Targeted delivery and enhanced cytotoxicity of cetuximab-saporin by photochemical internalization in EGFR-positive cancer cells.
Photochemical internalization (PCI) is a novel technology of macromolecular delivery. By PCI, endocytosed membrane-impermeable therapeutic drugs are photochemically released from entrapment in endo-lysosomal compartments to the cytosol of target cells. In the present report, we describe the in vitro proof-of-concept for PCI of cetuximab-saporin, an immunotoxin targeting EGFR-expressing cells. This immunotoxin consists of the chimeric murine-human IgG1 monoclonal antibody cetuximab (C225 or Erbitux) bound to the type I ribosome-inactivating protein toxin saporin by a biotin-streptavidin linkage. The photochemical treatment enhanced the cytotoxicity of the immunotoxin in a synergistic manner in three different EGFR-expressing carcinoma cell lines derived from different tumor tissues (colorectal, HCT-116; prostate, DU-145; and epidermis, A-431). Both cytotoxicity of cetuximab-saporin and epifluorescence of Alexa488-cetuximab were evaluated by competition with cetuximab demonstrating specific binding and uptake of cetuximab-saporin in EGFR positive cells. In the EGFR-negative uterine sarcoma cell line MES-SA, neither binding nor preferential accumulation of Alexa488-cetuximab was detected. In addition, PCI enhanced the cytotoxicity of cetuximab-saporin to the same extent as streptavidin-saporin in the MES-SA cells. In conclusion, PCI enhances selectivity of the cytotoxicity of the immunotoxin cetuximab-saporin in EGFR-expressing cells.
Yip
Wai Lam
WL
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
Weyergang
Anette
A
Berg
Kristian
K
Tønnesen
Hanne H
HH
Selbo
Pål K
PK
D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D002470:Cell Survival; D000068818:Cetuximab; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008027:Light; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D010778:Photochemotherapy; D012503:Saponins / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D012503:Saponins; D066246:ErbB Receptors; D000068818:Cetuximab