Ca125/Muc16 Suppresses Antibody-Dependent Cellular Cytotoxicity Of Igg1-Based Therapies Via Perturbation Of Antibody Fc-Receptor Engagement On Immune Effector Cells

Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of the tumor-shed antigen CA125 (MUC16) on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of an 1100 patient Phase 3 clinical trial testing the investigational agent farletuzumab, a monoclonal antibody (mAb) to folate receptor alpha, plus standard-of-care in patients with recurrent ovarian cancer. In this study, patients with low levels of CA125 [no greater than 3X the upper limit of normal ( Methods: Functional assays employing Jurkat-hCD16 reporter cells as well as primary NK cells were used to measure ADCC activity. CA125 isolates from various patients and cell lines were used in ADCC assays to monitor CA125 effects on immune-effector function. Multiple isogenic tumor cells expressing endogenous CA125 and their CA125-null counterparts were also used to monitor CD16a-mediated ADCC activity. CD16a+ cell binding assays were used to measure the effects of CA125 inhibition on CD16a Fc-Receptor interaction and activation. Recombinant CD16a and humanized mAbs were used in ELISA format to measure molecular binding. Results: Functional assays showed that exogenously added tumor-shed CA125 was able to suppress ADCC mediated by IgG1-type mAbs against several target cell lines. This CA125-mediated ADCC suppression was also observed in cells naturally expressing membrane-bound CA125 but not in isogenic CA125-null cells. Molecular studies suggest that CA125-mediated immunosuppression is caused by the perturbation of antibody interaction with the CD16a Fc-Receptor and that this effect is specific to IgG-type mAbs. Conclusions: Here we demonstrate that the tumor-shed antigen CA125 can elicit immunosuppression by blocking the interaction of tumor-targeting mAbs and CD16a Fc-Receptor on immune effector cells. This effect appears to be through a direct interaction of CA125 with antibody-CD16a proteins. These findings support a biological mechanism for the clinical observation that relapsed ovarian cancer patients with low CA125 blood levels have improved clinical responses to the experimental agent farletuzumab. These findings also provide new insights on the potential biological mechanisms for which tumors produce tumor-shed antigens such as CA125 to suppress host anti-tumor immune responses. Citation Format: J. Bradford Kline, Rina Kennedy, Shawn Fernando, Jennifer McDonough, Earl Albone, Elizabeth B. Somers, Wenquan Wang, Charles Schweizer, Luigi Grasso, Nicholas C. Nicolaides. CA125/MUC16 suppresses antibody-dependent cellular cytotoxicity of IgG1-based therapies via perturbation of antibody Fc-Receptor engagement on immune effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 644. doi:10.1158/1538-7445.AM2017-644