法国Innate Pharma公司Eric Vivier小组等人的最新研究成果——“以NKp46为靶点的多功能自然杀伤细胞接合器可触发保护性肿瘤免疫”，于2019年5月30日发表在《细胞》杂志上。

他们开发了一种三功能自然杀伤(NK)细胞接合器(NKCEs)，该接合器能靶向NK细胞（自然杀伤细胞）上的NKp46和CD16两种活性受体以及癌细胞上的一种肿瘤抗原。体外实验表明，针对相同的肿瘤抗原时，这种三功能NKCEs比临床治疗中使用的抗体更为有效。它们的体内药代动力学与完整的IgG抗体相类似，而在实体瘤和侵袭性肿瘤的小鼠模型的体内实验中，也无脱靶效应，并且能有效地控制肿瘤生长。该研究结果表明：这种三功能NKCEs是一种新一代的抗肿瘤分子。

研究人员表示，在过去的十年里，各种各样的新疗法被开发出来，以促进抗肿瘤免疫。尽管目前在血液系统恶性肿瘤中有一定的研究进展，但不论是开发直接针对肿瘤细胞的双特异性杀伤细胞接合器抗体形式还是诱导抗肿瘤T细胞产生免疫反应，都已被证明仍是具有挑战性的，而这主要的原因是毒性问题。

附：英文原文

Title: Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity

Author: Laurent Gauthier, Ariane Morel, Nadia Anceriz, Yannis Morel, Emilie Narni-Mancinelli, Eric Vivier

Issue&Volume: Jun 13, 2019 Volume 177Issue 7

Abstract: 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.

DOI: https://doi.org/10.1016/j.cell.2019.04.041

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30460-X