Improved Targeting Strategies

改进的目标策略

• 批准号: 6913344
• 负责人: Oliver W. Press
• 金额: $ 19.6万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913344
• 关键词: Macaca fascicularis; antitumor antibody; binding proteins; biotin; chimeric proteins; dosage; immunoconjugates; immunologic substance development /preparation; immunologic substance resource /registry /referral center; iodine; monoclonal antibody; neoplasm /cancer radioimmunotherapy; pharmacokinetics; radiation dosage; radionuclides; radiopharmacology; therapy design /development

We have demonstrated the feasibility and effectiveness of treating patients with relapsed leukemia and lymphoma with myeloablative doses of radiolabeled anti-CD20 and anti-CD45 monoclonal antibodies followed by autologous or allogeneic stem cell transplantation. Response rates to this therapy are high and many patients are cured. Despite these encouraging results, relapses still occur frequently and toxicities are substantial. In this Project we will investigate novel strategies to further improve the efficacy and diminish the toxicity of radioimmunotherapy by augmenting the amount of radioactivity delivered to tumor cells (by pretargeting with tetravalent fusion proteins) and by removing the proportion of radioisotope that fails to bind to tumor and remains in the bloodstream perfusing normal organs (by pretargeting or extracorporeal antibody adsorption). In Aim 1, we will evaluate the feasibility, safety, and toxicity of administering anti-CD20 lF5(scFv)4-streptavidin and anti-CD45 BC8(scFv)4-streptavidin fusion proteins to primates and will compare and contrast the pharmacokinetics and tissue penetration of the fusion proteins with those of directly radiolabeled anti-CD20 (1F5) and anti-CD45 (BC8) antibodies. In Aim 2, we will compare the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD20 1F5 (scFv)4-streptavidin and anti-CD45 BC8(scFv)4-streptavidin fusion proteins with the biodistributions and dosimetries of directly radiolabeled anti-CD20 1F5 and anti-CD45 BC8 Abs, respectively. In Aim 3 we will assess the impact of extracorporeal adsorption of circulating, radiolabeled anti-B cell and anti-myeloid radiolabeled antibodies on the pharmacokinetics, biodistribution and dosimetry of these radioimmunoconjugates in macaques. In Aim 4, we will generate and validate Master Cell Banks for the anti-CD20 lF5(scFv)4-streptavidin and the anti-CD45 BC8(scFv)4-streptavidin fusion proteins and produce, purify and characterize sufficient fusion protein under current good manufacturing practice (cGMP) conditions to conduct Phase I & II clinical trials in Projects 1 and 3. We hypothesize that pretargeting and EC AT will improve the delivery of radiation to tumor sites compared to normal tissues, thereby allowing us to escalate the tumor dose while maintaining well-defined, tolerable upper limits on the dose to critical normal organs. Based on the results of these studies, human clinical trials of pretargeting (and possibly ECAT) are planned in collaboration with Projects 1 and 3.

我们已经证明了患有髓质剂量的放射性标记抗CD20和抗CD45单克隆抗体，然后是自体或同种异体干细胞移植的患者的可行性和有效性。对该疗法的反应率很高，许多患者已治愈。尽管有这些令人鼓舞的结果，但复发仍然经常发生，毒性是实质性的。在该项目中，我们将研究新的策略，以进一步提高放射免疫疗法的毒性和降低放射性疗法的毒性，从而增加传递给肿瘤细胞的放射性量（通过用四腔融合蛋白进行预先定位），并通过消除无法与肿瘤的普通药物结合或脱离肿瘤的肿瘤（通过脱离肿瘤）的比例（吸附）。在目标1中，我们将评估抗CD20 LF5（SCFV）4-链霉亲和素和抗CD45 BC8（SCFV）4-链酸蛋白融合蛋白对灵长类动物的可行性，安全性和毒性，并将与这些f ipusim pripiation（直接）与这些药物渗透蛋白相比和对比，并将其与这些fiphipy protifion（直接）相比。和抗CD45（BC8）抗体。在AIM 2中，我们将比较使用抗CD20 1F5（SCFV）4-链霉亲和蛋白和抗CD45 BC8（SCFV）4-链霉亲和素的生物分布和剂量图。 直接标记抗CD20 1F5和抗CD45 BC8 ABS的生物分布和剂量分布的融合蛋白。在AIM 3中，我们将评估循环，放射标记的抗B细胞和抗乳状体放射性标记抗体对药代动力学的循环，放射标记的抗B细胞的影响，生物分布和剂量测量的这些放射性放射性抗体。在AIM 4中，我们将生成和验证抗CD20 LF5（SCFV）4-链酸蛋白酶和抗CD45 BC8（SCFV）4-链霉亲和素融合蛋白的抗CD20 LF5（SCFV）的主细胞库，并在目前的良好制造实践（CGMP）下进行临床II型临床，并生产，净化和生产，净化和表征足够的融合蛋白。与正常组织相比，EC将改善辐射到肿瘤部位的递送，从而使我们能够升级肿瘤剂量，同时维持对关键正常器官的剂量上定义明确，可耐受的上限。根据这些研究的结果，计划与项目1和3合作，计划了人类的预定性（可能是ECAT）的临床试验。