title: Monoclonal antibodies to six-transmembrane epithelial antigen of the prostate-1 inhibit intercellular communication in vitro and growth of human tumor xenografts in vivo.
abstract: Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein highly expressed in primary prostate cancer, with restricted expression in normal tissues. In this report, we show STEAP-1 expression in prostate metastases to lymph node and bone and in the majority of human lung and bladder carcinomas. We identify STEAP-1 function in mediating the transfer of small molecules between adjacent cells in culture, indicating its potential role in tumor cell intercellular communication. The successful generation of two monoclonal antibodies (mAb) that bind to cell surface STEAP-1 epitopes provided the tools to study STEAP-1 susceptibility to naked antibody therapy. Both mAbs inhibited STEAP-1-induced intercellular communication in a dose-dependent manner. Furthermore, both mAbs significantly inhibited tumor growth in mouse models using patient-derived LAPC-9 prostate cancer xenografts and established UM-UC-3 bladder tumors. These studies validate STEAP-1 as an attractive target for antibody therapy in multiple solid tumors and provide a putative mechanism for mAb-induced tumor growth inhibition.
authors.affiliation: Agensys, Inc., Santa Monica, California 90404, USA. pchallita@agensys.com
authors.forename: Pia M
authors.initials: PM
authors.lastname: Challita-Eid
authors.forename: Kendall
authors.initials: K
authors.lastname: Morrison
authors.forename: Soudabeh
authors.initials: S
authors.lastname: Etessami
authors.forename: Zili
authors.initials: Z
authors.lastname: An
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Morrison
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Perez-Villar
authors.forename: Arthur B
authors.initials: AB
authors.lastname: Raitano
authors.forename: Xiao-Chi
authors.initials: XC
authors.lastname: Jia
authors.forename: Jean M
authors.initials: JM
authors.lastname: Gudas
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
authors.forename: Aya
authors.initials: A
authors.lastname: Jakobovits
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D002450:Cell Communication / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010088:Oxidoreductases / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000556:secondary; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D034741:RNA, Small Interfering; D010088:Oxidoreductases; C432763:STEAP1 protein, human