薬剤運搬に適した腫瘍標的化抗体のスクリーニング法と創薬シーズ開発

抄録

  Establishment of a system that allows selective drug delivery and gene silencing to a tumor is expected to enable targeted therapy. We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33 (Adv-FZ33). By cross-linking the Adv-FZ33 virus and the surface antigen molecules with the targeting monoclonal antibodies (mAbs), we attained highly enhanced gene deliveries into the respective antigen-positive cancer cells. Therefore, we aimed to establish a systematic screening method to search for antibody and cell surface target candidates that would provide highly selective anti-cancer reagents to malignant tumors. Using an Adv-FZ33, hybridoma libraries producing a variety of mAbs for human pancreatic, prostate, lung or ovarian carcinoma cells were screened, and we were able to selectively obtain several mAbs which had potent high affinity and recognized antigens of high structure. Within these mAbs, we have identified tumor cell target molecules including not only carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), prostate specific membrane antigen (PSMA) but also novel tumor surface target molecules such as phosphatidic acid phosphatase type 2a (PAP2a) and interleukin-13 receptor variant α2 (IL-13Rα2) as tumor antigens. Overall, these results indicate that this type of inductive method approach is a reliable strategy for screening in antibody therapy on par with antibody-dependent drug-delivery system.