Bispecific Antibody Pretargeting for Therapy

双特异性抗体预靶向治疗

• 批准号: 7034913
• 负责人: Robert M Sharkey
• 金额: $ 12.22万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034913
• 关键词: antiantibody; antibody specificity; carcinoembryonal antigen; clinical research; clinical trial phase I; colorectal neoplasms; enzyme linked immunosorbent assay; human subject; human therapy evaluation; monoclonal antibody; neoplasm /cancer imaging; neoplasm /cancer radioimmunotherapy; neoplastic growth; patient oriented research; pharmacokinetics; radiation therapy dosage; radiotracer; recombinant proteins

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.

描述（由申请人提供）：本申请的主要目的是对新的双特异性抗体（BSMAB）的初步临床测试，该系统使用90Y标记的肽进行治疗结直肠癌。我们的假设是，与直接放射性标记抗体相比，这项有前途的研究将能够增加给肿瘤的辐射剂量。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，其与癌群抗原（CEA）的二价结合，用于靶向肿瘤，并与独特的化合物，组胺 - 核霉素基因基甘氨酸（HSG）结合。该肽具有2个HSG分子，可有助于与肿瘤细胞表面结合时BSMAB的稳定和一个适合结合111in和90Y的单个DOTA部分。该临床试验将寻求使用新型的双特异性三角体（81 kDa）来找到为111in/90y标记的肽预先定位111IN/90Y标记的肽的最佳条件。这些最初的研究将检查几剂BSMAB和肽，在BSMAB注射后以不同的时间间隔给出的肽。计划提供131i-BSMAB以帮助确定BSMAB的定位特性，每个患者将获得111in-和90y标记的肽的组合。在初始测试中，将固定90年剂量的肽，以便可以确定有限的参数。在试验的第一阶段部分中，将使用最大的条件，以最大程度地吸收肽，并使用最小的正常组织积聚，但是将升级90y-脱落性剂量以确定剂量限制毒性和MTD。放射标记肽注射后几天，将在所有患者的几天内检查定量成像和药代动力学，以帮助评估肿瘤中将产生最高积聚放射性标记肽的疾病，同时最大程度地减少正常组织。抗体反应也将测量到人源化的BSMAB。该临床试验将在Fox Chase癌症中心进行。