Bispecific Antibody Pretargeting for Therapy

双特异性抗体预靶向治疗

• 批准号: 7389001
• 负责人: Robert M Sharkey
• 金额: $ 51.26万
• 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/7389001
• 关键词: 90Y; Antibodies; Antibody Formation; Binding; Bispecific Antibodies; Carcinoembryonic Antigen; Cell surface; Clinical Research; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Condition; Data; Dose; Dose-Limiting; Drug Kinetics; Enrollment; Evaluation; Fox Chase Cancer Center; Glycine; Guanosine Monophosphate; Haptens; Histamine; Image; Immunoglobulin G; Injection of therapeutic agent; Label; Letters; Measures; Monitor; Normal tissue morphology; Nude Mice; Numbers; Patients; Peptides; Phase; Plasma; Preparation; Procedures; Property; Proteins; Radiation; Radioactivity; Radioimmunoconjugate; Radiolabeled; Recombinants; Safety; System; Testing; Time; Toxic effect; Xenograft procedure; base; day; dosage; follow-up; improved; medullary thyroid carcinoma; neoplastic cell; novel; preclinical study; radiotracer; research clinical testing; time interval; tumor

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.

本申请的主要目的是进行新型双特异性抗体的初步临床试验 （bsMAb）预靶向系统，其使用90 Y标记的肽用于治疗结直肠癌。我们 假设是，这种预靶向研究将能够增加递送到肿瘤的辐射剂量， 与历史上用直接放射性标记的抗体实现的比较。双特异性 在该临床试验中使用的抗体是一种新型人源化重组bsMAb，其具有与 用于肿瘤靶向和单价结合独特化合物的癌胚抗原（CEA）， 组胺琥珀酰甘氨酸（HSG）。该肽具有2个HSG分子，其有助于稳定肽。 bsMAb，当结合到肿瘤细胞表面时，和适合于结合90 Y的单个DOTA部分。 该临床试验将寻求找到使用以下方法预靶向inIn/90 Y标记的肽的最佳条件： 新的双特异性三抗体（~ 81 kDa）。这些初步研究将检查几种剂量的bsMAb， 肽与在bsMAb注射后不同时间间隔给予的肽。131 I-bsMAb计划 以帮助确定bsMAb的定位特性，并且每名患者将接受 1HIn-和90 Y-标记的肽的组合。在初始测试中，肽的90 Y剂量将被固定 从而可以确定预瞄准的参数。在试验的I期部分，最佳 允许肽的最大肿瘤增生和最小正常组织增生的条件将是 使用，但90 Y放射性剂量将递增，以确定剂量限制性毒性和MTD。 在给药后的几天内，将对所有患者进行定量成像和药代动力学检查。 放射性标记的肽注射，以帮助评估将产生最高的 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。这项临床试验将在福克斯蔡斯癌症中心进行。 中心