采用预靶向双特异性抗体（CD20 Ab-mPEG scFv）和主动吸引聚乙二醇化脂质体阿霉素的双重攻击策略，增强抗肿瘤活性。
Double attack strategy for leukemia using a pre-targeting bispecific antibody (CD20 Ab-mPEG scFv) and actively attracting PEGylated liposomal doxorubicin to enhance anti-tumor activity.
机构信息
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
出版信息
J Nanobiotechnology. 2021 Jan 9;19(1):16. doi: 10.1186/s12951-020-00752-w.
BACKGROUND
Tumor-targeted nanoparticles hold great promise as new tools for therapy of liquid cancers. Furthermore, the therapeutic efficacy of nanoparticles can be improved by enhancing the cancer cellular internalization.
METHODS
In this study, we developed a humanized bispecific antibody (BsAbs: CD20 Ab-mPEG scFv) which retains the clinical anti-CD20 whole antibody (Ofatumumab) and is fused with an anti-mPEG single chain antibody (scFv) that can target the systemic liquid tumor cells. This combination achieves the therapeutic function and simultaneously "grabs" Lipo-Dox® (PEGylated liposomal doxorubicin, PLD) to enhance the cellular internalization and anticancer activity of PLD.
RESULTS
We successfully constructed the CD20 Ab-mPEG scFv and proved that CD20 Ab-mPEG scFv can target CD20-expressing Raji cells and simultaneously grab PEGylated liposomal DiD increasing the internalization ability up to 60% in 24 h. We further showed that the combination of CD20 Ab-mPEG scFv and PLD successfully led to a ninefold increase in tumor cytotoxicity (LC: 0.38 nM) compared to the CD20 Ab-DNS scFv and PLD (lC: 3.45 nM) in vitro. Importantly, a combination of CD20 Ab-mPEG scFv and PLD had greater anti-liquid tumor efficacy (P = 0.0005) in Raji-bearing mice than CD20 Ab-DNS scFv and PLD.
CONCLUSION
Our results indicate that this "double-attack" strategy using CD20 Ab-mPEG scFv and PLD can retain the tumor targeting (first attack) and confer PLD tumor-selectivity (second attack) to enhance PLD internalization and improve therapeutic efficacy in liquid tumors.
背景
肿瘤靶向纳米颗粒作为治疗液体癌的新工具具有巨大的潜力。此外，通过增强癌细胞的内化作用，可以提高纳米颗粒的治疗效果。
方法
在本研究中，我们开发了一种人源化双特异性抗体（BsAbs：CD20 Ab-mPEG scFv），它保留了临床抗 CD20 全抗体（Ofatumumab），并融合了一种可以靶向全身液体肿瘤细胞的抗 mPEG 单链抗体（scFv）。这种组合实现了治疗功能，同时“抓住”Lipo-Dox®（聚乙二醇化阿霉素脂质体，PLD），以增强 PLD 的细胞内化和抗癌活性。
结果
我们成功构建了 CD20 Ab-mPEG scFv，并证明 CD20 Ab-mPEG scFv 可以靶向表达 CD20 的 Raji 细胞，并同时抓住聚乙二醇化脂质体 DiD，使内化能力在 24 小时内增加 60%。我们进一步表明，CD20 Ab-mPEG scFv 与 PLD 的组合导致肿瘤细胞毒性增加了九倍（LC：0.38 nM），与 CD20 Ab-DNS scFv 和 PLD（LC：3.45 nM）相比，在体外。重要的是，CD20 Ab-mPEG scFv 与 PLD 的组合在 Raji 荷瘤小鼠中的抗液体肿瘤疗效优于 CD20 Ab-DNS scFv 和 PLD（P=0.0005）。
结论
我们的结果表明，这种使用 CD20 Ab-mPEG scFv 和 PLD 的“双重攻击”策略可以保留肿瘤靶向性（第一次攻击），并赋予 PLD 肿瘤选择性（第二次攻击），以增强 PLD 的内化作用，提高液体肿瘤的治疗效果。
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