Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-γ receptor engagement

// James Bradford Kline 1 , Rina P. Kennedy 1 , Earl Albone 1 , Qimin Chao 1 , Shawn Fernando 1 , Jennifer M. McDonough 1 , Katherine Rybinski 1 , Wenquan Wang 1 , Elizabeth B. Somers 1 , Charles Schweizer 1 , Luigi Grasso 1 and Nicholas C. Nicolaides 1 1 Morphotek Inc., Exton, PA, USA Correspondence to: Nicholas C. Nicolaides, email: // Keywords : CA125, ADCC, farletuzumab, Fc-γ receptor, ovarian cancer Received : May 15, 2017 Accepted : May 19, 2017 Published : July 07, 2017 Abstract Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin-taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low serum CA125 levels treated with farletuzumab demonstrated improvements in progression free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108) as compared to placebo. Farletuzumab’s pharmacologic activity is mediated in part through ADCC. Here we show that CA125 inhibits ADCC by directly binding to farletuzumab that in turn perturbs Fc-γ receptor engagement on effector cells.