title: Potent and specific antitumor effect of CEA-targeted photoimmunotherapy.
abstract: Conventional photodynamic therapy (PDT) for cancer is limited by the insufficient efficacy and specificity of photosensitizers. We herein describe a highly effective and selective tumor-targeted PDT using a near-infrared (NIR) photosensitizer, IRDye700DX, conjugated to a human monoclonal antibody (Ab) specific for carcinoembryonic antigen (CEA). The antitumor effects of this Ab-assisted PDT, called photoimmunotherapy (PIT), were investigated in vitro and in vivo. The Ab-IRDye conjugate induced potent cytotoxicity against CEA-positive tumor cells after NIR-irradiation, whereas CEA-negative cells were not affected at all, even in the presence of excess photoimmunoconjugate. We found an equivalent phototoxicity and a predominant plasma membrane localization of Ab-IRDye after both one and six hours of incubation. Either no or little caspase activation and membrane peroxidation were observed in PIT-treated cells and a panel of scavengers for reactive oxygen species showed only partial inhibition of the phototoxic effect. Strikingly, Ab-IRDye retained significant phototoxicity even under hypoxia. We established a xenograft model, which allowed us to sensitively investigate the therapeutic efficacy of PIT by non-invasive bioluminescence imaging. Luciferase-expressing MKN-45-luc human gastric carcinoma cells were subcutaneously implanted into both flanks of nude mice. NIR-irradiation was performed for only the tumor on one side. In vivo imaging and measurement of the tumor size revealed that a single PIT treatment, with intraperitoneal administration of Ab-IRDye and subsequent NIR-irradiation, caused rapid cell death and significant inhibition of tumor growth, but only on the irradiated side. Together, these data suggest that Ab-IRDye-mediated PIT has great potential as an anticancer therapeutics targeting CEA-positive tumors.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Fukuoka University, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Shirasu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yamada
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Shibaguchi
authors.forename: Motomu
authors.initials: M
authors.lastname: Kuroki
authors.forename: Masahide
authors.initials: M
authors.lastname: Kuroki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000627:therapeutic use; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage; D007167:Immunotherapy; D015227:Lipid Peroxidation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D005456:Fluorescent Dyes; D018796:Immunoconjugates; D017319:Photosensitizing Agents
keywords: bioluminescence imaging; carcinoembryonic antigen; near-infrared light; photodynamic therapy; photoimmunoconjugate; photoimmunotherapy