Innate Pharma, Marseille, France.
Innate Pharma, Marseille, France.
Cell. 2019 Jun 13;177(7):1701-1713.e16. doi: 10.1016/j.cell.2019.04.041. Epub 2019 May 30.
Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. VIDEO ABSTRACT.
在过去的十年中，已经开发出各种新的疗法来促进抗肿瘤免疫。尽管在血液恶性肿瘤中取得了有趣的临床结果，但开发针对肿瘤细胞并刺激抗肿瘤 T 细胞免疫的双特异性杀伤细胞结合抗体形式一直具有挑战性，主要是由于毒性问题。我们在这里报告了针对自然杀伤 (NK) 细胞的三功能效应器 (NKCE) 的产生，该效应器针对 NK 细胞上的两个激活受体 NKp46 和 CD16 以及癌细胞上的肿瘤抗原。三功能 NKCE 在体外比针对相同肿瘤抗原的临床治疗性抗体更有效。它们与完整 IgG 抗体具有相似的体内药代动力学特性，没有脱靶效应，并能有效控制实体瘤和侵袭性肿瘤小鼠模型中的肿瘤生长。因此，三功能 NKCE 构成了新一代抗癌分子。视频摘要。
