Bispecific Antibody Pretargeting for Therapy

这项应用的主要目的是进行新的双特异性抗体的初步临床测试。 (BsMAb)使用90Y标记的多肽治疗结直肠癌的预靶向系统。我们的 假设这项预靶向研究将能够增加肿瘤的辐射剂量 与历史上用直接放射性标记抗体所取得的成就进行比较。双特异型 本临床试验中使用的抗体是一种新型人源化重组bsMAb，与 用于肿瘤靶向和与独特化合物的单价结合的癌胚抗原(CEA)， 组胺琥珀酰甘氨酸(HSG)。该多肽具有2个HSG分子，有助于稳定 BsMAb结合到肿瘤细胞表面时，以及适合结合In和90Y的单个DOTA部分。 这项临床试验将寻求找到使用Inin/90Y标记的多肽进行预靶向的最佳条件 新的双功能三胞体(-81 kDa)。这些初步研究将检查几种剂量的bsMAb和 在注射bsMAb后以不同的时间间隔给药的多肽。计划进行131I-bsMAb 以帮助确定bsMAb的定位属性，每个患者将收到一份 1HIn和90Y标记的多肽的组合。在最初的测试中，90Y剂量的多肽将是固定的 从而可以确定预定向的参数。在试验的第一阶段，最佳 以最小的正常组织生长最大限度地促进肿瘤生长的条件是 使用，但90Y放射性剂量将升级，以确定剂量限制毒性和MTD。 在接下来的几天里，将对所有患者进行定量成像和药代动力学检查 放射性标记多肽注射剂，以帮助评估将产生最高吸光度的条件 肿瘤中的放射性标记多肽，同时最大限度地减少正常组织的生长。抗抗体反应将 也被测量到人性化的bsMAb。这项临床试验将在福克斯·蔡斯癌症中心进行 中心。

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.