Targeted antibodies and methoxy-PEGylated nanocarriers have gradually become a mainstream of cancer therapy. To increase the anti-cancer effects of targeted antibodies combined with mPEGylated liposomes (mPEG-liposomes), we describe a bispecific antibody in which an anti-methoxy-polyethylene glycol scFv (αmPEG scFv) was fused to the C-terminus of an anti-HER2 (αHER2) antibody to generate a HER2 × mPEG BsAb that retained the original efficacy of a targeted antibody while actively attracting mPEG-liposomes to accumulate at tumor sites. HER2 ×mPEG BsAb can simultaneously bind to HER2-high expressing MCF7/HER2 tumor cells and mPEG molecules on mPEG-liposomal doxorubicin (Lipo-Dox). Pre-incubation of HER2 × mPEG BsAb with cells increased the endocytosis of Lipo-DiD and enhanced the cytotoxicity of Lipo-Dox to MCF7/HER2 tumor cells. Furthermore, pre-treatment of HER2 × mPEG BsAb enhanced the tumor accumulation and retention of Lipo-DiR 2.2-fold in HER2-high expressing MCF7/HER2 tumors as compared to HER2-low expressing MCF7/neo1 tumors. Importantly, HER2 × mPEG BsAb plus Lipo-Dox significantly suppressed tumor growth as compared to control BsAb plus Lipo-Dox in MCF7/HER2 tumor-bearing mice. These results indicate that HER2 × mPEG BsAb can enhance tumor accumulation of mPEG-liposomes to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy.

Statement of Significance

Antibody targeted therapy and PEGylated drugs have gradually become the mainstream of cancer therapy. To enhance the anti-cancer effects of targeted antibodies combined with PEGylated drugs is very important. To this aim, we fused an anti-PEG scFv to the C-terminal of HER2 targeted antibodies to generate a HER2×mPEG bispecific antibody (BsAb) to retain the original efficacy of targeted antibody whilst actively attract mPEG-liposomal drugs to accumulate at tumor sites. The present study demonstrates pre-treatment of HER2×mPEG BsAb can enhance tumor accumulation of mPEG-liposomal drugs to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy.

中文翻译：

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双特异性抗体（HER2×mPEG）通过精确靶向和聚乙二醇化脂质体来增强抗癌作用。

靶向抗体和甲氧基聚乙二醇化的纳米载体已逐渐成为癌症治疗的主流。为了增加与mPEG化脂质体（mPEG-脂质体）结合的靶向抗体的抗癌作用，我们描述了一种双特异性抗体，其中将抗甲氧基-聚乙二醇scFv（αmPEGscFv）融合到抗-PEG的C末端HER2（αHER2）抗体产生的HER2×mPEG BsAb保留了靶向抗体的原始功效，同时积极吸引mPEG-脂质体积聚在肿瘤部位。HER2×mPEG BsAb可以同时与高表达HER2的MCF7 / HER2肿瘤细胞和mPEG-脂质体阿霉素（Lipo-Dox）上的mPEG分子结合。HER2×mPEG BsAb与细胞的预孵育增加了Lipo-DiD的内吞作用，并增强了Lipo-Dox对MCF7 / HER2肿瘤细胞的细胞毒性。此外，与低表达HER2的MCF7 / neo1肿瘤相比，HER2×mPEG BsAb的预处理增强了高表达HER2的MCF7 / HER2肿瘤的肿瘤蓄积和脂质体DiR 2.2保留。重要的是，与带有MCF7 / HER2荷瘤小鼠的对照BsAb加Lipo-Dox相比，HER2×mPEG BsAb加Lipo-Dox显着抑制了肿瘤的生长。这些结果表明，HER2×mPEG BsAb可以增强mPEG-脂质体的肿瘤蓄积，从而提高联合治疗的疗效。可以将抗mPEG scFv与任何类型的靶向抗体融合，以生成BsAb，从而积极吸引mPEG药物并提高抗癌效力。与带有MCF7 / HER2荷瘤小鼠的对照BsAb加Lipo-Dox相比，HER2×mPEG BsAb加Lipo-Dox显着抑制了肿瘤的生长。这些结果表明，HER2×mPEG BsAb可以增强mPEG-脂质体的肿瘤蓄积，从而提高联合治疗的疗效。可以将抗mPEG scFv与任何类型的靶向抗体融合，以生成BsAb，从而积极吸引mPEG药物并提高抗癌效力。与带有MCF7 / HER2荷瘤小鼠的对照BsAb加Lipo-Dox相比，HER2×mPEG BsAb加Lipo-Dox显着抑制了肿瘤的生长。这些结果表明，HER2×mPEG BsAb可以增强mPEG-脂质体的肿瘤蓄积，从而提高联合治疗的疗效。可以将抗mPEG scFv与任何类型的靶向抗体融合，以生成BsAb，从而积极吸引mPEG药物并提高抗癌效力。

重要声明

抗体靶向治疗和聚乙二醇化药物已逐渐成为癌症治疗的主流。增强靶向抗体与聚乙二醇化药物联合的抗癌作用非常重要。为此，我们将抗PEG scFv融合到HER2靶向抗体的C端，以生成HER2xmPEG双特异性抗体（BsAb），以保留靶向抗体的原始功效，同时积极吸引mPEG-脂质体药物积聚在肿瘤上网站。本研究表明HER2×mPEG BsAb的预处理可以增强mPEG-脂质体药物的肿瘤蓄积，提高联合治疗的疗效。可以将抗mPEG scFv与任何类型的靶向抗体融合以生成BsAb，从而主动吸引mPEG药物并提高抗癌效力。