Bispecific Antibody Pretargeted Therapy of Pancreatic Cancer

描述(由申请人提供)：该项目将研究使用双特异性抗体(BsMAb)预靶向方法改善胰腺癌放射免疫治疗的可能性。我们之前已经展示了非常令人兴奋的数据，当90Y放射性标记并与吉西他滨结合时，胰腺癌特异性抗MUC1单抗PAM4显著增强了模仿人类等量剂量方案的吉西他滨方案的治疗效果。我们怀疑，由于预靶向方法可以将相似数量的放射性传递到肿瘤，但骨髓抑制较少，因此这种类型的靶向放射性核素的程序将被最终用于吉西他滨的临床应用。因此，这项工作的目标之一将是开发和测试使用带有90Y或177Lu标记的肽的PAM4 bsMAb的bsMAb预靶向程序。目标1包括旨在确定化学偶联F(ab‘)2xFab’或Fab‘xFab’PAM4 bsMAb的最佳靶向条件的研究。最佳的预靶向条件将基于生物分布和放射自显影方法。一旦优化，将评估预靶向程序在皮下和原位生长的CaPanl细胞系中的治疗潜力。将90Y-Lu和177Lu作为预靶向试剂，以及与直接放射性标记的PAM4抗体进行比较。将检查重复剂量和分次剂量。联合疗法将通过在标准吉西他滨方案中添加预靶向疗法进行测试，并评估基于EGFR的疗法(即西妥昔单抗和厄洛替尼)是否可以进一步增强这种联合。总体而言，这些研究将有助于确定这种类型的前靶向方法是否可以在胰腺癌的临床治疗中发挥作用。

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.