Design and activity of a murine and humanized anti-CEACAM6 single-chain variable fragment in the treatment of pancreatic cancer

Christopher J. Riley, Kevin P. Engelhardt, Jose W. Saldanha, Wenqing Qi, Laurence S. Cooke, Yingting Zhu, Satya T. Narayan, Kishore Shakalya, Kimiko Delia Croce, Ivan G. Georgiev, Raymond C. Nagle, Harinder D. Garewal, Daniel D. Von Hoff, Daruka Mahadevan

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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. PEGyIation 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 anti-body-based therapies against CEACAM6 in PDA. fCaHBBFfles.

Original languageEnglish (US)
Pages (from-to)1933-1940
Number of pages8
JournalCancer Research
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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