，以支持IND备案，包括放射性标记抗体的毒理学和安全性测试 和非人灵长类动物体内的ADC；2)89Zr标记的hAnnA1在转移性肿瘤患者中的初步显像临床试验 实体瘤；3)新型小凹靶向hAnnA1-ADC的第一阶段剂量递增研究。人性化的 抗体将在核心B中生产，这也将负责放大和cGMP的生产 将用于临床试验的ADC。Core D将为临床成像试验生产放射性标记抗体。 核心E将为统计分析和转换/临床方案提供支持，包括设计、 从调查员发起的试验中收集和分析数据。

PROJECT 3 SUMMARY All therapeutic agents injected intravenously for cancer therapy require doses well in excess of that needed if all the administered drug was placed inside the tumors; these elevated doses create high blood levels to maximize the blood-to-tissue concentration gradient that drives the drug passively across the vascular wall and into the tumors. Many times, despite near maximal tolerated doses, only a very small fraction of the therapeutic agents reach the interior tumors where the drug can be most effective. To overcome the restrictive barrier formed by the tumor vascular endothelium that prevents therapeutic agents from penetrating into solid tumors, we are exploring the clinical utility of the caveolae-pumping system to enable precision delivery of antibody-drug conjugates (ADC) and radioimmunotherapies directly into primary and metastatic tumors. Preliminary data supports the clinical translation of our approach, which will be further explored with rigorous preclinical development in testing in Projects 1 and 2. Part of that effort will be the humanization of the lead caveola- targeting antibody. Here in Project 3, clinical translation will be done stepwise by establishing a lack of significant toxicity of the humanized form of the targeting antibody (hAnnA1) conjugated to an imaging radionuclide and subsequently to a novel chemotherapy in the form of hAnnA1-ADC. Specific Aims of this project are to conduct: 1) preclinical evaluations to enable IND filings, including toxicology and safety testing of the radiolabeled antibody and ADC in non-human primates; 2) pilot imaging clinical trial of 89Zr-labeled hAnnA1 in patients with metastatic solid tumors; and 3) Phase 1 dose escalation study of novel caveolae-targeting hAnnA1-ADC. The humanized antibody will be produced in Core B, that will also be responsible for the scale-up and cGMP production of the ADC that will be used in clinical trials. Core D will produce the radiolabeled antibody for the clinical imaging trial. Core E will provide support for the statistical analysis and translational/clinical protocols, including design, conduct collection and analysis of data, from the investigator-initiated trials.