Abstract 1345: NAV-201, an orally bioavailable small molecule NK cell activator enhancing antibody-mediated cancer therapies

Abstract Tumors employ a number of mechanisms to suppress a patient’s immune anti-tumor responses. Recently, we uncovered an immunosuppression mechanism that tumors employ to avoid humoral immune responses that involves tumor-produced proteins, called Humoral Immuno-Oncology (HIO) factors. These HIO factors are able to suppress antibody-mediated tumor cell killing via direct binding to antibodies that alter their Fc domain interactions with the C1q protein to suppress complement dependent cytotoxicity (CDC) and reduce antibody engagement with CD16a Fc receptors on immune-effector cells, including NK cells, to suppress antibody dependent cellular cytotoxicity (ADCC). HIO factor immunosuppression of ADCC appears to involve the reduced binding affinity of antibody to CD16a Fc receptors. In an attempt to identify agents that may enhance antibody-CD16a binding affinity to overcome HIO factor immunosuppression, we sought to identify agents that can restore this interaction by screening natural small compound libraries via an IgG1-CD16a based ELISA assay. One lead compound was identified that was subsequently optimized by structural activity relationship analysis. This compound, named NAV-201, specifically binds CD16a and enhances the affinity of antibody binding to both the low affinity CD16a-158F and high affinity CD16a-158V allotypes. Moreover, we found that NAV-201 can also bind to the mouse CD16a ortholog and enhance its antibody binding affinity, making NAV-201 suitable for efficacy testing in mouse models. In vivo, NAV-201 was found to be well tolerated up to at least 120 mg/kg when administered orally and daily to mice, have a serum half-life of 18 hours, enhance systemic levels of the NK cell produced INF-γ and TNF-α cytokines, and enhance the therapeutic efficacy of antibodies in mouse xenografts. Together, these data support the further development of NAV-201 for human testing to improve and/or enhance the efficacy of antibody-based therapies in HIO factor positive cancers. Citation Format: Nicholas C. Nicolaides, Luigi Grasso, J. Brad Kline. NAV-201, an orally bioavailable small molecule NK cell activator enhancing antibody-mediated cancer therapies [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 1345.