Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4
Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4
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DOI：
10.4049/jimmunol.166.8.4891
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发表时间：
2001-04-15
影响因子：
4.4
通讯作者：
Kim, KJ
中科院分区：
文献类型：
--
作者：
Chuntharapai, A;Dodge, K;Kim, KJ
为了探索癌症中死亡受体靶向的方法，我们开发了针对人死亡受体4（DR 4）的鼠单克隆抗体。mAb 4 H6（IgG 1）与Apo 2L/TNF相关的细胞凋亡诱导配体（DR 4的配体）竞争结合DR 4，而mAb 4G 7（IgG 2a）则不竞争。在体外，这两种单克隆抗体显示出最小的内在凋亡诱导活性，但每一个触发强大的细胞凋亡后交联。在体内结肠肿瘤裸鼠模型中，不添加外源性连接体的mAb 4 H6处理诱导肿瘤细胞凋亡并导致完全肿瘤消退，而mAb 4G 7部分抑制肿瘤生长。mAb 4 H6的IgG 2a同种型转换变体在体内的有效性远低于亲本IgG 1 - 4 H6，尽管与DR 4的结合亲和力相似。通过比较其他IgG 1和IgG 2 mAb与DR 4的体内抗肿瘤活性，获得了相同的结论。因此，抗DR 4 mAb的同种型对于体内肿瘤消除可能比DR 4结合亲和力更重要。IgG 1同种型的抗DR 4单克隆抗体可能为研究癌症中死亡受体靶向的治疗潜力提供有用的工具。
To explore an approach for death receptor targeting in cancer, we developed murine mAbs to human death receptor 4 (DR4). The mAb 4H6 (IgG1) competed with Apo2L/TNF-related apoptosis-inducing ligand (DR4's ligand) for binding to DR4, whereas mAb 4G7 (IgG2a) did not. In vitro, both mAbs showed minimal intrinsic apoptosis-inducing activity, but each triggered potent apoptosis upon cross-linking. In a colon tumor nude mouse model in vivo, mAb 4H6 treatment without addition of exogenous linkers induced apoptosis in tumor cells and caused complete tumor regression, whereas mAb 4G7 partially inhibited tumor growth. An IgG2a isotype switch variant of mAb 4H6 was much less effective in vivo than the parent IgG1-4H6, despite similar binding affinities to DR4. The same conclusion was obtained by comparing other IgG1 and IgG2 mAbs to DR4 for their anti-tumor activities in vivo. Thus, the isotype of anti-DR4 mAb may be more important than DR4 binding affinity for tumor elimination in vivo. Anti-DR4 mAbs of the IgG1 isotype may provide a useful tool for investigating the therapeutic potential of death receptor targeting in cancer.