Design and Activity of a Murine and Humanized anti-CEACAM6 scFv in the Treatment of Pancreatic Cancer

摘要

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with surgery the only curative modality for localized disease; gemcitabine with or without erlotinib remains standard therapy for unresectable or metastatic disease. CEACAM6 is over-expressed in human PDA independent of stage or grade, and causes anoikis resistance when dysregulated. Because murine Mab 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed humanized anti-CEACAM6 single chain variable fragments (scFv’s) based on Mab 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFv’s bound CEACAM6 with high affinity, exhibited cytotoxic activity and induced dose-dependent PARP-cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition (TGI), which was enhanced in combination with gemcitabine. Immunohistochemistry (IHC) showed significant apoptosis, with inhibition of angiogenesis and proliferation, with preservation of the target. Collectively, our results have important implications for development of novel antibody-based therapies against CEACAM6 in PDA.