三靶点抗体可激活免疫通杀乳腺癌

　　对于肿瘤，人体具有天然的免疫力。不过，这取决于T淋巴细胞能否被有效激活而产生强大的免疫反应。近年来，免疫细胞程序死亡受体PD-1或其配体PD-L1等免疫检查点抑制剂、T淋巴细胞衔接剂、嵌合抗原受体T淋巴细胞（CAR-T）等免疫疗法对于部分肿瘤患者可以诱发有效的抗肿瘤免疫，已经彻底改变了肿瘤治疗的临床实践。虽然CD8受体阳性T淋巴细胞作为这些免疫反应的关键效应细胞而发挥作用，但是CD4受体阳性T淋巴细胞在其辅助功能之外的作用尚不明确。

　　2022年2月23日，全球自然科学三大旗舰期刊之首、英国《自然》正刊在线发表美国赛诺菲研发中心、ModeX治疗学、德国赛诺菲研发中心、法国赛诺菲研发中心的研究报告，发现针对HER2、CD3和CD28的三靶点抗体通过激活CD4受体阳性T淋巴细胞可有效抑制各种乳腺癌生长。

　　该研究利用来源于人类乳腺癌细胞的小鼠乳腺癌模型证实，针对HER2、CD3和CD28的三靶点抗体通过CD4受体可抑制癌细胞有丝分裂周期，刺激乳腺癌缩小甚至消失。而且，不仅对HER2阳性乳腺癌细胞AU565有效，对HER2阴性乳腺癌细胞HCC1428、激素受体阳性乳腺癌细胞BT474、激素受体阴性乳腺癌细胞HCC1937和HCC1954、三阴性乳腺癌细胞MDA-MB-231和HCC70和BT549、HER2阳性胃癌细胞OE19和GSU也有效。

　　虽然CD8受体阳性T淋巴细胞在体外可直接引起肿瘤溶解，但是CD4受体阳性T淋巴细胞可通过阻断癌细胞有丝分裂周期由DNA合成前期进入DNA合成期，从而间接抑制癌细胞增殖。

　　此外，将这些T淋巴细胞亚群过继转移至来源于人类乳腺癌细胞的小鼠乳腺癌模型，CD4受体阳性T淋巴细胞可独立抑制体内HER2阳性乳腺癌的生长。

　　根据核糖核酸（RNA）微阵列分析，CD4受体阳性T淋巴细胞可显著减少肿瘤细胞有丝分裂周期和增殖，同时还可加强促进炎症反应的信号传导通路。

　　因此，该研究结果表明，针对HER2、CD3和CD28的三靶点抗体不仅可直接抗HER2，而且可通过CD4受体阳性T淋巴细胞间接促进炎症反应和免疫反应，从而诱发各种乳腺癌缩小甚至消失。

Nature. 2022 Feb 23. Online ahead of print.

A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells.

Edward Seung, Zhen Xing, Lan Wu, Ercole Rao, Virna Cortez-Retamozo, Beatriz Ospina, Liqing Chen, Christian Beil, Zhili Song, Bailin Zhang, Mikhail Levit, Gejing Deng, Andrew Hebert, Patrick Kirby, Aiqun Li, Emma-Jane Poulton, Rita Vicente, Audrey Garrigou, Peter Piepenhagen, Greg Ulinski, Michele Sanicola-Nadel, Dinesh S. Bangari, Huawei Qiu, Lily Pao, Dmitri Wiederschain, Ronnie Wei, Zhi-yong Yang, Gary J. Nabel.

Sanofi R&D, North America, Cambridge, MA, USA; ModeX Therapeutics, Natick, MA, USA; Sanofi R&D, Frankfurt, Frankfurt am Main, Germany; Sanofi R&D, Montpellier, Montpellier, France.

Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells.

DOI: 10.1038/s41586-022-04439-0

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