Identification of a novel prostate tumor target, mindin/RG-1, for antibody-based radiotherapy of prostate cancer.
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.
Parry
Renate
R
Berlex Biosciences, Richmond, California 94806, USA. renate_parry@berlex.com
Schneider
Doug
D
Hudson
Debra
D
Parkes
Debbie
D
Xuan
Jian-Ai
JA
Newton
Alicia
A
Toy
Pam
P
Lin
Rick
R
Harkins
Rick
R
Alicke
Bruno
B
Biroc
Sandra
S
Kretschmer
Peter J
PJ
Halks-Miller
Meredith
M
Klocker
Helmut
H
Zhu
Ying
Y
Larsen
Brent
B
Cobb
Ronald R
RR
Bringmann
Peter
P
Roth
Georg
G
Lewis
Jason S
JS
Dinter
Harald
H
Parry
Gordon
G
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics / Q000494:pharmacology; D000918:Antibody Specificity; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D016466:CHO Cells; D006224:Cricetinae; D004306:Dose-Response Relationship, Immunologic; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology* / Q000493:pharmacokinetics / Q000494:pharmacology; D017879:Isothiocyanates / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016326:Extracellular Matrix Proteins; D000922:Immunotoxins; D017879:Isothiocyanates; D012333:RNA, Messenger; D015021:Yttrium Radioisotopes; C121491:mindin; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid