Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate.
We conducted an expression analysis of prostate stem cell antigen (PSCA)in normal urogenital tissues, benign prostatic hyperplasia (n = 21), prostatic intraepithelial neoplasia (n = 33), and primary (n = 137) and metastatic (n = 42) prostate adenocarcinoma, using isotopic in situ hybridization on tissue microarrays. In normal prostate, we observe PSCA expression in the terminally differentiated, secretory epithelium; strong expression was also seen in normal urothelium. Forty-eight percent of primary and 64% of metastatic prostatic adenocarcinomas expressed PSCA RNA. Our studies did not confirm a positive correlation between level of PSCA RNA expression and high Gleason grade. We characterized monoclonal anti-PSCA antibodies that recognize PSCA expressed on the surface of live cells, are efficiently internalized after antigen recognition, and kill tumor cells in vitro in an antigen-specific fashion upon conjugation with maytansinoid. Unconjugated anti-PSCA antibodies demonstrated efficacy against PSCA-positive tumors by delaying progressive tumor growth in vivo. Maytansinoid-conjugated antibodies caused complete regression of established tumors in a large proportion of animals. Our results strongly suggest that maytansinoid-conjugated anti-PSCA monoclonal antibodies should be evaluated as a therapeutic modality for patients with advanced prostate cancer.
Ross
Sarajane
S
Department of Pathology, Genentech, Inc., South San Francisco, California 94080, USA.
Spencer
Susan D
SD
Holcomb
Ilona
I
Tan
Christine
C
Hongo
JoAnne
J
Devaux
Brigitte
B
Rangell
Linda
L
Keller
Gilbert A
GA
Schow
Peter
P
Steeves
Rita M
RM
Lutz
Robert J
RJ
Frantz
Gretchen
G
Hillan
Kenneth
K
Peale
Franklin
F
Tobin
Patti
P
Eberhard
David
D
Rubin
Mark A
MA
Lasky
Laurence A
LA
Koeppen
Hartmut
H
D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000494:pharmacology; D017403:In Situ Hybridization; D008297:Male; D008453:Maytansine / Q000493:pharmacokinetics / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; C504399:Psca protein, mouse; D008453:Maytansine