Abstract 1622: Block-Removed Immunoglobulin Technology (BRITE) to enhance rituximab effector function by counteracting CA125/MUC16-mediated immunosuppression

Abstract Rituximab is a CD20-targeting antibody that is the standard-of-care for patients with Non-Hodgkin Lymphoma (NHL) cases. Rituximab's mechanism of action includes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) - herein referred to as Humoral Immuno-Oncology (HIO) mechanism. Recent clinical evidence suggest that high serum levels of the tumor-produced MUC16/CA125 protein has a negative impact on the effectiveness of rituximab clinical activity on up to 40% of follicular lymphoma patients. In this study we demonstrate that CA125 binds to rituximab and reduces its tumor cell killing activity. Moreover, we describe the generation of a rituximab variant, named NAV-006, using a proprietary technology called Block-Removed Immunoglobulin Technology (BRITE) that employs randomized amino substitution and high-throughput screening to identify HIO-refractory rituximab variants. Here, we demonstrate that NAV-006 is more refractory to the immunosuppressive effects mediated by CA125 as shown by its reduced CA125 interaction and increased HIO activity. These data warrants further investigation of NAV-006 as a next generation anti-CD20 antibody that could improve upon the efficacy of the parent rituximab in NHL patients with high levels of CA125. Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. Block-Removed Immunoglobulin Technology (BRITE) to enhance rituximab effector function by counteracting CA125/MUC16-mediated immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1622.