CD45 Pretargeted Radioimmunotherapy for AML

CD45 预靶向放射免疫疗法治疗 AML

• 批准号: 6914974
• 负责人: Oliver W. Press
• 金额: $ 34.54万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914974
• 关键词: CD antigens; Macaca nemestrina; SCID mouse; acute myelogenous leukemia; antibody; athymic mouse; autoradiography; binding proteins; biopsy; biotin; cell bank /registry; cell line; chimeric proteins; neoplasm /cancer radioimmunotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; pharmacokinetics; postmortem; protein tyrosine phosphatase; radiation dosage; radiotracer; xenotransplantation; yttrium

DESCRIPTION (provided by applicant): Conventional chemotherapy cures only 25-45% of patients with newly diagnosed acute myeloid leukemia (AML) and <5% of patients with relapsed AML. High dose chemoradiotherapy with allogeneic stem cell transplantation (SCT) improves the rates of cure to 50-60% for newly diagnosed AML and 20-30% for relapsed AML, however, it is clear that improved therapy is needed. Our group has previously documented the promise of incorporating radiolabeled anti- CD45 monoclonal antibodies (Ab) into SCT conditioning regimens for AML, but toxicity remains high and cure rates are still only 65% for newly diagnosed AML and <30% for relapsed AML using directly radiolabeled anti-hCD45 Ab and SCT. In this application, we investigate a novel approach to delivering radioimmunotherapy (RIT) for AML using a recombinant tetravalent single chain antibody-SA fusion protein, (scFv)4SA, directed against human hCD45, a dendrimeric N-acetylgalactosamine-containing "clearing agent" and radiolabeled-DOTA-biotin. This multi-step anti- CD45 "pretargeting" approach is hypothesized to amplify the amount of radiation delivered to AML cells, decrease the amount of radiation delivered to the liver, lungs, and other normal organs, and markedly attenuate infusion-related toxicities. In Aim 1, we will investigate the pharmacokinetics and biodistributions of an anti-hCD45 (scFv)4SA fusion protein and radiobiotin in leukemia xenografts in athymic and SCID mouse models and will compare the biodistributions, toxicities, efficacies and dosimetries achieved with pretargeted RIT with those using conventional anti-CD45 RIT. In Aim 2, we will compare the relative merits of conventional KIT and pretargeted RIT in a rigorous, syngeneic murine leukemia model using an Ab and an (scFv)4SA fusion protein directed against murine mCD45 using the approaches described in Aim 1. In Aim 3, we will evaluate the safety, pharmacokinetics, and biodistributions of both the (scFv)4SA directed to hCD45 and the radiobiotin component in non-human primates (macaques), using serial quantitative gamma camera imaging, blood sampling, biopsies, radioautography, and necropsy. In Aim 4, we will generate a Master Cell Bank for the anti-human CD45 (scFv)4SA fusion protein and produce, purify and characterize sufficient material to initiate Phase I & II clinical trials of the pretargeting approach in AML. We hypothesize that the pretargeting strategies defined in this proposal will improve the tumor-to-normal organ ratios of absorbed radiation compared with conventional RIT, allowing improvement in response rates and response durations with less toxicity than is currently feasible. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for human AML.

描述（由申请人提供）：传统化疗只能治愈 25-45% 的新诊断急性髓性白血病 (AML) 患者，以及 <5% 的复发性 AML 患者。高剂量放化疗联合同种异体干细胞移植 (SCT) 可将新诊断的 AML 的治愈率提高至 50-60%，将复发的 AML 的治愈率提高至 20-30%，但显然需要改进治疗。我们的小组之前已经记录了将放射性标记的抗 CD45 单克隆抗体 (Ab) 纳入 AML 的 SCT 预处理方案中的前景，但毒性仍然很高，并且直接使用新诊断的 AML 的治愈率仍然仅为 65%，对于复发的 AML 的治愈率仍低于 30%放射性标记的抗 hCD45 Ab 和 SCT。在此应用中，我们研究了一种针对 AML 进行放射免疫治疗 (RIT) 的新方法，使用重组四价单链抗体-SA 融合蛋白 (scFv)4SA，针对人 hCD45（一种含有 N-乙酰半乳糖胺的树枝状“清除剂”）和放射性标记的-DOTA-生物素。假设这种多步骤抗CD45“预靶向”方法可以放大输送到AML细胞的辐射量，减少输送到肝脏、肺和其他正常器官的辐射量，并显着减弱输注相关的毒性。在目标 1 中，我们将研究抗 hCD45 (scFv)4SA 融合蛋白和放射性生物素在无胸腺和 SCID 小鼠模型的白血病异种移植物中的药代动力学和生物分布，并将使用预靶向 RIT 实现的生物分布、毒性、功效和剂量与预靶向 RIT 实现的生物分布、毒性、功效和剂量进行比较。使用常规抗CD45 RIT。在目标 2 中，我们将使用目标 1 中描述的方法，使用针对小鼠 mCD45 的 Ab 和 (scFv)4SA 融合蛋白，在严格的同基因小鼠白血病模型中比较传统 KIT 和预靶向 RIT 的相对优点。 在目标 3 中，我们将评估针对 hCD45 的 (scFv)4SA 和放射性生物素成分的安全性、药代动力学和生物分布非人类灵长类动物（猕猴），使用连续定量伽玛相机成像、血液采样、活组织检查、放射自显影和尸检。在目标 4 中，我们将为抗人 CD45 (scFv)4SA 融合蛋白生成主细胞库，并生产、纯化和表征足够的材料，以启动 AML 预靶向方法的 I 期和 II 期临床试验。我们假设，与传统 RIT 相比，本提案中定义的预靶向策略将提高吸收辐射的肿瘤与正常器官的比率，从而提高响应率和响应持续时间，同时毒性比目前可行的更低。我们预计这些临床前实验的结果将快速转化为人类 AML 的临床 RIT 计划。