Bispecific antibodies (BsAb) that engage T cells bind to tumor cells via a tumor-associated antigen and to T cells through surface CD3. BsAbs have promising antitumor properties in vivo Here, we describe the effects of Fc silencing on BsAb-driven T-cell trafficking to solid tumors. We used BsAbs specific for disialoganglioside GD2 or oncoprotein ErbB2 (HER2) and built on the IgG(L)-scFv platform with or without Fc silencing. We studied the kinetics of T-cell infiltration from blood into solid tumor masses when driven by these BsAbs. We also investigated the therapeutic efficacy of these BsAbs in two mouse models: immunodeficient mice xenografted with patient-derived GD2+ neuroblastoma or HER2+ breast cancer, and human CD3ε transgenic mice implanted with a GD2+ murine tumor. BsAbs built with intact Fc domain were unable to drive T cells to tumor, thereby failing to achieve an antitumor effect in mice. T cells became sequestered in lungs by myeloid cells or depleted in circulation. In contrast, when Fc function was silenced by N297A ± K322A mutations, T cells were able to infiltrate into subcutaneous solid tumors, a prerequisite for successful therapy outcome.

中文翻译：

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在与T细胞结合的双特异性抗体中沉默Fc结构域可改善T细胞贩运和抗肿瘤潜能。

参与T细胞的双特异性抗体（BsAb）通过肿瘤相关抗原与肿瘤细胞结合，并通过表面CD3与T细胞结合。BsAbs在体内具有良好的抗肿瘤特性。在这里，我们描述了Fc沉默对BsAb驱动的T细胞向实体瘤运输的影响。我们使用了对双唾液酸神经节苷脂GD2或癌蛋白ErbB2（HER2）具有特异性的BsAb，并在具有或不具有Fc沉默的IgG（L）-scFv平台上构建。当这些BsAb驱动时，我们研究了T细胞从血液浸入实体瘤块的动力学。我们还研究了这些BsAb在两种小鼠模型中的治疗功效：异种移植了患者衍生的GD2 +神经母细胞瘤或HER2 +乳腺癌的免疫缺陷小鼠，以及植入GD2 +鼠肿瘤的人CD3ε转基因小鼠。用完整的Fc结构域构建的BsAb无法将T细胞驱动至肿瘤，因此不能在小鼠中达到抗肿瘤作用。T细胞被髓样细胞隔离在肺中或在循环中耗竭。相反，当N297A±K322A突变使Fc功能沉默时，T细胞能够浸入皮下实体瘤，这是治疗成功的前提。