Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
EBioMedicine. 2020 Oct;60:102996. doi: 10.1016/j.ebiom.2020.102996. Epub 2020 Sep 16.
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.
帕妥珠单抗目前与曲妥珠单抗联合用于治疗 HER2 阳性转移性乳腺癌的一线治疗。然而，帕妥珠单抗最初是与曲妥珠单抗独立开发的，后来意外发现与曲妥珠单抗联合使用具有协同疗效，目前仍不清楚曲妥珠单抗是否存在更有效的协同作用伙伴。
使用基于曲妥珠单抗的功能测定法筛选具有协同抗肿瘤活性的抗 HER2 抗体。候选药物 5G9 与曲妥珠单抗联合使用，进一步研究其在细胞增殖、细胞凋亡、抗原抗体内吞和 HER2 介导的细胞信号通路阻断方面的生物学活性。最后，使用动物模型评估 5G9 与曲妥珠单抗联合使用的体内协同抗肿瘤疗效。
与帕妥珠单抗相比，5G9 与曲妥珠单抗联合使用时表现出更强的协同细胞生长抑制活性（85%比 55%，P<0.001）。此外，5G9 的内化率高于帕妥珠单抗（20%比 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。5G9 与曲妥珠单抗联合使用的内化率高于帕妥珠单抗与曲妥珠单抗联合使用的内化率（35%比 14%，P<0.001）。体内动物研究表明，5G9 与曲妥珠单抗联合使用比帕妥珠单抗与曲妥珠单抗联合使用具有更强的协同抗肿瘤疗效。
5G9 与曲妥珠单抗联合使用可能为治疗 HER2 阳性癌症提供更有效的治疗机会。
国家自然科学基金；国家重点实验室分析化学生命科学。
