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The Homodimer of Prostate-Specific Membrane Antigen Is a Functional Target for Cancer Therapy
Norbert Schülke, Olga A. Varlamova, Gerald P. Donovan, Dangshe Ma, Jason P. Gardner, Donna M. Morrissey, Robert R. Arrigale, Cenchen Zhan, Amy J. Chodera, Kenneth G. Surowitz, Paul J. Maddon, Warren D. W. Heston and William C. Olson
Proceedings of the National Academy of Sciences of the United States of America
Vol. 100, No. 22 (Oct. 28, 2003), pp. 12590-12595
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3148004
Page Count: 6
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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.
Proceedings of the National Academy of Sciences of the United States of America © 2003 National Academy of Sciences