CD45 Pretargeted Radioimmunotherapy for AML

CD45 预靶向放射免疫疗法治疗 AML

• 批准号: 6815864
• 负责人: Oliver W. Press
• 金额: $ 50.49万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815864
• 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）：常规化学疗法仅治愈25-45％的新诊断为急性髓样白血病（AML）和<5％的复发AML患者。高剂量的化学放放疗法与同种异体干细胞移植（SCT）的新诊断AML的治疗率提高到50-60％，而复发AML的治疗率为20-30％，但是，很明显，需要改善治疗。我们的小组以前已经记录了将放射标记的抗CD45单克隆抗体（AB）纳入AML的SCT条件方案中的承诺，但是毒性仍然很高，新诊断的AML的治愈率仍然只有65％，使用直接使用AML的AML使用直接放射线radiolabel radiolabel的抗HCD45 AB和SCT。在此应用中，我们研究了一种新的方法，用于使用重组四链单链单链抗体-SA融合蛋白（SCFV）4SA进行AML提供AML，该方法针对人类HCD45（针对人HCD45），一种树枝状聚合物N-乙酰乳糖苷氨基乳酰胺氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基胺的“清除剂”和RadiolabeLabeLebeled-biotiCIN。假设这种多步抗CD45“预先定位”方法可以扩增传递给AML细胞的辐射量，减少传递给肝脏，肺部和其他正常器官的辐射量，并显着减弱与输注相关的毒性。在AIM 1中，我们将研究抗HCD45（SCFV）4SA融合蛋白的药代动力学和生物分布在白血病和SCID小鼠模型中白血病中的放射性生物素，并将比较生物分布，毒性，效率，效率，以及使用Pretimetries的prectionly 5 convention 5 condion 5比较。在AIM 2中，我们将使用AB和（SCFV）4SA融合蛋白在AIM 1中描述的方法进行AB和（SCFV）4SA融合蛋白在严格的，同步的鼠白血病模型中比较常规套件的相对优点，并在严格的，同步的鼠白血病模型中进行比较。以及非人类灵长类动物（猕猴）中的放射性植物素成分，使用串行定量伽马相机成像，血液采样，活检，放射性造影和尸检。在AIM 4中，我们将生成一个用于抗人CD45（SCFV）4SA融合蛋白的主细胞库，并生产，纯化和表征足够的材料，以启动AML中预处理方法的I和II期临床试验。我们假设，与常规RIT相比，该提案中定义的预先定义的策略将改善吸收辐射的肿瘤与正常器官比率，从而提高了比目前可行性的毒性较低的反应率和毒性较低的应答持续时间。我们预计这些临床前实验的结果可以快速地转换为我们的人类AML临床RIT计划。