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.

Abstract

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.

• Authors: Jie Gao, Geng Kou, Huaiwen Chen, Hao Wang, Bohua Li, Ying Lu, Dapeng Zhang, Shuhui Wang, Sheng Hou, Weizhu Qian, Jianxin Dai, Jian Zhao, Yanqiang Zhong, Yajun Guo
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 10 Pg. 3399-407 (Oct 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18852143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Antibodies, Monoclonal
• Immunoglobulin Fab Fragments
• Immunotoxins
• Polylactic Acid-Polyglycolic Acid Copolymer
• Polyglycolic Acid
• Lactic Acid

Topics

• Animals
• Antibodies
• Antibodies, Monoclonal (therapeutic use)
• Binding, Competitive (drug effects)
• Carcinoma, Hepatocellular (drug therapy)
• Cell Proliferation (drug effects)
• Endocytosis (drug effects)
• Humans
• Immunoglobulin Fab Fragments (therapeutic use, toxicity)
• Immunotoxins (therapeutic use, toxicity)
• Lactic Acid (metabolism)
• Liver Neoplasms (drug therapy)
• Mice
• Microscopy, Confocal
• Nanoparticles
• Polyglycolic Acid (metabolism)
• Polylactic Acid-Polyglycolic Acid Copolymer
• Xenograft Model Antitumor Assays