Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi , Shinagawa-ku, Tokyo 140-8710 , Japan.
Mol Pharm. 2018 Sep 4;15(9):3729-3740. doi: 10.1021/acs.molpharmaceut.7b01167. Epub 2018 Apr 27.
We have developed a technology for efficiently enhancing the anticancer apoptosis-inducing activity of agonistic antibodies against the tumor necrosis factor receptor (TNFR) superfamily by the formation of immunoliposomes. To induce apoptosis in cancer cells, agonistic antibodies to the TNFR superfamily normally need cross-linking by internal immune effector cells via the Fc region after binding to receptors on the cell membrane. To develop apoptosis-inducing antibodies that do not require the support of cross-linking by immune cells, we prepared immunoliposomes conjugated with TRA-8, an agonistic antibody against death receptor 5 (DR5), with various densities of antibody on the liposome surface, and evaluated their activities. The TRA-8 immunoliposomes exhibited apoptosis-inducing activity against various DR5-positive human carcinoma cells at a significantly lower concentration without cross-linking than that of the original TRA-8 and its natural ligand (TRAIL). The activity of the immunoliposomes was correlated with the density of antibodies on the surface. As the antibody component, not only the full-length antibody but also the Fab' fragment could be used, and the TRA-8 Fab' immunoliposomes also showed exceedingly high activity compared with the parental antibody, namely, TRA-8. Moreover, cytotoxicity of the TRA-8 full-length or Fab' immunoliposome against normal cells, such as human primary hepatocytes, was lower than that for TRAIL. Enhanced activity was also observed for immunoliposomes conjugated with other apoptosis-inducing antibodies against other receptors of the TNFR superfamily, such as death receptor 4 (DR4) and Fas. Thus, immunoliposomes are promising as a new modality that could exhibit significant activity at a low dose, for cost-effective application of an antibody fragment and with stable efficacy independent of the intratumoral environment of patients as a TNF superfamily agonistic therapy.
我们开发了一种技术，通过形成免疫脂质体，有效地增强了针对肿瘤坏死因子受体（TNFR）超家族的激动型抗体的抗癌凋亡诱导活性。为了诱导癌细胞凋亡，针对 TNFR 超家族的激动型抗体通常需要在与细胞膜上的受体结合后，通过 Fc 区域由内部免疫效应细胞交联。为了开发不需要免疫细胞交联支持的凋亡诱导抗体，我们制备了与 TRA-8 缀合的免疫脂质体，TRA-8 是一种针对死亡受体 5（DR5）的激动型抗体，脂质体表面的抗体密度不同，并评估了它们的活性。与原始 TRA-8 和其天然配体（TRAIL）相比，TRA-8 免疫脂质体在没有交联的情况下以显著更低的浓度对各种 DR5 阳性人癌细胞表现出诱导凋亡的活性。免疫脂质体的活性与表面抗体的密度相关。作为抗体成分，不仅可以使用全长抗体，还可以使用 Fab'片段，并且 TRA-8 Fab'免疫脂质体与亲本抗体 TRA-8 相比也表现出极高的活性。此外，TRA-8 全长或 Fab'免疫脂质体对正常细胞（如人原代肝细胞）的细胞毒性低于 TRAIL。与其他 TNFR 超家族受体（如死亡受体 4（DR4）和 Fas）的凋亡诱导抗体缀合的免疫脂质体也观察到增强的活性。因此，免疫脂质体作为一种新的治疗模式具有很大的潜力，在低剂量下即可表现出显著的活性，能够以具有成本效益的方式应用抗体片段，并具有稳定的疗效，而不受患者肿瘤内环境的影响，可作为 TNF 超家族激动剂治疗。
