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Therapeutic antibodies have improved survival of both hematologic and solid cancer patients, inducing long-lasting responses and even cures. Clinically successful antibodies exert antitumor activity by targeting tumor cells directly (e.g. anti-HER2 mAb in HER2+ breast cancer, anti-CD20 mAb in B cell cancer) or by targeting and activating immune cells that seek and destroy cancer cells in the tumor microenvironment (immune checkpoint blocking antibodies; ICB). Still, many patients fail to respond or acquire resistance to these therapies. Understanding mechanisms and overcoming resistance to distinct classes of antibody drugs, is therefore clearly warranted and has the potential to further improve cancer outcomes. The inhibitory Fc gamma receptor (FcγR) IIB imbues resistance to cancer immunotherapy by several mechanisms, acting both on tumor and immune effector cells. We previously developed an FcγRIIB blocking antibody (BI-1206) which is currently being explored in clinical trials (NCT03571568, NCT04219254, and NCT02933320). BI-1206 was found to have cytolytic activity against malignant B cells and the ability to block rituximab internalization from tumor cells, as well as enhance rituximab therapeutic activity in mice humanized for CD20 and FcγRIIB or bearing relapsed/refractory CLL in vivo. Emerging data demonstrate that FcγRs modulate the therapeutic activity of many therapeutic antibodies among them HER2 targeting antibodies such as Trastuzumab. Trastuzumab alone or in combination with chemotherapy significantly improves overall survival of HER2+ breast cancer patients. However, many patients remain uncured and develop Trastuzumab resistance resulting in relapse of the disease. Means of improving anti-HER2 therapy and overcoming resistance are therefore highly desirable. We report the generation of a fully human FcγRIIB-blocking antibody (BI-1607) engineered to eliminate Fc-mediated FcγR binding and function (Fc-null anti-FcγRIIB). Using a mechanism-of-action-matched surrogate antibody, we demonstrate that Fc-null anti-FcγRIIB enhances therapeutic efficacy, both in tumor growth and overall survival of anti-HER2 in the syngeneic immune competent TUBO mouse model. This enhanced therapeutic efficacy is associated with increased tumor influx of myeloid and NK-cells. Collectively our results provide proof-of-concept for Fc-null anti-FcγRIIB to enhance anti-HER2 in the treatment of cancer. Citation Format: Linda Mårtensson, Robert Oldham, Marie Borggren, Mathilda Kovacek, Therese Blidberg, Ulla-Carin Tornberg, Ingrid Karlsson, Steve Beers, Mark Cragg, Ingrid Teige, Björn Frendeus. A novel FcγRIIB-blocking antibody to enhance FcγR-dependent antitumor immunity with anti-HER2 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3423. |
