Abstract 5346: A novel humanized CD16A model to evaluate efficacy of human antibody therapeutics in triggering ADCC

Abstract

Abstract Antibody-dependent cellular cytotoxicity (ADCC) is a mechanism by which immune effector cells engage the Fc portion of antibodies bound to antigen on the surface of another cell, thereby targeting that cell for destruction. In mice, the Fcgr4 receptor is primarily responsible for triggering ADCC, while the FCGR3A receptor (CD16A) mediates this function in human NK cells, which are an attractive target cell type for cancer immunotherapy. Given these differences, we sought to generate humanized CD16A preclinical models to evaluate the efficacy of antibodies in triggering human CD16A-mediated ADCC in vivo. Previously, we established humanized CD16A mice on immunocompetent backgrounds for evaluating efficacy of novel antibodies in preventing growth of syngeneic tumor models. Here, we introduce a novel humanized CD16A mouse on the CB-17-SCID background, in order to inoculate human tumor cells for therapeutic efficacy testing. We confirmed expression of CD16A in human NK cells and monocytes/macrophages, but not granulocytes in the model; expression of murine Fcgr4 was no longer detectable, indicating successful generation of the model. Assessment of leukocyte populations in the humanized model indicated no significant alterations in the percentages of NK cells, dendritic cells, granulocytes, monocytes and macrophages in the spleen or blood of the humanized mice compared with wild-type CB-17 SCID mice. Subsequently, the ability of these mice to grow human tumor cells was evaluated: B-hHep3B-Luc, HC116, K-562, and NCI-N87 tumors were all successfully established. Finally, efficacy of an anti-human CLDN18.2 antibody was evaluated against B-hCLDN18.2 BxPC-3 tumors in the humanized mice, which showed modest anti-tumor efficacy at 30 mg/kg when compared to isotype control-treated mice. In summary, humanized B-hCD16A mice (CB-17-SCID) provide a suitable model for evaluating the ability of antibody candidates to induce ADCC. Citation Format: Xiao Liu, Zhenlan Niu, Ruili Lv, Qingcong Lin, Mari Kuraguchi, Qingqing Xu. A novel humanized CD16A model to evaluate efficacy of human antibody therapeutics in triggering ADCC [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 5346.