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Updated: Aug 30, 2026
MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent
Published on: September 3, 2013
The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy
Norbert Schülke1, Olga A Varlamova, Gerald P Donovan
1Progenics Pharmaceuticals, Inc., and PSMA Development Company, LLC, Tarrytown, NY 10591, USA. nschuelke@progenics.com
Abstract:
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.
Insights
Prostate-specific membrane antigen (PSMA) forms dimers on tumor cells, which are crucial for its function and for eliciting an immune response. Understanding PSMA dimerization is key for developing effective cancer immunotherapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Prostate-specific membrane antigen (PSMA) is a protein highly expressed on prostate cancer cells and tumor blood vessels.
- Its structure and function are not fully understood, limiting its therapeutic potential.
Purpose of the Study:
- To investigate the molecular structure and dimerization of PSMA.
- To understand how PSMA structure relates to its enzymatic activity and immunogenicity.
Main Methods:
- Analysis of PSMA protein structure and dimerization using biochemical assays.
- Characterization of PSMA enzymatic activity in monomeric and dimeric forms.
- Development and testing of antibodies targeting PSMA dimers.
Main Results:
- PSMA exists as a noncovalent homodimer on tumor cells.
- The extracellular domain alone is sufficient for PSMA dimerization.
- PSMA dimers, not monomers, exhibit native conformation and high carboxypeptidase activity.
- A dimer-specific epitope was identified, and antibodies against it effectively recognized PSMA-expressing tumor cells.
Conclusions:
- PSMA dimerization is essential for its native conformation, enzymatic activity, and recognition by antibodies.
- These findings provide critical insights into PSMA biology for advancing prostate cancer immunotherapy.
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