title: Glypican-3 targeted human heavy chain antibody as a drug carrier for hepatocellular carcinoma therapy.
abstract: Glypican-3 (GPC3) represents an attractive target for hepatocellular carcinoma (HCC) therapy because it is highly expressed in HCC but not in adult normal tissue. Recently, high affinity anti-GPC3 antibodies have been developed; however, full antibodies may not penetrate evenly into tumor parenchyma, reducing their effectiveness. In this study, we compared a whole IgG antibody, anti-GPC3 YP7, with an anti-GPC3 human heavy chain antibody, HN3, with regard to their relative therapeutic effects. Both YP7 and HN3 bound to GPC3-positive A431/G1 cells and were internalized by the cells by in vitro evaluation with (125)I- and (111)In-radiolabeling antibodies. In vivo biodistribution and tumor accumulation was performed with (111)In-labeled antibodies, and intratumoral microdistribution was evaluated using fluorescently labeled antibodies (IR700). HN3 showed similar high tumor accumulation but superior homogeneity within the tumor compared with YP7. Using the same IR700 conjugated antibodies photoimmunotherapy (PIT) was performed in vitro and in a tumor-bearing mouse model in vivo. PIT with IR700-HN3 and IR700-YP7 demonstrated that comparable results could be achieved despite of low reaccumulation 24 h after the first NIR light exposure. These results indicated that a heavy-chain antibody, HN3, showed more favorable characteristics than YP7, a conventional IgG, as a therapeutic antibody platform for designing molecularly targeted agents against HCC.
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Nagaya
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Sato
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Rira
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Harada
authors.affiliation: ‡Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: ‡Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Mingqian
authors.initials: M
authors.lastname: Feng
authors.affiliation: ‡Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Yen
authors.initials: Y
authors.lastname: Phung
authors.affiliation: §Applied/Developmental Research Directorate, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, Maryland 21702, United States.
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.affiliation: ∥Nuclear Medicine Department, Warren Grant Magnuson Clinical Center, Radiology and Imaging Science, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Paik
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.affiliation: ‡Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Ho
authors.affiliation: †Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D053673:Glypicans / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology / Q000627:therapeutic use*; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D004337:Drug Carriers; C105937:GPC3 protein, human; D053673:Glypicans; D007143:Immunoglobulin Heavy Chains
keywords: Glypican-3; heavy-chain antibody; hepatoma; intratumoral distribution; photoimmunotherapy