A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity.
A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic antitumor activity.
复制标题
通过基于曲妥珠单抗的大规模筛选鉴定出一种新型 HER2 靶向抗体 5G9，该抗体表现出强大的协同抗肿瘤活性
DOI：
10.1016/j.ebiom.2020.102996
复制
发表时间：
2020-10
期刊：
影响因子：
11.1
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Ding X;Gu W;Zhong Y;Hao X;Liu J;Xia S;Luo L;Chen M;Zhang C
帕妥珠单抗目前与曲妥珠单抗联合使用，作为HER 2阳性转移性乳腺癌的一线治疗。然而，帕妥珠单抗最初是独立于曲妥珠单抗开发的，后来偶然发现与曲妥珠单抗联合使用时具有协同疗效，还有待观察曲妥珠单抗是否存在更有效的协同疗效伴侣。使用基于曲妥珠单抗的功能试验筛选具有曲妥珠单抗协同抗肿瘤活性的抗HER 2抗体。主要候选物5G 9与曲妥珠单抗组合进一步表征其在细胞增殖、细胞凋亡、抗原-抗体内吞作用和HER 2介导的细胞信号传导途径阻断中的生物活性。最后，使用动物模型来评估5G 9与曲妥珠单抗组合的体内协同抗肿瘤功效。与帕妥珠单抗相比，当与曲妥珠单抗组合时，5G 9表现出更有效的协同细胞生长抑制活性（85%对55%，P<0.001）。此外，5G 9表现出比帕妥珠单抗更高的内化率（20%对9%，P<0.05），并且能够与曲妥珠单抗进一步协同促进抗原-抗体内吞作用。5G 9联合曲妥珠单抗的内化率高于帕妥珠单抗和曲妥珠单抗（35% vs. 14%，P<0.001）。体内动物研究表明，5G 9与曲妥珠单抗的组合显示出比帕妥珠单抗和曲妥珠单抗的组合更有效的协同抗肿瘤功效。5G 9与曲妥珠单抗一起可能为更有效地治疗HER 2阳性癌症提供潜在的机会。国家自然科学基金委员会;生命科学分析化学国家重点实验室。
Pertuzumab is currently used in combination with trastuzumab as the first-line treatment for HER2-positive metastatic breast cancer. However, pertuzumab was originally developed independently from trastuzumab and was later incidentally found to have synergistic efficacy when combined with trastuzumab, it remains to be seen whether a more potent synergistic efficacy partner exists for trastuzumab. A trastuzumab-based functional assay was used to screen anti-HER2 antibodies harboring trastuzumab-synergistic antitumor activity. The lead candidate 5G9, in combination with trastuzumab, was further characterized for its bioactivities in cell proliferation, cell apoptosis, antigen-antibody endocytosis and HER2-mediated cell signaling pathway blocking. Finally, animal models were used to evaluate the in vivo synergistic antitumor efficacy of 5G9 in combination with trastuzumab. Compared to pertuzumab, 5G9 demonstrated more potent synergistic cell growth inhibitory activity when combined with trastuzumab (85% vs. 55%, P<0.001). In addition, 5G9 exhibited a higher internalization rate than pertuzumab (20% vs. 9%, P<0.05), and was able to further synergize with trastuzumab to promote antigen-antibody endocytosis. The internalization rate of the combination of 5G9 and trastuzumab was higher than that of pertuzumab and trastuzumab (35% vs. 14%, P<0.001). In vivo animal studies demonstrated that 5G9 in combination with trastuzumab showed more potent synergistic antitumor efficacy than the combination of pertuzumab and trastuzumab. 5G9, together with trastuzumab, may provide a potential opportunity for more efficacious treatment of HER2-positive cancers. National Natural Science Foundation of China; State Key Laboratory of Analytical Chemistry for Life Science.
登录
查看更多内容
DOI：
10.1200/jco.2016.67.4887
发表时间：
2017-01-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Perez EA;Barrios C;Eiermann W;Toi M;Im YH;Conte P;Martin M;Pienkowski T;Pivot X;Burris H 3rd;Petersen JA;Stanzel S;Strasak A;Patre M;Ellis P
通讯作者：
Ellis P
DOI：
10.1073/pnas.0409610102
发表时间：
2005-02-08
影响因子：
11.1
作者：
Friedman, LM;Rinon, A;Yarden, Y
通讯作者：
Yarden, Y
影响因子：
11.2
作者：
Nahta, R;Hung, MC;Esteva, FJ
通讯作者：
Esteva, FJ
影响因子：
3.1
作者：
Baselga, Jose;Swain, Sandra M.
通讯作者：
Swain, Sandra M.
影响因子：
11.2
作者：
Scheuer, Werner;Friess, Thomas;Hasmann, Max
通讯作者：
Hasmann, Max