Treatment of hepatocellular carcinoma in mice with PE38KDEL type I mutant-loaded poly(lactic-co-glycolic acid) nanoparticles conjugated with humanized SM5-1 F(ab′) fragments

• Published in: Molecular cancer therapeutics 2008-10, Vol.7 (10), p.3399-3407
• Main Authors: Gao, Jie, Kou, Geng, Chen, Huaiwen, Wang, Hao, Li, Bohua, Lu, Ying, Zhang, Dapeng, Wang, Shuhui, Hou, Sheng, Qian, Weizhu, Dai, Jianxin, Zhao, Jian, Zhong, Yanqiang, Guo, Yajun
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - therapeutic use; Antitumor Activity; Binding, Competitive - drug effects; Carcinoma, Hepatocellular - drug therapy; Cell Proliferation - drug effects; Endocytosis - drug effects; Humans; Immunogenicity; Immunoglobulin Fab Fragments - therapeutic use; Immunoglobulin Fab Fragments - toxicity; Immunotoxins - therapeutic use; Immunotoxins - toxicity; Lactic Acid - metabolism; Liver Neoplasms - drug therapy; Mice; Microscopy, Confocal; Nanoparticle; Nanoparticles; PE38KDEL; Polyglycolic Acid - metabolism; SM5-1; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0514

We reported previously the development of SMFv-PE38KDEL type I mutant (PE38KDEL-I; Mut-I), a recombinant immunotoxin in which a single-chain antibody derived from mouse SM5-1 monoclonal antibody is genetically fused to PE38KDEL-I. In comparison with the SMFv-PE38KDEL wild-type, Mut-I showed improved therapeutic efficacy and reduced toxicity. To overcome the problems associated with the immune response to the Pseudomonas exotoxin A (PE) component of Mut-I, we have constructed PE38KDEL-I-loaded poly(lactic-co-glycolic acid) nanoparticles conjugated with F(ab′) fragments of a humanized SM5-1 monoclonal antibody (PE-NP-S). PE-NP-S specifically bound to SM5-1 binding protein-expressing hepatocellular carcinoma cell lines and was then internalized by these cells, resulting in significant cytotoxic effect. In SM5-1 binding protein-overexpressing tumor xenograft model, administration of PE-NP-S significantly inhibited tumor development and induced tumor regression. Moreover, PE-NP-S was shown to be much weaker in inducing vascular leakage syndrome in mice than Mut-I. The LD 50 of PE-NP-S was about 4-fold higher than that of Mut-I. Remarkably, PE-NP-S was of low immunogenicity in development of anti-PE neutralizing antibodies in vivo and was less susceptible to inactivation by anti-PE neutralizing antibodies compared with Mut-I. In conclusion, the resultant PE-NP-S possessed increased cancer therapeutic efficacy and had reduced nonspecific toxicity and immunogenicity, suggesting that it is a potential candidate in cancer therapy. [Mol Cancer Ther 2008;7(10):3399–407]