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Design and Activity of a Murine and Humanized Anti-CEACAM6 Single-Chain Variable Fragment in the Treatment of Pancreatic Cancer

¹ Arizona Cancer Center; ² Southern Arizona VA Medical Center, Tucson, Arizona; ³ TGen, Phoenix, Arizona; and ⁴ National Institute for Medical Research, London, United Kingdom

Requests for reprints: Daruka Mahadevan, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-4331; Fax: 520-626-2225; E-mail: dmahadevan{at}azcc.arizona.edu.

Key Words: Pancreatic carcinoma • Carcinoembryonic antigen cell adhesion molecule 6 • Anoikis resistance • Monoclonal antibody • Humanization

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, with surgery being the only curative modality for localized disease, and gemcitabine with or without erlotinib remains the standard of therapy for unresectable or metastatic disease. CEACAM6 is overexpressed in human PDA independent of stage or grade and causes anoikis resistance when dysregulated. Because murine monoclonal antibody 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed a humanized anti-CEACAM6 single-chain variable fragment (scFv) based on monoclonal antibody 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFvs bound CEACAM6 with high affinity, exhibited cytotoxic activity, and induced dose-dependent poly(ADP-ribose) polymerase cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition, which was enhanced in combination with gemcitabine. Immunohistochemistry showed significant apoptosis, with inhibition of angiogenesis and proliferation, and preservation of the target. Collectively, our results have important implications for the development of novel antibody-based therapies against CEACAM6 in PDA. [Cancer Res 2009;69(5):1933–40]