Abstract 3706: Novel therapeutic strategy for pancreatic cancer with lectin drug conjugate (LDC): The efficacy and pilot safety test

Abstract

Abstract Background: We recently developed lectin-drug conjugate (LDC) for targeting pancreatic cancer specific glycan and showed potent anti-cancer effect both in vitro and in vivo (Osamu Shimomura et al., Molecular Cancer Therapeutics 2017). The additional evaluation of anti-cancer effects and the toxicity studies of LDC need to be clarified. Methods: LDC, rBC2LC-N lectin fused with 38 kDa of pseudomonas exotoxin (PE) A, was used in this study. We confirmed of the anti-cancer effect of LDC in orthotopic mouse models and developed dissemination mouse models to make sure of the survival benefits in LDC by both intra-peritoneally and intra-venously injection by log-rank test. We checked the damage of all organs pathologically after injection of the minimal or maximal tolerance doses and performed the blood sample analyses. Results: We have already validated the cytotoxic effect of LDC for PDAC cell lines in vitro i.e., IC50= 1.04 pico g/ml. Intraperitoneal and intravenous injection of LDC reduced tumor weight from 390 mg in normal saline group to 130.8 mg and 203 mg, respectively in the orthotopic models (P=0.001 and P=0.007, respectively), and improved median survival duration from 62 days to 105 and 90 days in the peritoneal dissemination models, respectively (P<0.0001 and P<0.0001, respectively). Intravenous injection of LDC conferred comparable therapeutic effects to intraperitoneal injection. Inconsistent with the apprehension that all lectins mediate harmful hemagglutination, the rBC2LC-N never caused hemagglutination with human erythrocytes in every blood types. The laboratory test after injection of therapeutic dose (1µg/mouse) of LDC showed no obvious abnormality except slightly elevation of aspartate and alanine aminotransferase. Surprisingly, no adverse event were observed after administration of rBC2LC-N lectins without PE up to 15 µg/mouse in wild type mice. Although some epithelial desquamations were revealed in the mucosa of the gut after fatal dose of LDC injection, we could not figure out the organ damage after the therapeutic dose of LDC injection pathologically. Conclusions: We show the successful in vivo application of a lectin for cancer treatment. Lectin itself did not cause severe adverse events and could be a potential candidate of a drug carrier, providing a new insight into anti-cancer drug development. Citation Format: Osamu Shimomura, Tatsuya Oda, Hiroaki Tateno, Yusuke Ozawa, Sota Kimura, Jun Hirabayashi, Nobuhiro Ohkohchi. Novel therapeutic strategy for pancreatic cancer with lectin drug conjugate (LDC): The efficacy and pilot safety test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3706.