Bispecific Antibody Pretargeting for Therapy

描述（由申请人提供）：本申请的主要目的是对使用90y标记肽治疗结直肠癌的新型双特异性抗体（bsMAb）预靶向系统进行初步临床试验。我们的假设是，与历史上直接放射性标记抗体相比，这种预靶向研究将能够增加传递到肿瘤的辐射剂量。该临床试验中使用的双特异性抗体是一种新型的人源化重组bsMAb，它与癌胚抗原（CEA）二价结合用于肿瘤靶向，并与一种独特的化合物组胺-琥珀酰甘氨酸（HSG）单价结合。该肽具有2个HSG分子，当结合到肿瘤细胞表面时有助于bsMAb的稳定，并且单个DOTA片段适合结合111In和90Y。该临床试验将寻求使用新型双特异性三体（81 kDa）预先靶向111In/ 90y标记肽的最佳条件。这些初步研究将检查bsMAb和肽的几种剂量，在bsMAb注射后不同的时间间隔给予肽。计划给予131I-bsMAb以帮助确定bsMAb的定位特性，每位患者将接受111In和90y标记肽的组合。在初始测试中，将固定肽的90y剂量，以便确定预靶向的参数。在试验的I期部分，将使用允许肽的最大肿瘤增生和最小正常组织增生的最佳条件，但90y放射性剂量将逐步增加，以确定剂量限制毒性和MTD。定量成像和药代动力学将在所有患者注射放射标记肽后的几天内进行检查，以帮助评估在肿瘤中产生最高放射标记肽的条件，同时最大限度地减少正常组织的增生。对人源化bsMAb的抗抗体反应也将进行测定。这项临床试验将在福克斯蔡斯癌症中心进行。

DESCRIPTION (provided by applicant): The primary objective of this application is to conduct the initial clinical testing of new bispecific antibody (bsMAb) pretargeting system that uses a 90Y-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 111In and 90Y. The clinical trial will seek to find the optimal conditions for pretargeting the 111In/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 111In- and 90Y-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.