Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study
Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study
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Anterior Gradient-2 单克隆抗体通过上调 p53 通路抑制肺癌生长和转移，且不产生任何毒理学作用：临床前研究
DOI：
10.1016/j.canlet.2019.01.025
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Li, Dawei
中科院分区：
文献类型：
--
作者：
Negi, Hema;Merugu, Siva Bharath;Li, Dawei
传统的肿瘤化疗和放疗的主要缺点是耐药性增加和对正常器官的急性副作用。这增加了对靶向治疗策略的关注，例如基于单克隆抗体的癌症疗法。基于抗体的疗法的主要优点是特异性抑制癌症相关靶点，减少脱靶副作用。前梯度-2（AGR 2）是一种促转移和促血管生成的肿瘤标志物，在多种癌症中过表达。因此，抗AGR 2抗体可能是用于治疗不同癌症的潜在治疗剂。在本研究中，我们检测了一种新的抗AGR 2单克隆抗体mAb 18 A4，发现该抗体抑制肺癌的进展和转移，而不会对小鼠的主要器官和血液产生任何不良副作用。此外，我们发现mAb 18 A4激活p53通路，减弱ERK 1/2-MAPK通路。此外，mAb 18 A4处理的癌细胞系表现出减弱的增殖和集落形成，增强的凋亡，增加的p53表达，和减少的磷酸化ERK 1/2表达。在不同的异种移植肿瘤模型中，用mAb 18 A4治疗显著减小肿瘤大小并抑制肿瘤转移，并且增加存活。此外，mAb 18 A4有效地抑制AGR 2诱导的血管生成。药代动力学和毒理学分析的结果证实了mAb 18 A4作为抗肿瘤治疗的安全性。
Increased drug resistance and acute side effects on normal organs are the major disadvantages of traditional cancer chemotherapy and radiotherapy. This has increased the focus on targeted therapeutic strategies such as monoclonal antibody-based cancer therapies. The major advantage of antibody-based therapies is the specific inhibition of cancer-related targets, with reduced off-target side effects. Anterior gradient-2 (AGR2) is a pro-metastatic and proangiogenic tumor marker that is overexpressed in multiple cancers. Therefore, anti-AGR2 antibodies may be potential therapeutic agents for treating different cancers. In the present study, we examined a novel anti-AGR2 monoclonal antibody mAb18A4 and found that this antibody inhibited lung cancer progression and metastasis without exerting any adverse side effects on the major organs and blood in mice. Moreover, we found that mAb18A4 activated p53 pathway and attenuated ERK1/2-MAPK pathway. Furthermore, mAb18A4-treated cancer cell lines showed attenuated proliferation and colony formation, enhanced apoptosis, increased p53 expression, and reduced phosphorylated ERK1/2 expression. Treatment with mAb18A4 significantly reduced tumor size and suppressed tumor metastasis in and increased the survival of different xenograft tumor models. In addition, mAb18A4 potently suppressed AGR2-induced angiogenesis. Results of pharmacokinetic and toxicological analyses confirmed the safety of mAb18A4 as an antitumor treatment.