Abstract 7327: Harnessing FcγR glycoengineering to enhance anti-tumor monoclonal antibody efficacy

Abstract New strategies to enhance the activity of anti-tumor monoclonal antibodies (mAbs) that mediate cytotoxicity are needed. Glycoengineering of certain anti-tumor mAbs has been employed to increase their cytotoxic activity; however, the benefits of this approach are limited to specific patient groups. Beyond mAb engineering, an additional strategy involves modifying Fc gamma receptors (FcγRs), the receptors for IgG antibodies on effector cells, to augment specific antibody effector functions including cytotoxicity. One method for improving FcγR binding to mAbs is through glycoengineering, though the potential to modulate anti-tumor mAb activity via in vivo FcR glycoform engineering remains unexplored. We investigated the impact of FcγR glycosylation on therapeutic mAb activity and demonstrated that modifying FcγR glycoforms can enhance antibody-mediated anti-cancer responses. Underprocessed N-linked glycoforms were associated with improved binding affinity of Rituximab and Trastuzumab to FcRs, which enhanced the antibody-dependent cellular cytotoxicity activity of human peripheral blood mononuclear cells against target cells expressing CD20 or HER2, respectively. In vivo, glycoengineering of FcγRs improved the therapeutic efficacy of both a wild-type and an afucosylated anti-tumor mAb, demonstrating that this approach can further potentiate the activity of mAbs that have already been engineered for increased cytotoxicity. These findings underscore the potential of FcγR glycoengineering as a strategy to optimize mAb-based cancer immunotherapy. Citation Format: Bowie Yik-Ling Cheng, Raquel M. Centeio, David Kung-Chun Chiu, Taia T. Wang. Harnessing FcγR glycoengineering to enhance anti-tumor monoclonal antibody efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7327.