{
  "abstract": "Background Myeloid cells are the most abundant immune population within the tumor microenvironment (TME), yet their anti-tumor potential remains underexploited. To harness their immunotherapeutic capacity, we developed a series of bispecific myeloid engager (BiMEs) antibodies using our proprietary BiME platform. These antibodies simultaneously target tumor-associated antigens (TAAs) and block SIRPα, a key inhibitory receptor of phagocytosis on myeloid cells. Our previous studies demonstrated that BiMEs significantly enhance macrophage phagocytic activity and stimulate CD8+ T cell-mediated tumor killing in multiple murine models. Here, we further elucidate the mechanisms of action (MOAs) underlying BiME efficacy.Methods The impact of BiMEs on bone marrow-derived macrophage (BMDM) function was assessed using in vitro phagocytosis and tumor killing assays. The role of T cells in BiME-mediated tumor control was evaluated in the MC38-hCD47/CLDN18.2 tumor model, with or without co-administration of FTY720 (an immune cell trafficking inhibitor), anti-IFNγ, or anti-IFNAR1 antibodies. To investigate immune memory induction, tumor-rechallenge experiments were performed using MC38-hCD47/CLDN18.2 and MC38-hCD47 cells in mice previously cured by BiME treatment.Results BiMEs robustly enhanced macrophage phagocytosis and induced inflammatory cytokine production specifically in the presence of TAA-positive tumor cells, polarizing macrophages toward a pro-inflammatory M1-like phenotype and enhancing antigen presentation molecules. This reprogramming and antigen-presentation from myeloid cells likely drives subsequent T cell engagement. Consistently, blocking T cell trafficking with FTY720 did not impair the anti-tumor efficacy of a CLDN18.2/SIRPα BiME (ES028) in the MC38-hCD47/CLDN18.2 model, suggesting the involvement of resident intratumoral T cells. However, neutralization of IFNγ completely abolished ES028’s efficacy, underscoring a critical role for local IFNγ-mediated responses. Notably, blockade of IFNAR1—a mediator of the STING pathway implicated in anti-CD47 antibody activity—had no effect on ES028 function, suggesting a distinct MOA from anti-CD47 therapies. Strikingly, ES028-cured mice rechallenged with MC38-hCD47/CLDN18.2 cells ~3 months later exhibited complete tumor rejection. Moreover, these mice also exhibited impaired growth of MC38-hCD47 tumors lacking CLDN18.2 expression, indicating induction of immune memory and antigen spreading.Conclusions BiME antibodies enhance macrophage phagocytic function and reprogram myeloid cells toward a pro-inflammatory state, leading to potent T cell activation, durable immune memory, and in vivo antigen spreading. These findings support the therapeutic potential of BiMEs as novel multifaceted macrophage-targeting agents in cancer immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Elpiscience Biopharmaceuticals, Shanghai, China"
      ],
      "name": "Rui Gao"
    },
    {
      "affiliations": [
        "Elpiscience Biopharmaceuticals, Shanghai, China"
      ],
      "name": "Hongtao Lu"
    }
  ],
  "title": "1168 Novel bispecific macrophage engager (BiME) antibodies activate T cells and induce durable immune memory to suppress tumor growth",
  "uid": "04f185be-2c53-5b72-90b1-572c920fef17"
}