Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity
Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity
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DOI：
10.1016/j.cell.2019.04.041
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发表时间：
2019-06-13
期刊：
影响因子：
64.5
通讯作者：
Vivier, Eric
中科院分区：
文献类型：
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作者：
Gauthier, Laurent;Morel, Ariane;Vivier, Eric
在过去的十年中，已经开发了各种新疗法来促进抗肿瘤免疫。尽管在血液恶性肿瘤中有令人感兴趣的临床结果，但针对肿瘤细胞并刺激抗肿瘤T细胞免疫的双特异性巨噬细胞-巨噬细胞抗体形式的开发已被证明是具有挑战性的，主要是由于毒性问题。我们在这里报告的三功能自然杀伤（NK）细胞的生成（NKCEs），针对两个活化受体，NKp 46和CD 16，对NK细胞和癌细胞的肿瘤抗原。三功能NKCE在体外比靶向相同肿瘤抗原的临床治疗抗体更有效。它们具有与完整IgG抗体相似的体内药代动力学，并且没有脱靶效应，并且在实体和侵袭性肿瘤的小鼠模型中有效地控制肿瘤生长。因此，三功能NKCE构成了新一代抗癌分子。
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 killercell-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.