期刊
ACTA BIOMATERIALIA
卷 86, 期 -, 页码 373-380出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2019.01.011
关键词
Oriented immobilization; Scaffold; Antibody drug; Bio-nanocapsule; Cancer therapy
资金
- KAKENHI [16H06314]
- Japan Agency for Medical Research and Development [17cm0106214h0002, 17fk0310105h0001]
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- Impulsing Paradigm Change through Disruptive Technologies Program (ImPACT)
- [16K04888]
- Grants-in-Aid for Scientific Research [16H06314] Funding Source: KAKEN
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 Significance Antibody 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.
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