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.

Fig. 1

Effect of MORAb-009 on serum CA-125 levels. The serum CA-125 levels before, during and following completion of MORAb-009 therapy are shown for a patient with peritoneal mesothelioma (1003) and pleural mesothelioma (1005). Arrowheads indicate day of MORAb-009 infusion. Patient 1005 received two cycles of MORAb-009, while as patient 1003 received one cycle of MORAb-009.

Fig. 2

Effect of MORAb-009 on serum CA-125 assay. Serum samples obtained from patients with ovarian cancer with CA-125 levels within normal range (sample A) or with elevated CA-125 concentration (sample B) were mixed with MORAb-009 (100 μg/ml), rituximab (100 μg/ml) as isotype matched control antibody, or phosphate buffered saline and CA-125 levels measured using the AxSYM CA-125 assay.

Fig. 3

Schematic illustration of potential mechanism of increased CA-125 levels following MORAb-009 treatment. CA-125 released from the tumor is secreted into the peritoneal/pleural cavity and binds to mesothelin present on mesothelial cells and the unbound CA-125 enters the systemic circulation. MORAb-009 by binding to mesothelin results in excess free tumor secreted CA-125 in peritoneal/pleural cavities, which in turn enters the systemic circulation leading to increased serum CA-125 levels.

Fig. 4

Proposed model of mesothelin-CA-125 interaction and role in tumor metastasis. The binding of CA-125 present on tumor cells to mesothelin on the mesothelial cells lining the peritoneum or pleura can lead to heterotypic adhesion and tumor spread. Also interaction between CA-125 that is normally present on mesothelial cells to tumor associated mesothelin can lead to heterotypic adhesion and tumor metastasis. In addition, homotypic interactions between CA-125 and mesothelin present on tumor cells can lead to tumor aggregation and potentiate intra-cavitary metastasis.