Abstract 2356: NAV-006: A next-generation rituximab targeting CD20 for the treatment of B-cell lymphomas immunosuppressed by MUC16/CA125

Abstract

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) mechanisms. Recent clinical evidence suggest that high serum levels of the MUC16 (CA125) protein inversely correlate with the effectiveness of rituximab clinical activity in 40-50% of follicular lymphoma (FL) as well as diffuse large B-cell lymphoma patients with newly diagnosed or relapsed/refractory (R/R) disease. In this study we demonstrated that CA125 binds to and suppresses the activity of rituximab, tafasitamab as well as the bispecific mosunetuzumab and glofitamab antibodies, which are approved for treating cases with indolent disease. These therapies have an overall response rate around 50-60%, suggesting the presence of a mechanism that allows lymphoma cells to escape these agents’ immune-mediated killing effects. CA125 may facilitate this immunosuppressive mechanism, and in fact, upon binding rituximab, CA125 reduces its affinity for the Fc receptor, CD16a, thus suppressing ADCC. Using a proprietary technology called Block-Removed Immunoglobulin Technology (BRITE) that employs randomized amino acid substitution and HIO effector function screening, we have identified a rituximab variant named NAV-006. NAV-006 is refractory to the immunosuppressive effects mediated by CA125 via its reduced CA125 interaction and increased HIO activity as compared to parent rituximab as well as the other antibodies used to treat R/R FL. In an in vivo model of human B-cell lymphoma, NAV-006 showed superior efficacy compared to parent rituximab. These data warrant further investigation of NAV-006 as a next generation anti-CD20 antibody that could improve upon the efficacy of antibody-mediated therapies used to treat NHL patients with high levels of CA125. Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. NAV-006: A next-generation rituximab targeting CD20 for the treatment of B-cell lymphomas immunosuppressed by MUC16/CA125 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2356.