Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.

尽管免疫检查点阻断和嵌合抗原受体 T 细胞治疗提供了显着的治疗进展，但许多恶性肿瘤仍然对免疫治疗无反应。针对肿瘤抗原和激活 T 细胞受体信号传导的双特异性抗体已显示出一定的临床疗效；然而，提供共刺激信号可能会改善 T 细胞对肿瘤的反应。在这里，我们开发了一种与 CD38、CD3 和 CD28 相互作用的三特异性抗体，以增强 T 细胞活化和肿瘤靶向。CD3 和 CD28 的结合提供了有效的 T 细胞刺激，而抗 CD38 结构域将 T 细胞引导至骨髓瘤细胞，以及某些淋巴瘤和白血病。这种抗体在人源化小鼠模型中的体内给药抑制了骨髓瘤的生长，并且在耐受良好的剂量下也刺激了非人灵长类动物的记忆/效应 T 细胞增殖和减少了调节性 T 细胞。总的来说，三特异性抗体代表了癌症免疫治疗的有希望的平台。