Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
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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