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PE38KDEL-loaded anti-HER2 nanoparticles inhibit breast tumor progression with reduced toxicity and immunogenicity

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Abstract

The clinical use of Pseudomonas exotoxin A (PE)-based immunotoxins is limited by the toxicity and immunogenicity of PE. To overcome the limitations, we have developed PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles conjugated with Fab′ fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2). The PE38KDEL-loaded nanoparticles-anti-HER2 Fab′ bioconjugates (PE-NP-HER) were constructed modularly with Fab′ fragments of rhuMAbHER2 covalently linked to PLGA nanoparticles containing PE38KDEL. Compared with nontargeted nanoparticles that lack anti-HER2 Fab′, PE-NP-HER specifically bound to and were sequentially internalized into HER2 overexpressing breast cancer cells, which result in significant cytotoxicity in vitro. In HER2 overexpressing tumor xenograft model system, administration of PE-NP-HER showed a superior efficacy in inhibiting tumor growth compared with PE-HER referring to PE38KDEL conjugated directly to rhuMAbHER2. Moreover, PE-NP-HER was well tolerated in mice with a higher LD50 (LD50 of 6.86 ± 0.47 mg/kg vs. 2.21 ± 0.32 mg/kg for PE-NP-HER vs. PE-HER (mean ± SD); n = 3), and had no influence on the plasma level of plasma alanine aminotransferase (ALT) of animals when injected at a dose of 1 mg/kg where PE-HER caused significant increase of serum ALT in the treated mice. Notably, PE-NP-HER was of low immunogenicity in development of anti-PE38KDEL neutralizing antibodies and was less susceptible to inactivation by anti-PE38KDEL antibodies compared with PE-HER. This novel bioconjugate, PE-NP-HER, may represent a useful strategy for cancer treatment.

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Acknowledgements

We thank Ms. Yang Yang and Ms. Jing Xu for their technical assistance. This work was supported by National Natural Science Foundation of China, Shanghai Commission of Science & Technology, Ministry of Science and Technology of China (973&863 program projects), Pudong Commission of Science and Technology of Shanghai and a special grant from E-Institute of Universities, Immunology Division, Shanghai Commission of Education.

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Authors and Affiliations

  1. International Joint Cancer Institute, and Department of Pharmaceutical Science of College of Pharmacy, New Library Building West 10th-11th Floor, The Second Military Medical University, 800 Xiang Yin Road, Shanghai, 200433, People’s Republic of China

    Jie Gao, Geng Kou, Hao Wang, Huaiwen Chen, Bohua Li, Ying Lu, Dapeng Zhang, Shuhui Wang, Sheng Hou, Weizhu Qian, Jianxin Dai, Jian Zhao, Yanqiang Zhong & Yajun Guo

  2. Shanghai Center for Cell Engineering and Antibody, 399 Libing Road, Shanghai, 201203, People’s Republic of China

    Geng Kou, Hao Wang, Bohua Li, Sheng Hou, Weizhu Qian & Yajun Guo

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  1. Jie Gao
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Correspondence to Yanqiang Zhong or Yajun Guo.

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J. Gao, G. Kou and H. Wang contributed equally to this work.

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Gao, J., Kou, G., Wang, H. et al. PE38KDEL-loaded anti-HER2 nanoparticles inhibit breast tumor progression with reduced toxicity and immunogenicity. Breast Cancer Res Treat 115, 29–41 (2009). https://doi.org/10.1007/s10549-008-0043-0

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