title: Targeting tomoregulin for radioimmunotherapy of prostate cancer.
abstract: Radiotherapy is an effective approach for the treatment of local prostate cancer. However, once prostate cancer metastasizes, radiotherapy cannot be used due to the distribution of multiple metastases to lymph nodes and bones. In contrast, radioimmunotherapy should still be efficacious in metastatic prostate cancer as radioisotopes are brought to tumor cells by targeting antibodies. Here we identify and validate a prostate-expressed molecule, tomoregulin, as a target for radioimmunotherapy of prostate cancer. Tomoregulin is a transmembrane protein selectively expressed in the brain, prostate, and prostate cancer, but not expressed in other normal tissues. Immunohistochemical studies of tomoregulin protein in clinical samples show its location in the luminal epithelium of normal prostate, benign prostatic hyperplasia, and prostatic intraepithelial neoplasia. More importantly, the tomoregulin protein is expressed in primary prostate tumors and in their lymph node and bone metastases. The nature of tomoregulin as a transmembrane protein and its tissue-specific expression make tomoregulin an attractive target for radioimmunotherapy, in which tomoregulin-specific antibodies will deliver a radioisotope to prostate tumor cells and metastases. Indeed, biodistribution studies using a prostate tumor xenograft model showed that the (111)In-labeled anti-tomoregulin antibody 2H8 specifically recognizes tomoregulin protein in vivo, leading to a strong tumor-specific accumulation of the antibody. In efficacy studies, a single i.p. dose of 150 microCi (163 microg) (90)Y-labeled 2H8 substantially inhibits the growth rate of established LNCaP human prostate tumor xenograft in nude mice but produces no overt toxicity despite cross-reactivity of 2H8 with mouse tomoregulin. Our data clearly validate tomoregulin as a target for radioimmunotherapy of prostate cancer.
authors.affiliation: Berlex Biosciences, Richmond, California 94806, USA. xiao-yan_zhao@berlex.com
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhao
authors.forename: Doug
authors.initials: D
authors.lastname: Schneider
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Biroc
authors.forename: Renate
authors.initials: R
authors.lastname: Parry
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Pamela
authors.initials: P
authors.lastname: Toy
authors.forename: Jian-Ai
authors.initials: JA
authors.lastname: Xuan
authors.forename: Choitsu
authors.initials: C
authors.lastname: Sakamoto
authors.forename: Ken
authors.initials: K
authors.lastname: Wada
authors.forename: Michael
authors.initials: M
authors.lastname: Schulze
authors.forename: Beate
authors.initials: B
authors.lastname: Müller-Tiemann
authors.forename: Gordon
authors.initials: G
authors.lastname: Parry
authors.forename: Harald
authors.initials: H
authors.lastname: Dinter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015018:Ytterbium / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D000922:Immunotoxins; D007205:Indium Radioisotopes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C423567:TMEFF2 protein, human; D015018:Ytterbium