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Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated
S S Chang1, V E Reuter, W D Heston
1Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
Prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that was initially characterized by the monoclonal antibody (mAb) 7E11. PSMA is highly expressed in prostate secretory-acinar epithelium and prostate cancer as well as in several extraprostatic tissues. Recent evidence suggests that PSMA is also expressed in tumor-associated neovasculature. We examined the immunohistochemical characteristics of 7E11 and those of four recently developed anti-PSMA mAbs (J591, J415, and Hybritech PEQ226.5 and PM2J004.5), each of which binds a distinct epitope of PSMA. Using the streptavidin-biotin method, we evaluated these mAbs in viable prostate cancer cell lines and various fresh-frozen benign and malignant tissue specimens. In the latter, we compared the localization of the anti-PSMA mAbs to that of the anti-endothelial cell mAb CD34. With rare exceptions, all five anti-PSMA mAbs reacted strongly with the neovasculature of a wide spectrum of malignant neoplasms: conventional (clear cell) renal carcinoma (11 of 11 cases), transitional cell carcinoma of the urinary bladder (6 of 6 cases), testicular embryonal carcinoma (1 of 1 case), colonic adenocarcinoma (5 of 5 cases), neuroendocrine carcinoma (5 of 5 cases), glioblastoma multiforme (1 of 1 cases), malignant melanoma (5 of 5 cases), pancreatic duct carcinoma (4 of 4 cases), non-small cell lung carcinoma (5 of 5 cases), soft tissue sarcoma (5 of 6 cases), breast carcinoma (5 of 6 cases), and prostatic adenocarcinoma (2 of 12 cases). Localization of the anti-PSMA mAbs to tumor-associated neovasculature was confirmed by CD34 immunohistochemistry in sequential tissue sections. Normal vascular endothelium in non-cancer-bearing tissue was consistently PSMA negative. The anti-PSMA mAbs reacted with the neoplastic cells of prostatic adenocarcinoma (12 of 12 cases) but not with the neoplastic cells of any other tumor type, including those of benign and malignant vascular tumors (0 of 3 hemangiomas, 0 of 1 hemangioendothelioma, and 0 of 1 angiosarcoma). The mAbs to the extracellular PSMA domain (J591, J415, and Hybritech PEQ226.5) bound viable prostate cancer cells (LNCaP and PC3-PIP), whereas the mAbs to the intracellular domain (7E11 and Hybritech PM2J004.5) did not. All five anti-PSMA mAbs reacted with fresh-frozen benign prostate secretory-acinar epithelium (28 of 28 cases), duodenal columnar (brush border) epithelium (11 of 11 cases), proximal renal tubular epithelium (5 of 5 cases), colonic ganglion cells (1 of 12 cases), and benign breast epithelium (8 of 8 cases). A subset of skeletal muscle cells was positive with 7E11 (7 of 7 cases) and negative with the other four anti-PSMA mAbs. PSMA was consistently expressed in the neovasculature of a wide variety of malignant neoplasms and may be an effective target for mAb-based antineovasculature therapy.
Insights
Prostate-specific membrane antigen (PSMA) is found in the neovasculature of many cancers. This discovery suggests PSMA as a potential target for new anti-cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Prostate-specific membrane antigen (PSMA) is a protein primarily found in prostate cancer cells.
- Recent studies indicate PSMA expression in tumor-associated neovasculature.
- Understanding PSMA's expression patterns is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the immunohistochemical characteristics of five anti-PSMA monoclonal antibodies (mAbs).
- To evaluate PSMA expression in various cancer types and normal tissues.
- To determine if PSMA in tumor neovasculature is a viable therapeutic target.
Main Methods:
- Utilized streptavidin-biotin method for immunohistochemistry on cell lines and tissue specimens.
- Tested five anti-PSMA mAbs (7E11, J591, J415, Hybritech PEQ226.5, PM2J004.5) against diverse malignant and benign tissues.
- Compared PSMA localization with CD34, an endothelial cell marker, in tumor neovasculature.
Main Results:
- All five anti-PSMA mAbs strongly reacted with the neovasculature of a broad range of malignant neoplasms, including renal carcinoma, bladder carcinoma, melanoma, and lung carcinoma.
- PSMA expression in tumor neovasculature was confirmed by CD34 co-localization.
- Normal vascular endothelium consistently lacked PSMA expression.
- Anti-PSMA mAbs recognized neoplastic prostate cancer cells but not other tumor types.
- Extracellular domain-binding mAbs (J591, J415, PEQ226.5) bound viable prostate cancer cells, unlike intracellular domain-binding mAbs (7E11, PM2J004.5).
- PSMA was detected in benign prostate epithelium, duodenal brush border, and proximal renal tubules.
Conclusions:
- PSMA is consistently expressed in the neovasculature of various malignant tumors.
- PSMA represents a promising target for antibody-based anti-vasculature therapy in cancer treatment.
- Differential binding of mAbs to PSMA's extracellular or intracellular domains may have therapeutic implications.
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