A Novel Angiopoietin-2 Selective Fully Human Antibody with Potent Anti-Tumoral and Anti-Angiogenic Efficacy and Superior Side Effect Profile Compared to Pan-Angiopoietin-1/-2 Inhibitors

There is increasing experimental evidence for an important role of Angiopoietin-2 (Ang-2) in tumor angiogenesis and progression. In addition, Ang-2 is up-regulated in many cancer types and correlated with poor prognosis. To investigate the functional role of Ang-2 inhibition in tumor development and progression, we generated novel fully human antibodies that neutralize specifically the binding of Ang-2 to its receptor Tie2. The selected antibodies LC06 and LC08 recognize both rodent and human Ang-2 with high affinity, but LC06 shows a higher selectivity for Ang-2 over Ang-1 compared to LC08 which can be considered an Ang-2/Ang-1 cross-reactive antibody. Our data demonstrate that Ang-2 blockade results in potent tumor growth inhibition and pronounced tumor necrosis in subcutaneous and orthotopic tumor models. These effects are attended with a reduction of intratumoral microvessel density and tumor vessels characterized by fewer branches and increased pericyte coverage. Furthermore, anti-Ang-2 treatment strongly inhibits the dissemination of tumor cells to the lungs. Interestingly, in contrast to the Ang-2/Ang-1 cross-reactive antibody LC08 that leads to a regression of physiological vessels in the mouse trachea, the inhibition with the selective anti-Ang-2 antibody LC06 appears to be largely restricted to tumor vasculature without obvious effects on normal vasculature. Taken together, these data provide strong evidence for the selective Ang-2 antibody LC06 as promising new therapeutic agent for the treatment of various cancers.越来越多的实验证据表明，血管生成素-2（Angiopoietin-2, Ang-2）在肿瘤血管生成与肿瘤进展中发挥重要作用。此外，Ang-2在多种癌症类型中呈高表达状态，且与不良预后密切相关。为探究Ang-2抑制在肿瘤发生发展中的功能作用，本研究制备了可特异性中和Ang-2与其受体Tie2结合的新型全人源抗体。筛选获得的抗体LC06与LC08均可高亲和力结合啮齿类及人源Ang-2；但相较于可被归类为Ang-2/Ang-1交叉反应性抗体的LC08，LC06对Ang-2的选择性远高于Ang-1。本研究数据显示，在皮下及原位肿瘤模型中，阻断Ang-2可强效抑制肿瘤生长，并引发显著的肿瘤坏死。该效应同时伴随肿瘤内微血管密度降低，肿瘤血管呈现分支减少、周细胞覆盖度提升的特征。此外，抗Ang-2治疗可显著抑制肿瘤细胞向肺部的转移扩散。值得注意的是，与可引发小鼠气管生理性血管退化的Ang-2/Ang-1交叉反应性抗体LC08不同，选择性抗Ang-2抗体LC06的抑制作用主要局限于肿瘤血管，对正常血管无明显影响。综上，本研究数据充分证明，选择性抗Ang-2抗体LC06是一种极具应用前景的新型治疗制剂，可用于多种癌症的临床治疗。