Chuntharapai A, Dodge K, Grimmer K, Schroeder K, Marsters S A, Koeppen H, Ashkenazi A, Kim K J
Department of Antibody Technology, Genentech, South San Francisco, CA 94080, USA.
J Immunol. 2001 Apr 15;166(8):4891-8. doi: 10.4049/jimmunol.166.8.4891.
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.
为探索一种癌症中靶向死亡受体的方法，我们制备了针对人死亡受体4（DR4）的鼠单克隆抗体。单克隆抗体4H6（IgG1）与Apo2L/肿瘤坏死因子相关凋亡诱导配体（DR4的配体）竞争结合DR4，而单克隆抗体4G7（IgG2a）则不竞争。在体外，两种单克隆抗体均显示出最小的内在凋亡诱导活性，但每种在交联后均引发强烈凋亡。在体内结肠肿瘤裸鼠模型中，未添加外源性连接体的单克隆抗体4H6治疗可诱导肿瘤细胞凋亡并导致肿瘤完全消退，而单克隆抗体4G7则部分抑制肿瘤生长。单克隆抗体4H6的IgG2a同种型转换变体在体内的效果远不如亲本IgG1-4H6，尽管其与DR4的结合亲和力相似。通过比较其他针对DR4的IgG1和IgG2单克隆抗体在体内的抗肿瘤活性也得出了相同的结论。因此，抗DR4单克隆抗体的同种型对于体内消除肿瘤可能比DR4结合亲和力更重要。IgG1同种型的抗DR4单克隆抗体可能为研究癌症中靶向死亡受体的治疗潜力提供有用的工具。
