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Published OnlineFirst June 6, 2017; DOI: 10.1158/1541-7786.MCR-17-0164 Cell Death and Survival Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody Tadanobu Nagaya, Yuko Nakamura, Shuhei Okuyama, Fusa Ogata, Yasuhiro Maruoka, Peter L. Choyke, and Hisataka Kobayashi Abstract Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treat- ment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in vitro. In the in vivo study, anti-PSMA-IR700 showed high tumor accumulation and high tumor–background ratio. Tumor- bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 mg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 mg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (P < 0.001), and significantly prolonged survival was achieved (P < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Fur- thermore, NIR-PIT with the anti-PSMA-IR700 antibody is a prom- ising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans. Implications: NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed poten- tial therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. Mol Cancer Res; 15(9); 1153–62. !2017 AACR. Introduction Prostate cancer is the most common cancer in men, with 161,360 estimated new cases and it is the third leading cause of cancer-related death among men in the United States, with 26,730 deaths estimated in 2017 (1). Localized prostate cancer typically is treated with surgery or radiation, and recurrent disease can be controlled temporarily with radiation often combined with androgen ablation (2). However, many prostate cancers eventu- ally become hormone refractory and then rapidly progress (3). Hormone-refractory or androgen-independent metastatic pros- tate cancer is usually lethal. Therefore, it is important that the clinical trajectory of prostate cancer be intercepted as early in the course of the disease as possible (4, 5). New molecularly targeted therapies are urgently needed for this task. Monoclonal antibody (mAb) therapies have shown consider- able value in the treatment of many malignant tumors (6–9). As monotherapy, mAbs can either block receptors needed for growth Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Corresponding Author: Hisataka Kobayashi, National Cancer Institute, Bldg. 10, Rm B3B69, 10 Center Dr., MD 20892-1088. Phone: 301-435-4086; Fax: 301-402- 3191; E-mail: kobayash@mail.nih.gov doi: 10.1158/1541-7786.MCR-17-0164 !2017 American Association for Cancer Research. www.aacrjournals.org or induced antibody-dependent complement-mediated cytotox- icity (ADCC). Antibodies can also be used to deliver drugs or therapeutic radioisotopes. However, for antibodies to be most effective, a distinct antigen must be commonly expressed on the cancer cell surface. Prostate-specific membrane antigen (PSMA) is a well-estab- lished cell membrane marker of prostate cancer and therefore is a plausible target for molecular therapy. PSMA is a type 2 integral membrane glycoprotein, also known as glutamate carboxypepti- dase II (GCPII) or folate hydrolase 1 (FOLH1; refs. 10–12) and it was originally discovered in the androgen-dependent LNCap human prostatic adenocarcinoma cell line (13). PSMA is expressed in nearly all prostate cancers, and expression is highest in poorly differentiated, metastatic, and hormone-refractory cases (14–17). Compared with other therapies, antibody-directed photother- apy has several advantages over conventional therapies because it is minimally invasive and can be used repeatedly without limi- tation of the total dose or treatment resistance (18). In the past, antibodies were conjugated to very hydrophobic photosensitizers in conventional photodynamic therapy (PDT). As a consequence of their hydrophobicity, these conjugates tended to be nonspecific and limited by toxicity. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that employs a highly targeted mAb-photoabsorber conjugate (APC). The photoabsorber, IRDye700DX (IR700, silica-phthalocyanine dye), is a highly hydrophilic dye, differentiating it from prior hydrophobic dyes used in PDT (19). The first-in-human phase I trial of NIR-PIT in Downloaded from mcr.aacrjournals.org on December 1, 2020. © 2017 American Association for Cancer Research. 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