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中文摘要
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本申请的主要目的是进行新型双特异性抗体的初步临床测试 (bsMAb) 预靶向系统,使用 90Y 标记的肽来治疗结直肠癌。我们的 假设这项预靶向研究将能够增加递送到肿瘤的辐射剂量 与历史上直接放射性标记抗体所取得的成果进行比较。双特异性 本临床试验中使用的抗体是一种新型人源化重组 bsMAb,具有二价结合 癌胚抗原(CEA)用于肿瘤靶向和单价结合独特的化合物, 组胺-琥珀酰-甘氨酸(HSG)。该肽有 2 个 HSG 分子,有助于稳定 bsMAb 与肿瘤细胞表面结合时,单个 DOTA 部分适合结合 ''' 和 90Y。 该临床试验将寻求使用以下方法寻找预靶向 inIn/90Y 标记肽的最佳条件: 新型双特异性三体 (-81 kDa)。这些初步研究将检查几种剂量的 bsMAb 和 肽与bsMAb注射后在不同时间间隔给予的肽。 131I-bsMAb 已计划 用于帮助确定 bsMAb 的定位特性,每位患者都会收到一份 1HIn-和90Y-标记肽的组合。在最初的测试中,肽的90Y剂量将被固定 从而确定预定目标的参数。在试验的第一阶段部分,最佳 允许肽最大程度地肿瘤增生而正常组织增生最少的条件是 使用,但 90Y 放射性剂量将逐步增加以确定剂量限制毒性和 MTD。 在治疗后的几天内将对所有患者进行定量成像和药代动力学检查 放射性标记肽注射液可帮助评估可产生最高聚集量的条件 放射性标记的肽在肿瘤中,同时最大限度地减少正常组织的增生。抗抗体反应将 也可以测量人源化bsMAb。该临床试验将在福克斯蔡斯癌症中心进行 中心。
英文摘要
The primary objective of this application is to conduct the initial clinical testing of new bispecific antibody (bsMAb) pretargeting system that uses a90Y-labeled peptide for the treatment colorectal cancer. Our hypothesis is that this pretargeting study will be able to increase the radiation dose delivered to the tumor in comparison to what has historically been achieved with directly radiolabeled antibodies. The bispecific antibody used in this clinical trial is a novel humanized recombinant bsMAb with divalent binding to carcinoembryonic antigen (CEA) for tumor targeting and monovalent binding to a unique compound, histamine-succinyl-glycine (HSG). The peptide has 2 HSG molecules that aid in the stabilization of the bsMAb when bound to the tumor cell surface and a single DOTA moiety suitable for binding '' 'in and 90Y. The clinical trial will seek to find the optimal conditions for pretargeting the inIn/90Y-labeled peptide using the novel bispecific triabody (-81 kDa). These initial studies will examine several doses of the bsMAb and peptide with the peptide given at differing time intervals after the bsMAb injection. 131I-bsMAb is planned to be given to aid in determining the localization properties of the bsMAb, and each patient will receive a combination of the 1HIn- and90Y-labeled peptide. In the initial testing, the 90Y-dose of peptide will be fixed so that the parameters of pretargeting can be determined. In the Phase I portion of the trial, optimum conditions to allow maximum tumor accretion of the peptide with minimal normal tissue accretion will be used, but the 90Y-radioactivity dose will be escalated to determine the dose limiting toxicity and the MTD. Quantitative imaging and pharmacokinetics will be examined in all patients over several days following the radiolabeled peptide injection to aid in the assessment of conditions that will yield the highest accretion of radiolabeled peptide in the tumor, while minimizing normal tissue accretion. Anti-antibody responses will also be measured to the humanized bsMAb. This clinical trial will be conducted at the Fox Chase Cancer Center.
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