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.

尽管最近取得了治疗进展，但急性髓系白血病（AML）仍然是一个治疗挑战。尽管单克隆抗体 (mAb) 通过抗体依赖性细胞毒性 (ADCC) 作用于自然杀伤 (NK) 细胞，有望在癌症治疗中发挥作用，但迄今为止，几乎没有一种抗体获得了治疗 AML 的临床批准。最近，CD276 (B7-H3) 因其在 AML 患者的白血病母细胞中高表达而成为 AML 免疫治疗的一个有前景的靶标。在这里，我们介绍了具有增强的 CD16 亲和力的 Fc 优化 CD276 mAb 8H8_SDIE 的临床前开发。我们证明 8H8_SDIE 特异性结合 AML 细胞系和原代 AML 细胞上的 CD276，并诱导明显的 NK 细胞活化和脱颗粒（通过 CD69、CD25 和 CD107a 测量）。 8H8_SDIE 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 的细胞毒性测定中观察到 AML 细胞系和原代 AML 细胞明显的靶细胞限制性裂解。最后，带有8H8_SDIE的异种移植模型不会引起脱靶免疫激活，并有效抑制体内白血病生长。我们在这里提出了一种新颖的、有吸引力的免疫治疗化合物，它可以在体外和体内有效诱导抗白血病 NK 细胞反应性，作为 AML 的治疗选择。