%0 Journal Article
%T CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients
%A Charles Schweizer
%A Elizabeth B. Somers
%A Erin N. Ross
%A J. Bradford Kline
%A Luigi Grasso
%A Nicholas C. Nicolaides
%A Raffit Hassan
%A Shawn Fernando
%A Wenquan Wang
%J Archive of "Cancer Biology & Therapy".
%D 2018
%R 10.1080/15384047.2018.1449614
%X The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-¦Ã activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (¡«3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-¦Ã-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125
%K CA125
%K ADCC
%K amatuximab
%K Fc-¦Ã receptor
%K mesothelioma
%K immune suppression
%K mesothelin
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989791/