Oriented immobilization to nanoparticles enhanced the therapeutic efficacy of antibody drugs
Oriented immobilization to nanoparticles enhanced the therapeutic efficacy of antibody drugs
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DOI：
10.1016/j.actbio.2019.01.011
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发表时间：
2019-03-01
影响因子：
9.7
通讯作者：
Kuroda, Shun'ichi
中科院分区：
文献类型：
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作者：
Iijima, Masumi;Araki, Kyoko;Kuroda, Shun'ichi
在过去的三十年里，抗体药物一直是治疗各种疾病的重要治疗剂，如癌症、风湿病和高胆固醇血症。尽管它们在体内表现出良好的治疗效果和良好的安全性，但它们需要高剂量。我们研制了一种类似于30 nm的生物纳米胶囊(ZZ-BNC)，它由乙肝病毒包膜L蛋白与串联形式的蛋白A衍生的免疫球蛋白Fc结合Z结构域(ZZ-L蛋白)融合而成，用于定向固定化抗体。在本研究中，抗体药物自发地偶联到ZZ-BNC上，ZZ-BNC向外展示了Ig G FV区。与ZZ-BNC偶联的抗人表皮生长因子受体Ig G(α-hEGFR-ZZ-BNC)被人表皮样癌A431细胞内吞，其摄取能力比单独使用α-hEGFR Ig G提高约1.5倍。结合ZZ-BNC后，晚期内体和溶酶体中α-hEGFR-Ig G的含量从4%增加到33%。α-hEGFR-ZZ-BNC的体外杀伤活性比单独使用的α-hEGFR-ZZ-BNC高约10倍。此外，在体内，α-hEGFR-ZZ-BNC组的肿瘤生长明显低于单独使用α-hEGFR-Ig G组。综上所述，由于在EGFR介导的信号级联中起关键作用的是胞体内的EGFR，而不是细胞表面的EGFR，ZZ-BNC通过有效地抑制hEGFR在细胞表面以及可能在内小体中的激活来提高α-hEGFR的亲和力。这些结果有力地表明，ZZ-BNC是一种很有前途的纳米支架，可以提高治疗效果，减少抗体药物的用量。意义陈述抗体药物被广泛用于治疗癌症、风湿病和高胆固醇血症等严重疾病。这些药物由天然生物材料组成，免疫原性和毒性低，体内血清半衰期长。为了达到足够的治疗效果，抗体药物的剂量不可避免地高于常规药物。本研究展示了一种通过使用纳米载体偶联抗体来减少抗体药物剂量的创新方法。定向固定化提高了抗体的亲和力、吞噬效率和治疗效果。(C)2019 Acta Materialia Inc.由Elsevier Ltd.出版。保留所有权利。
Antibody drugs have been important therapeutic agents for treating various diseases, such as cancer, rheumatism, and hypercholesterolemia, for the last three decades. Despite showing excellent therapeutic efficacy with good safety in vivo, they require high doses. We have developed a similar to 30-nm bio-nanocapsule (ZZ-BNC) consisting of hepatitis B virus envelope L protein fused with the tandem form of protein A-derived IgG Fc-binding Z domain (ZZ-L protein), for tethering antibodies in an oriented immobilization manner. In this study, antibody drugs were spontaneously conjugated to ZZ-BNC, which displayed the IgG Fv regions outwardly. The anti-human epidermal growth factor receptor IgG conjugated to ZZ-BNC (alpha-hEGFR-ZZ-BNC) was endocytosed by the human epidermoid carcinoma A431 cells, with increases in cellular uptake by similar to 1.5 fold, compared that of alpha-hEGFR IgG alone. The amount of alpha-hEGFR IgG in the late endosomes and lysosomes was increased from 4% to 33% by the conjugation to ZZ-BNC. The in vitro cytotoxicity of alpha-hEGFR-ZZ-BNC was higher by similar to 10-fold than that of alpha-hEGFR IgG alone. Furthermore, in vivo tumor growth was significantly reduced by alpha-hEGFR-ZZ-BNC than by alpha-hEGFR IgG alone. Taken together, since endosomal EGFR, not cell surface EGFR, played a pivotal role in the EGFR-mediated signaling cascade, ZZ-BNC increased alpha-hEGFR IgG avidity by efficiently repressing the activation of hEGFR not only on the cell surface, but presumably also in the endosomes. These results strongly suggested that ZZ-BNC is a promising nano-scaffold for enhancing the therapeutic efficacy and reducing the dose of antibody drugs.Statement of SignificanceAntibody drugs are widely used for treating severe diseases, such as cancer, rheumatism, and hypercholesterolemia. These drugs are composed of naturally occurring biomaterials with low immunogenicity and toxicity, as well as long in vivo serum half-life. To achieve sufficient therapeutic efficacy, the dose of antibody drugs are unavoidably higher than those of conventional drugs. The present study shows an innovative way to reduce the dose of antibody drugs by using a nanocarrier-conjugated antibody. Oriented immobilization of the antibody enhanced its avidity, endocytosis efficiency, and therapeutic efficacy. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.