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

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.

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity.

Because of its high mortality rate, ovarian cancer is a leading cause of death among women and a highly unmet medical need. New therapeutic agents that are effective and well tolerated are needed and cancer antigen-specific monoclonal antibodies that have direct pharmacologic effects or can stimulate immunological responses represent a promising class of agents for the treatment of this disease. The human folate receptor α (FOLR1), which is overexpressed in ovarian cancer but largely absent in normal tissues, appears to play a role in the transformed phenotype in ovarian cancer, cisplatin sensitivity, and growth in depleted folate conditions and therefore has potential as a target for passive immunotherapy. The anti-FOLR1 monoclonal antibody MORAb-003 (farletuzumab) was previously shown to elicit antibody dependent cellular cytotoxicity (ADCC) and inhibit tumor growth of human tumor xenografts in nude mice. Because of its promising preclinical profile, farletuzumab has been evaluated in clinical trials as a potential therapeutic agent for ovarian cancer. In this report, we demonstrated that farletuzumab's antitumor effect against an experimental model of ovarian cancer is mediated by its ADCC activity.