Identification of a novel prostate tumor target, Mindin/RG-1, for antibody-based radiotherapy of prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 18; pp. 8397 - 8405
• Main Authors: PARRY, Renate, SCHNEIDER, Doug, BIROC, Sandra, KRETSCHMER, Peter J, HALKS-MILLER, Meredith, KLOCKER, Helmut, YING ZHU, LARSEN, Brent, COBB, Ronald R, BRINGMANN, Peter, ROTH, Georg, LEWIS, Jason S, HUDSON, Debra, DINTER, Harald, PARRY, Gordon, PARKES, Debbie, XUAN, Jian-Ai, NEWTON, Alicia, TOY, Pam, LIN, Rick, HARKINS, Rick, ALICKE, Bruno
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-2005
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - pharmacology; Antibody Specificity; Antineoplastic agents; Biological and medical sciences; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; CHO Cells; Combined treatment; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Cricetinae; Dose-Response Relationship, Immunologic; Extracellular Matrix Proteins - biosynthesis; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - immunology; Gynecology. Andrology. Obstetrics; Humans; Immunotoxins - immunology; Immunotoxins - pharmacokinetics; Immunotoxins - pharmacology; Isothiocyanates - immunology; Isothiocyanates - pharmacokinetics; Isothiocyanates - pharmacology; Male; Male genital diseases; Medical sciences; Molecular Sequence Data; Nephrology. Urinary tract diseases; Pentetic Acid - analogs & derivatives; Pentetic Acid - immunology; Pentetic Acid - pharmacokinetics; Pentetic Acid - pharmacology; Pharmacology. Drug treatments; Positron-Emission Tomography; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - radiotherapy; Radioimmunotherapy - methods; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tissue Distribution; Treatment. General aspects; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays; Yttrium Radioisotopes - administration & dosage; Yttrium Radioisotopes - pharmacokinetics; Yttrium Radioisotopes - pharmacology; Prostate tumor; Urinary system disease; Prostate disease; Targeting; Antibody; Homology; Identification; Malignant tumor; Radiotherapy; Target; Treatment; Immunoradiotherapy; Male genital diseases; Prostate cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-1203

Gene expression analysis showed that a human mindin homologue, mindin/RG-1, is expressed selectively in prostate tissues and that its expression level is elevated in some prostate tumors. Mindin/RG-1 protein expression is maintained in >80% of prostate cancers metastatic to bone or lymph nodes as well as in locally recurrent tumors in androgen-unresponsive patients. In contrast, mindin/RG-1 expression in other normal tissues is significantly lower than that seen in the prostate. A fully human antibody, 19G9, was generated against mindin/RG-1 protein and was shown to accumulate at high abundance in LNCaP tumor xenografts. Conjugates of this antibody with the chelator CHX-A''-DTPA were generated and radiolabeled with either 111In, 90Y, or 86Y. Small animal positron emission tomography imaging with the 86Y-radiolabeled conjugate showed very specific accumulation of the antibody in LNCaP tumor xenografts with clear tumor delineation apparent at 4 hours. The therapeutic efficacy of [90Y]-CHX-A''-DTPA-19G9 was evaluated in mice bearing LNCaP xenografts. A dose-finding study identified a nontoxic therapeutic dose to be approximately 75 microCi. Significant antitumor effects were seen with a single administration of radiolabeled antibody to animals bearing 200 to 400 mm3 tumors. Inhibition of tumor growth was observed in all treated animals over a 49-day period. At 49 days posttreatment, slow tumor growth recurred but this could be prevented for an additional 40-day period by a second administration of a 75 microCi dose at day 49. We conclude that [90Y]-CHX-A''-DTPA-19G9 is a novel antibody conjugate that has considerable promise for therapy of metastatic prostate cancer in androgen-unresponsive patients.