Inhibition of mesothelin-CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy.

Abstract

BACKGROUND:

Mesothelin, a tumor differentiation antigen highly expressed in mesothelioma and ovarian cancer, is the receptor for CA-125 (MUC 16) and this interaction may play a role in tumor metastasis. MORAb-009 is a chimeric anti-mesothelin monoclonal antibody.

METHODS:

Twenty-four patients with mesothelin expressing cancers were treated on a phase I study of MORAb-009 administered as an intravenous infusion (12.5-400mg/m(2)) weeklyx4 doses with 2 weeks off before the next cycle. This report summarizes the effect of MORAb-009 on serum CA-125 kinetics in the eight patients with mesothelioma who had CA-125 levels measured before and at different time-points following therapy.

RESULTS:

MORAb-009 treatment led to a marked increase in serum CA-125 levels in all patients including those without elevated CA-125 levels before therapy. The increase in CA-125 levels was not due to disease progression since CA-125 levels decreased rapidly after stopping MORAb-009 therapy. No patients had signs of peritoneal or pleural inflammation as the possible cause of CA-125 rise. In addition, the elevated CA-125 levels were not due to MORAb-009 interfering with the laboratory assay used to measure CA-125.

CONCLUSION:

The increase in serum CA-125 produced by treatment with MORAb-009 is most likely due to MORAb-009 inhibiting the binding of tumor shed CA-125 to mesothelin present on mesothelial cells lining the pleural and peritoneal cavities. Inhibiting the mesothelin-CA-125 interaction could be a useful strategy to prevent tumor metastasis in mesotheliomas and ovarian cancer.

• Authors: Raffit Hassan, Charles Schweizer, Kun F Lu, Barbara Schuler, Alan T Remaley, Susan C Weil, Ira Pastan
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 68 Issue 3 Pg. 455-9 (Jun 2010) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 19744744 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Ireland Ltd.

Chemical References

• Antibodies, Monoclonal
• CA-125 Antigen
• GPI-Linked Proteins
• Membrane Glycoproteins
• Mesothelin

Topics

• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• CA-125 Antigen (blood)
• Cell Adhesion
• Disease Progression
• Female
• GPI-Linked Proteins
• Humans
• Immunotherapy
• Male
• Membrane Glycoproteins (immunology)
• Mesothelin
• Mesothelioma (blood, immunology, metabolism, pathology, therapy)
• Middle Aged
• Neoplasm Metastasis
• Ovarian Neoplasms (blood, immunology, metabolism, pathology, therapy)
• Pancreatic Neoplasms (blood, immunology, metabolism, pathology, therapy)