Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response
Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response
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DOI：
10.1073/pnas.0806849105
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发表时间：
2008-10-21
影响因子：
11.1
通讯作者：
Smyth, Mark J.
中科院分区：
文献类型：
--
作者：
Stagg, John;Sharkey, Janelle;Smyth, Mark J.
尽管开发了人表皮生长因子受体-2（ErbB-2/HER 2）靶向治疗，但ErbB-2过表达的乳腺癌患者的医疗需求仍未得到满足。我们研究了小鼠肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体-2（DR 5）激动剂mAb对ErbB 2驱动的乳腺癌的治疗活性。在表达组成型活性ErbB-2/neuT的BALB/c转基因小鼠中建立的肿瘤用抗DR 5 mAb和/或抗ErbB-2 mAb处理，并监测肿瘤进展。用抗DR 5或抗mAb作为单一药剂治疗显著延迟肿瘤生长，尽管所有肿瘤最终进展。值得注意的是，用抗DR 5和抗ErbB-2 mAb的组合治疗在大多数小鼠中诱导了完全应答。体内阻断CD 11b（+）细胞，而非自然杀伤细胞耗竭，可显著消除早期抗肿瘤反应。值得注意的是，CD 8（+）T细胞的耗竭引起原发性和继发性肿瘤复发，揭示了联合治疗诱导的抗肿瘤免疫。抗DR 5和抗ErbB-2单克隆抗体的联合治疗进一步显著抑制了ErbB-2/neuT转基因小鼠中晚期自发性肿瘤的生长，即使治疗延迟至肿瘤可触及。因此，我们证明了抗DR 5和抗ErbB 2单克隆抗体的组合可能是治疗ErbB-2过表达乳腺癌的有效形式。
Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. in vivo blockade of CD11b(+) cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8(+) T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.