Complement-mediated mechanisms in anti-GD2 monoclonal antibody therapy of murine metastatic cancer.
Complement-mediated mechanisms in anti-GD2 monoclonal antibody therapy of murine metastatic cancer.
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DOI：
10.1158/0008-5472.can-05-1894
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Tomlinson, S
中科院分区：
文献类型：
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作者：
Imai, M;Landen, C;Tomlinson, S
人们普遍对补体在癌症抗体治疗中的作用知之甚少。我们使用转移性淋巴瘤的 EL4 同基因小鼠模型来研究补体在针对 GD2（临床相关靶点）的免疫治疗中的作用。 IgG2a 和 IgM 抗 GD2 疗法可保护 EL4 攻击的小鼠免受转移并延长生存期。 CD59（一种直接补体介导的细胞毒性（CMC）抑制剂）的表达可在体外有效保护 EL4 细胞免受 CMC 影响，但不影响单克隆抗体治疗的结果。 IgG 疗法的保护作用在 C3 或补体受体 3 (CR3) 缺陷的小鼠中也不受影响，但在 Fc gamma R I/III 缺陷的小鼠中几乎完全消除。这些数据表明抗体依赖性细胞介导的细胞毒性（ADCC）发挥着至关重要的作用。然而，在较低剂量的 IgG 下，C3 缺陷小鼠的治疗效果部分消失，表明补体介导的 ADCC 在限制 IgG 浓度下增强。与 IgG 相比，IgM 的治疗效果在 C3 缺陷小鼠中完全消失。 EL4 上 CD59 的高水平表达并不影响 IgM 治疗，这表明 IgM 通过补体依赖性细胞介导的细胞毒性 (CDCC) 发挥作用，这种机制被认为对肿瘤细胞无活性。因此，IgG和IgM可以通过不同的主要作用机制起作用，并且CDCC和ADCC机制的补体依赖性增强在体内起作用。补体的作用可以补充其他抗体介导的机制，并且可能在限制抗体浓度或低抗原密度方面具有更大的重要性。
The role of complement in antibody therapy of cancer is in general poorly understood. We used the EL4 syngeneic mouse model of metastatic lymphoma to investigate the role of complement in immunotherapy directed against GD2, a target of clinical relevance. lgG2a and IgM anti-GD2 therapy protected EL4-challenged mice from metastases and prolonged survival. Expression of CD59, an inhibitor of direct complement-mediated cytotoxicity (CMC), effectively protected EL4 cells from CMC in vitro but did not affect the outcome of monoclonal antibody therapy. Protection by IgG therapy was also unaffected in mice deficient in C3 or complement receptor 3 (CR3) but was almost completely abrogated in Fc gamma R I/III-deficient mice. These data indicate a crucial role for antibody-dependent cell-mediated eytoxicity (ADCC). However, at lower doses of IgG, therapeutic effect was partially abrogated in C3-deficient mice, indicating complement-mediated enhancement of ADCC at limiting IgG concentration. in contrast to IgG, the therapeutic effect of lgM was completely abrogated in C3-deficient mice. High level expression of CD59 on EL4 did not influence IgM therapy, suggesting IgM functions by complement-dependent cell-mediated cytotoxicity (CDCC), a mechanism thought to be inactive against tumor cells. Thus, IgG and IgM can operate via different primary mechanisms of action, and CDCC and complement-dependent enhancement of ADCC mechanisms are operative in vivo. The effects of complement can be supplemental to other antibody-mediated mechanisms and likely have increased significance at limiting antibody concentration or low antigen density.