Targeting CD89 on tumor-associated macrophages overcomes resistance to immune checkpoint blockade

• DOI: 10.1136/jitc-2022-005447
• Publication Date: 2022-12-02T13:56:20Z
• Authors: Lijun Xu; Bingyu Li; Chenyu Pi; Zhaohua Zhu; Fei Tao; Kun Xie; Yan Feng; Xiaoqing Xu; Yanxin Yin; Hua Gu; Jianmin Fang
• Keywords: Immune checkpoint; CTLA-4

Despite the survival benefits observed with immune checkpoint blockade (ICB) treatment-programmed cell death-1/programmed death ligand-1 (PD-1/PD-L1), many patients cancer have not benefited from these agents because of impaired antigen presentation and other resistance mechanisms. To overcome to therapy, we designed bispecific antibodies (BsAbs) targeting CD89 tumor antigens. We demonstrated their immunomodulatory efficacy as a separate treatment strategy or combined inhibitors. previously generated heterodimeric one-arm IgG1 Fc-based antibody. For animal studies, murine tumors in humanized transgenic mice model were used determine effects CD89-bispecific on recruitment. The antibody against resistant pembrolizumab was evaluated double-transgenic mice. BsAbs tumor-associated macrophages (TAMs) increased ratio M1:M2 activated presentation, leading cytotoxic T cell-mediated regression. CD89-BsAbs also potentiated combinational antitumor effect PD-1/PD-L1 inhibitors overcame ICB by augmenting T-cell infiltration reshaping microenvironment. In an hCD89/hPD-1 double mouse engrafted pembrolizumab-resistant B16-HER2 cells, HER2-CD89 potently inhibited growth. antigens TAMs controlled growth models improving infiltration. Our results suggest general for overcoming ICB.