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

Abstract

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.

• Authors: Renate Parry, Doug Schneider, Debra Hudson, Debbie Parkes, Jian-Ai Xuan, Alicia Newton, Pam Toy, Rick Lin, Rick Harkins, Bruno Alicke, Sandra Biroc, Peter J Kretschmer, Meredith Halks-Miller, Helmut Klocker, Ying Zhu, Brent Larsen, Ronald R Cobb, Peter Bringmann, Georg Roth, Jason S Lewis, Harald Dinter, Gordon Parry
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 18 Pg. 8397-405 (Sep 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16166318 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Extracellular Matrix Proteins
• Immunotoxins
• Isothiocyanates
• RNA, Messenger
• Yttrium Radioisotopes
• mindin
• N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid
• Pentetic Acid

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (immunology, pharmacokinetics, pharmacology)
• Antibody Specificity
• Bone Neoplasms (metabolism, secondary)
• CHO Cells
• Cricetinae
• Dose-Response Relationship, Immunologic
• Extracellular Matrix Proteins (biosynthesis, genetics, immunology)
• Humans
• Immunotoxins (immunology, pharmacokinetics, pharmacology)
• Isothiocyanates (immunology, pharmacokinetics, pharmacology)
• Male
• Molecular Sequence Data
• Pentetic Acid (analogs & derivatives, immunology, pharmacokinetics, pharmacology)
• Positron-Emission Tomography
• Prostatic Neoplasms (diagnostic imaging, immunology, metabolism, radiotherapy)
• RNA, Messenger (biosynthesis, genetics)
• Radioimmunotherapy (methods)
• Tissue Distribution
• Xenograft Model Antitumor Assays
• Yttrium Radioisotopes (administration & dosage, pharmacokinetics, pharmacology)