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首页> 外文会议>Protein Engineering Summit. >Non-Covalent Modification of mPEGylated Nanoparticles by Humanized Bispecific Antibodies for Selective Therapy
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Non-Covalent Modification of mPEGylated Nanoparticles by Humanized Bispecific Antibodies for Selective Therapy

机译：通过人源化双特异性抗体进行选择性疗法的非共价修饰

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Background: Methoxy-polyethylene glycol (mPEG) modified nano-molecules (mPEG-NPs, such as liposomes, micelles, nanoparticles and proteins) are highly regarded as the third generation therapeutic agents. However, mPEG-NPs have the passive accumulation in tumor area that causes the reducing therapeutic efficacy and drug resistant. PEG-NPs can be chemically modified by ligands or antibodies to increase their targeting specificity. However, this method often leads to the generation of heterogeneously modified Ab-PEG-NPs (variations in number and orientation of Ab), which limits its clinical applicability.Materials and Methods: To overcome these problems, we have developed bispecific antibodies (BsAb) by fusing anti-HER2 scFv to the C-terminus of a humanized anti-methoxy polyethylene glycol Fab (anti-mPEG) to form HER2 BsAb. The anti-mPEG end of the BsAb could noncovalently bind to the methoxy ends of mPEG-NPs. The other anti-HER2 end confers mPEG-NPs with HER2 specificity for targeting of HER2 expressing cancer cells. Results: We demonstrate that HER2 BsAb can simultaneously bind to mPEG on mPEG-NPs and to HER2 expressed on cancer cells. Non-covalent modification of HER2 BsAb with Lipo-DOX endowed the NPs with specificity to HER2 on cancer cells and also significantly increased cancer cell killing by anti-HER2/Lipo-Dox to HER2+ cancer cells, especially in the doxorubicin-resistant and Herceptin-resistant cells. Importantly, HER2 BsAb significantly increased the anticancer activity of Lipo/DOX against HER+ tumors and the doxorubicin-resistant and Herceptin-resistant tumors. Additionally, we also develop the several BsAbs that target EGFR, CD20 to modify on Lipo-DOX to enhance the tumor specific targeting and anticancer activity. Discussion: We believe that anti-mPEG BsAbs can provide a simple one-step method for non-covalent modification of any mPEG-NP, allowing increased specific targeting and therapeutic efficacy of mPEG-NPs such as liposomes, micelles and gold nanoparticles for tumors in the clinic.Key Words: Methoxy-PEGylated nanoparticles (mPEG-NPs), Bispecific antibodies (BsAb), Liposomal doxorubicin (Lipo-Dox), Noncovalent modification, anti-HER2-Lipo-Dox: Noncovalent modification of Lipo-Dox with HER2 BsAb.
机译：背景技术甲氧基 - 聚乙二醇（MPEG）改性纳米分子（MPEG-NPS，例如脂质体，胶束，纳米颗粒和蛋白质）被高度被认为是第三代治疗剂。然而，MPEG-NPS具有导致降低治疗效果和耐药性的肿瘤区域中的被动积累。 PEG-NPS可以通过配体或抗体化学改性，以增加其靶向特异性。然而，该方法通常导致产生异构改性的AB-NPS（AB的数量和取向的变化），这限制了其临床适用性。以克服这些问题，我们已经开发了双特异性抗体（BSAB）通过将抗HER2SCFV融合到人源化抗甲氧基聚乙二醇FAB（抗MPEG）的C-末端以形成HER2 BSAB。 BSAB的抗MPEG末端可以非共价结合到MPEG-NP的甲氧基端。另一种抗HER2末端将MPEG-NPS与HER2表达癌细胞靶向HER2的特异性。结果：我们证明HER2 BSAB可以同时与MPEG-NPS上的MPEG结合，并在癌细胞上表达HER2。用Lipo-Dox的非共价修饰HELO-DOX赋予HER2对癌细胞特异性的NPS，并且抗HER2 / LIPO-DOX对HER2 +癌细胞的癌细胞杀死显着增加，特别是在多柔枯蛋白抗性和赫赛汀 - 抗细胞。重要的是，HER2 BSAB显着提高了脂肪/ DOX对患者+肿瘤和抗植物抗性和沉降肿瘤的抗癌活性。此外，我们还开发了靶向EGFR，CD20的几种BSAB，以改变Lipo-Dox，以增强肿瘤特异性靶向和抗癌活动。讨论：我们认为抗MPEG BSABs可以提供一种简单的一种用于任何MPEG-NP的非共价修饰的简单一步法，允许MPEG-NPS如脂质体，胶束和金纳米颗粒的增加的特异性靶向和治疗效果临床.Key单词：甲氧基聚乙烯化纳米颗粒（MPEG-NPS），双特异性抗体（BSAB），脂质体DOXORUBICIN（LIPO-DOX），非共价修饰，抗HER2-LIPO-DOX：用HER2 BSAB的Lipo-Dox的非共价修饰。

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