Abstract PR17: Targeted blockade of FcγRIIB on dendritic cells and macrophages enhances cellular activation and Fc-dependent immune responses
Authors: Molony Ryan D. , Jang Sunyoung , Oka Adwait , Isim Sinam , Xu Fangmin , Platzer Barbara , Wong Karrie , Meyer Matthew , Lu Haihui 
Published: June 2021

Abstract
FcγRIIB (CD32b) is the sole inhibitory member of the Fcγ family of IgG-binding receptors, suppressing cellular activation in response to Fc-dependent stimuli. Human FcγRIIB is expressed by both dendritic cells (DCs) and macrophages, and the ratio of activating to inhibitory signals from their cell surface Fcγ receptors sets the threshold for their activation. Anti-tumor antibodies with an Fc-dependent mode of action (MoA) can bind to FcγRIIB on these myeloid cells, limiting effector responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) and DC-mediated priming of T cells. Agents that lower the immunologic threshold for Fc-dependent cellular activation therefore represent an ideal means of enhancing antitumor antibody therapeutic efficacy. We hypothesized that anti-FcγRIIB antibodies that can block the Fc-binding domain of human FcγRIIB can enhance the activation and effector functions of human DCs and macrophages, thereby bolstering innate and adaptive antitumor immunity. We found that anti-FcγRIIB treatment specifically blocked the binding of immune complexes (ICs) to human FcγRIIB in vitro, demonstrating a functional consequence of blocking the Fc binding pocket of FcγRIIB. Treatment of human monocyte-derived DCs (moDCs) with anti-FcγRIIB antibodies induced DC maturation as measured by CD86 upregulation and CD14 downregulation, and this enhancement of DC maturation was dependent upon the expression of activating FcγRIIa. Treatment of DC-like cells derived from the FcγRIIB-expressing monocytic human THP-1 cell line with anti-FcγRIIB led to their improved performance when combined with primary human T cells in a mixed lymphocyte reaction, consistent with a functional enhancement of DC maturation. Treatment of human monocyte-derived macrophages with an Fc-enhanced anti-FcγRIIB was also sufficient to induce TNFα secretion and downregulation of cell surface CD163, consistent with robust FcγR-dependent macrophage activation. Ongoing studies to test the cell type-specific roles of FcγRIIB in the context of an in vivo model that can read out Fc-dependent antitumor antibody activity will further clarify the mechanism by which disrupting FcγRIIB signaling can enhance antitumor mAb therapeutic efficacy. In conclusion, our work highlights the ability of a novel antibody directed against the Fc-binding domain of human FcγRIIB to both directly enhance DC and macrophage activation and further bolster the activation and effector functions of these cells in response to Fc-dependent stimuli, offering a viable avenue for enhancing the efficacy of mAbs with an Fc-dependent MoA.
This abstract is also being presented as Poster A77.
Citation Format: Ryan D. Molony, Sunyoung Jang, Adwait Oka, Sinam Isim, Fangmin Xu, Barbara Platzer, Karrie Wong, Matthew Meyer, Haihui Lu. Targeted blockade of FcγRIIB on dendritic cells and macrophages enhances cellular activation and Fc-dependent immune responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR17.