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


CONCLUSIONS
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.
Hassan
Raffit
R
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. hassanr@mail.nih.gov
Schweizer
Charles
C
Lu
Kun F
KF
Schuler
Barbara
B
Remaley
Alan T
AT
Weil
Susan C
SC
Pastan
Ira
I
D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D018394:CA-125 Antigen / Q000097:blood; D002448:Cell Adhesion; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D000090204:Mesothelin; D008654:Mesothelioma / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D018394:CA-125 Antigen; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D000090204:Mesothelin