Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655.
针对急性髓系白血病（AML）的自然杀伤（NK）细胞免疫疗法正日益受到关注。本研究对新型CD33/CD16a/NKG2D免疫调节三特异性抗体CC-96191进行了功能表征。该抗体可同时结合CD33、NKG2D与CD16a，其中NKG2D与CD16a的共结合能增强NK细胞对靶标的亲和力并激活NK细胞。CC-96191通过严格依赖CD33的机制对多种人类白血病细胞发挥广谱抗肿瘤活性，其最大效能需要CD16a与NKG2D的共同参与。常见的CD33单核苷酸多态性R69G会降低CC-96191的效力但不影响最大活性，这可能是由于CD33结合能力减弱所致。同样，高浓度可溶性CD33会降低CC-96191的效力而非最大活性；相比之下，可溶性NKG2D配体MICA则不影响其活性。在CD33阳性AML细胞存在条件下，CC-96191能特异性激活NK细胞而非T细胞；虽然其最大抗AML疗效与CD33/CD3双特异性抗体相当，但可溶性细胞因子水平降低10至100倍以上。尽管CC-96191介导的细胞溶解不受ABC转运蛋白影响，但会被抗凋亡BCL-2家族蛋白抑制。最后在患者骨髓样本中，CC-96191能清除AML细胞而不损伤正常单核细胞，表明三特异性抗体诱导的细胞毒性对肿瘤细胞具有选择性。这些发现共同支持CC-96191在临床试验（NCT04789655）中的进一步探索。
肿瘤(癌症)患者之家