The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy.
Prostate-specific membrane antigen (PSMA) is a type 2 integral membrane glycoprotein that serves as an attractive target for cancer immunotherapy by virtue of its abundant and restricted expression on the surface of prostate carcinomas and the neovasculature of most other solid tumors. However, relatively little is known about the molecular structure of this target. Here, we report that PSMA is expressed on tumor cells as a noncovalent homodimer. A truncated PSMA protein, lacking transmembrane and cytoplasmic domains, also formed homodimers, indicating that the extracellular domain is sufficient for dimerization. PSMA dimers but not monomers displayed a native conformation and possessed high-level carboxypeptidase activity. A unique dimer-specific epitope was identified by using one of a panel of novel mAbs. When used to immunize animals, dimer but not monomer elicited antibodies that efficiently recognized PSMA-expressing tumor cells. These findings on PSMA structure and biology may have important implications for active and passive immunotherapy of prostate and other cancers.
Schülke
Norbert
N
Progenics Pharmaceuticals, Inc., and PSMA Development Company, LLC, Tarrytown, NY 10591, USA. nschuelke@progenics.com
Varlamova
Olga A
OA
Donovan
Gerald P
GP
Ma
Dangshe
D
Gardner
Jason P
JP
Morrissey
Donna M
DM
Arrigale
Robert R
RR
Zhan
Cenchen
C
Chodera
Amy J
AJ
Surowitz
Kenneth G
KG
Maddon
Paul J
PJ
Heston
Warren D W
WD
Olson
William C
WC
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D000970:Antineoplastic Agents / Q000633:toxicity*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D006224:Cricetinae; D019281:Dimerization; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000201:enzymology; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II