Research on the development of antibody therapeutics to increase the survival rate of pancreatic cancer patients

Abstract

Pancreatic cancer is difficult to be recognized, because there are no symptoms in its early stages. In most cases, after being diagnosed with pancreatic cancer, the survival rate is very low because of its metastasis to other organs. If antibodies that specifically bind to pancreatic cancer are found, it is premised that antibody-therapeutic conjugates can be created only for certain cancer cells and used for treatment. Therefore, the goal is to identify patient-derived antibodies, and create new customized antibody therapy through specific antigen-antibody binding of tumors. An antibody (scFv) library is created using pDR-D1 (phagemid vector) from the blood obtained from 10 pancreatic cancer patients, and an antibody library is screened using the phage display technology to select antibody clones that specifically bind to the cancer cell. The selected scFv candidates were cloned into pDR-OriP-Fc1 (mammalian cassette vector) as an expression vector. HEK 293E cells were used to express scFv-Fc and tested for binding to pancreatic cancer cells through FACS. As a result, we screened antibodies that strongly bind to PANC-1, a human pancreatic cancer cell line isolated from a pancreatic carcinoma of ductal cell origin. [38] In addition, it was confirmed that the selected antibodies also bound to breast cancer, lung cancer, colon cancer, and ovarian cancer cell lines. The selected antibody is used for immunoprecipitation with pancreatic cancer cells to identify antigen through LC-MS/MS. After siRNA to knockdown of the candidate antigen, altered antibody binding was monitored by FACS. The difference in antigen-antibody binding after candidate gene knockdown was confirmed by FACS analysis. The most promising genes for antigens are MUC5AC, LARP7, DSP, SERPINA4, and GRPEL1. Once the antigen for the selected antibody binds is confirmed, its antitumor effect will be examined in patient-derived heterogeneous transplant (PDX) model by antibody monotherapy or combinatory immunotherapy. Our study suggests that antibodies selected from the pancreatic cancer patient can be used as a therapeutic agent for the treatment of pancreatic cancer.