Bispecific Antibody Pretargeted Therapy of Pancreatic Cancer

双特异性抗体靶向治疗胰腺癌

• 批准号: 7253359
• 负责人: Robert M Sharkey
• 金额: $ 31.9万
• 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: 2006-06-28 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253359
• 关键词: 90Y; Acute; Age; Animals; Antibodies; Antigen Targeting; Autoradiography; Biodistribution; Bispecific Antibodies; CA-15-3 Antigen; Cancer cell line; Cell Line; Cetuximab; Cetuximab/Gemcitabine; Chronic; Clinical; Clinical Management; Clinical Research; Colon; Combined Modality Therapy; Condition; Data; Doctor of Philosophy; Dose; Dose-Limiting; Enrollment; Epidermal Growth Factor Receptor; Erlotinib; Gallbladder; Genus Cola; Goals; Human; Immunoglobulin G; In Vitro; Label; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Methods; Modeling; Monoclonal Antibodies; Mus; Myelosuppression; Nude Mice; Organ; Outcome; Pancreas; Patients; Peptides; Preclinical Testing; Procedures; Property; Radiation; Radioactivity; Radioimmunotherapy; Radioisotopes; Radiolabeled; Research Design; Role; Safety; Standards of Weights and Measures; Swiss Mice; System; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Treatment Protocols; United States National Institutes of Health; Weight; Work; Xenograft procedure; base; experience; gemcitabine; human tissue; implantation; improved; in vivo; interest; novel; preclinical study; radiotracer; response; size; tumor; uptake; urinary

DESCRIPTION (provided by applicant): This project will examine the potential for improving radioimmunotherapy of pancreatic cancer using a bispecific antibody (bsMAb) pretargeting approach. We have previously shown very exciting data that pancreatic cancer specific anti-MUC1 MAb, PAM4, when radiolabeled with 90Y and combined with gemcitabine significantly enhanced the therapeutic effects of a gemcitabine regimen modeled after a human equivalent dosing regimen. We suspect that because pretargeting approaches can deliver similar amounts of radioactivity to tumors, but with less myelosuppression, that this type of procedure for targeting radionuclides would be preferred for eventual clinical use with gemcitabine. Therefore, one of the goals of this work will be to develop and test a bsMAb pretargeting procedure using PAM4 bsMAb with a 90Y or 177Lu- labeled peptide. AIM 1 includes studies designed to determine optimal targeting conditions for chemically conjugate F(ab')2 x Fab' or Fab' x Fab' PAM4 bsMAb. The optimal pretargeting conditions will be based on biodistribution and autoradiographic methods. Once optimized, the pretargeting procedures will be assessed for their therapeutic potential in the CaPanl cell line grown subcutaneously and orthotopically. Comparisons will be made between 90Y- and 177Lu as pretargeted agents, as well as to the directly radiolabeled PAM4 IgG. Repeat and fractionated doses will be examined. Combinational therapies will be tested using pretargeting added to a standard gemcitabine regimen, as well as assessing whether EGFR-based therapies (i.e., cetuximab and erlotinib) can further enhance this combination. Overall, these studies will assist in establishing whether this type of pretargeting approach could have a role in the clinical management of pancreatic cancer.

描述（由申请人提供）：该项目将使用双特异性抗体（BSMAB）预定的方法来研究改善胰腺癌的放射免疫疗法的潜力。先前，我们已经显示出非常令人兴奋的数据表明，胰腺癌特异性抗MUC1 MAB PAM4，当放射性标记为90年并与吉西他滨结合起来，显着增强了以人等剂量剂量剂量建模的吉西他滨方案的治疗作用。我们怀疑，由于预先定位的方法可以给肿瘤提供相似数量的放射性，但是由于骨髓抑制较少，因此最终，靶向放射性核素的这种类型的靶向放射性核素是最终与吉西他滨一起使用的方法。因此，这项工作的目标之一将是使用带有90Y或177lu标记的肽的PAM4 BSMAB开发和测试BSMAB预示程序。 AIM 1包括旨在确定化学结合F（AB'）2 X Fab'或Fab'X Fab'Pam4 BSMAB的最佳靶向条件的研究。最佳预定条件将基于生物分布和放射自显影方法。一旦优化，将在皮下和原位上生长的Capanl细胞系中评估其预先试验程序的治疗潜力。比较将在90y-和177lu之间作为预先定位的剂以及直接标记的PAM4 IgG进行比较。将检查重复和分级剂量。组合疗法将使用添加到标准的吉西他滨方案中的预先定位进行测试，并评估基于EGFR的疗法（即Cetuximab和Erlotinib）是否可以进一步增强这种组合。总体而言，这些研究将有助于确定这种有限的方法是否可以在胰腺癌的临床管理中发挥作用。