Design and activity of a murine and humanized anti-CEACAM6 single-chain variable fragment in the treatment of pancreatic cancer.
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.
Riley
Christopher J
CJ
Arizona Cancer Center, Tucson, AZ 85724, USA.
Engelhardt
Kevin P
KP
Saldanha
Jose W
JW
Qi
Wenqing
W
Cooke
Laurence S
LS
Zhu
Yingting
Y
Narayan
Satya T
ST
Shakalya
Kishore
K
Croce
Kimiko Della
KD
Georgiev
Ivan G
IG
Nagle
Raymond B
RB
Garewal
Harinder
H
Von Hoff
Daniel D
DD
Mahadevan
Daruka
D
D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000276:immunology*; D045744:Cell Line, Tumor; D022801:Complementarity Determining Regions; D019281:Dimerization; D058851:GPI-Linked Proteins; D006801:Humans; D007128:Immunoglobulin Fragments / Q000627:therapeutic use*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000628:therapy*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D022801:Complementarity Determining Regions; D058851:GPI-Linked Proteins; D007128:Immunoglobulin Fragments; C055966:immunoglobulin Fv