Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells.
Anti-Axl monoclonal antibodies attenuate the migration of MDA-MB-231 breast cancer cells.
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抗AXL单克隆抗体减弱了MDA-MB-231乳腺癌细胞的迁移。
DOI：
10.3892/ol.2021.13010
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发表时间：
2021-11
期刊：
影响因子：
2.9
通讯作者：
Lv M
中科院分区：
文献类型：
--
作者：
Chang H;An R;Li X;Lang X;Feng J;Lv M
受体酪氨酸激酶anexelekto（Axl）参与肿瘤细胞的生长、迁移和侵袭，并且与化疗耐药性相关，这使得其成为癌症治疗的有吸引力的靶点。在过去的10年中，总共报道了六种Axl靶向单克隆抗体（mAb）和两种抗体-药物缀合物，它们已被证明具有抑制肿瘤细胞增殖和迁移的生物活性。Axl外部细胞结构域（Axl-ECD）由426个氨基酸组成，一直被用作所有六种Axl靶向mAb的筛选过程中的抗原。然而，Axl功能结构域与其天然配体生长停滞特异性蛋白6（Gas 6）相互作用，只是Axl−ECD的一小部分。靶向Axl功能结构域的抗体可以有效地阻断Gas 6-Axl结合并减弱其下游信号和活性。据我们所知，尚未报道靶向Axl功能结构域的mAb。在本研究中，一个主要的Axl功能域与Gas 6的相互作用，确定使用生物信息学和结构生物学方法。在MDA-MB-231乳腺癌细胞测定中，靶向该相对特异性Axl功能结构域的抗Axl mAb在Axl磷酸化和细胞迁移测定中几乎完全中和了Gas 6的刺激，并且在细胞迁移测定中显示出与阳性对照药物R428（目前处于II期临床试验的Axl的小分子酪氨酸激酶抑制剂）相似的活性。鉴于Axl在肿瘤发展和化疗耐药性中的重要作用，Axl靶向mAb可用于直接抑制肿瘤细胞，以及通过阻断Axl活性来减少化疗耐药性的发展。Axl靶向mAb联合化疗的应用为肿瘤患者提供了一种有希望的治疗策略，特别是那些目前没有靶向治疗的三阴性乳腺癌患者。
The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl−ECD), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl−ECD. Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.
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