title: Photoimmunotherapy targeting prostate-specific membrane antigen: are antibody fragments as effective as antibodies?
abstract: Photoimmunotherapy is a highly cell-selective cancer therapy based on an armed antibody conjugate with a phthalocyanine-based photosensitizer, IR700. Photoimmunotherapy induces rapid and highly specific necrosis in targeted cancer cells after exposure to near-infrared (NIR) light. Cells not expressing the antigen are not affected. To date, photoimmunotherapy has been demonstrated only with full antibody-IR700 conjugates. In this study, small and bivalent antibody fragments, including anti-prostate-specific membrane antigen (PSMA) diabody (Db) and minibody (Mb), were compared with intact IgG for their effectiveness as photoimmunotherapy agents.
  
  
  METHODS
  Radioiodinated antibody and antibody fragments with (125)I were used to determine the timing of maximum binding of each anti-PSMA antibody fragment on the cell surface in vivo in mice bearing either PSMA-positive or -negative PC3 tumors. Then therapeutic efficacy of photoimmunotherapy was examined by exposing mice to NIR light at 2 time points based on the time of maximum cell surface binding at 6 h after injection for Db-IR700 and 24 h after injection for Mb-IR700 and IgG-IR700 as well as 24 h after the peak uptake times.
  
  
  RESULTS
  Photoimmunotherapy with the same molar concentration of PSMA-Db-IR700, PSMA-Mb-IR700, and PSMA-IgG-IR700 conjugate showed similar therapeutic effects in vitro and in vivo on PSMA-positive PC3 tumor xenografts in cytotoxicity and survival curves (P > 0.05).
  
  
  CONCLUSIONS
  The use of PSMA-Db-IR700 conjugate results in the shortest time interval between injection and NIR exposure without compromising therapeutic effects of photoimmunotherapy.
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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.
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.
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.
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.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Harada
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mitsunaga
authors.affiliation: Applied/Developmental Research Directorate, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, Maryland.
authors.forename: Insook
authors.initials: I
authors.lastname: Kim
authors.affiliation: Nuclear Medicine Department, Radiology and Imaging Science, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Paik
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wu
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Kobayash@mail.nih.gov.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007259:Infrared Rays; D054833:Isoindoles; D008297:Male; D051379:Mice; D009336:Necrosis / Q000139:chemically induced; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy; D014018:Tissue Distribution
chemical_list: D000954:Antigens, Surface; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D007211:Indoles; D054833:Isoindoles; D017319:Photosensitizing Agents; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; C013647:phthalocyanine
keywords: diabody; minibody; monoclonal antibody; pharmacokinetics; photoimmunotherapy; prostate specific membrane antigen