A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

募集T细胞双特异性抗体在治疗实体瘤方面取得成功的主要障碍是缺乏肿瘤特异性靶标，导致T细胞自身反应性对表达靶器官的靶标上肿瘤外不良反应。为了克服这个问题，我们开发了一种抗HER2 / CD3 T细胞依赖性双特异性（TDB）抗体，该抗体以高效力选择性靶向过表达HER2的肿瘤细胞，同时保留了在正常人组织中表达少量HER2的细胞。选择性基于两个低亲和力的抗HER2 Fab臂对过表达HER2的细胞的高靶标密度的亲和力。对过表达HER2的细胞的选择性增加有望减轻不良反应的风险并提高治疗指数。该手稿中的结果不仅支持抗HER2 / CD3 1Fab免疫球蛋白G TDB的临床开发，而且为其他以T细胞为导向的疗法引入了可能广泛应用的策略。这一发现的潜力具有广泛的应用前景，可以进一步考虑先前受靶标上但肿瘤外的自身免疫所限制的实体瘤靶标。