Acute myeloid leukemia (AML) remains a therapeutic challenge despite recent therapeutic advances. Although monoclonal antibodies (mAbs) engaging natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC) hold promise in cancer therapy, almost none have received clinical approval for AML, so far. Recently, CD276 (B7-H3) has emerged as a promising target for AML immunotherapy, due to its high expression on leukemic blasts of AML patients. Here, we present the preclinical development of the Fc-optimized CD276 mAb 8H8_SDIE with enhanced CD16 affinity. We demonstrate that 8H8_SDIE specifically binds to CD276 on AML cell lines and primary AML cells and induces pronounced NK cell activation and degranulation as measured by CD69, CD25, and CD107a. Secretion of IFNγ, TNF, granzyme B, granulysin, and perforin, which mediate NK cell effector functions, was induced by 8H8_SDIE. A pronounced target cell-restricted lysis of AML cell lines and primary AML cells was observed in cytotoxicity assays using 8H8_SDIE. Finally, xenograft models with 8H8_SDIE did not cause off-target immune activation and effectively inhibited leukemia growth in vivo. We here present a novel attractive immunotherapeutic compound that potently induces anti-leukemic NK cell reactivity in vitro and in vivo as treatment option for AML.
尽管近期治疗取得进展，急性髓系白血病（AML）的治疗仍面临挑战。尽管通过抗体依赖性细胞介导的细胞毒性作用（ADCC）激活自然杀伤（NK）细胞的单克隆抗体（mAbs）在癌症治疗中展现出前景，但迄今几乎未有此类药物获临床批准用于AML治疗。近期，CD276（B7-H3）因其在AML患者白血病原始细胞中的高表达，已成为AML免疫治疗的一个潜在靶点。本文介绍了具有增强CD16亲和力的Fc优化CD276单克隆抗体8H8_SDIE的临床前研发进展。我们证实8H8_SDIE能特异性结合AML细胞系及原代AML细胞表面的CD276，并通过CD69、CD25和CD107a指标检测到其诱导显著的NK细胞活化与脱颗粒。该抗体还能诱导介导NK细胞效应功能的IFNγ、TNF、颗粒酶B、颗粒溶素和穿孔素的分泌。在使用8H8_SDIE的细胞毒性实验中，观察到其对AML细胞系和原代AML细胞产生显著的特异性裂解作用。最后，在异种移植模型中，8H8_SDIE未引起脱靶免疫激活，并能有效抑制体内白血病生长。本研究提出了一种新型免疫治疗化合物，能在体外和体内有效诱导抗白血病NK细胞活性，为AML治疗提供了新选择。
肿瘤(癌症)患者之家