Discovery of Novel Tumor-targeted Ribosome-inactivating Proteins from Combinatorial Protein Librarie

• 作 者: JeanGariépy;LRevers;S.Perampalam;MCheung;R.Kiarash;E.Green;
• 机 构: Department of Medical Biophysics Pharmaceutical Sciences The University of Toronto Canada
• 出 处: BIT Life Sciences' 1st Annual World Cancer Congess-2008(
• 发表日期: 2008年期

　　Ribosome-inactivating proteins such as ricin and Shiga-Like Toxin 1 (SLT-1) are highly effective at killing eukaryotic cells.Such molecules can be redirected to kill diseased cells by altering their receptor specificity.We report the design of combinatorial SLT-1 libraries expressing a large repertoire of SLT-1 variants, each harboring a unique peptide ligand inserted within their cytotoxic A subunit.High-throughput cell-based cytotoxicity assays performed on thousands of purified SLT-1 variants led to the discovery of a single-chaln, ribosome-inactivating protein displaying selectivity for human melanoma cell-lines.Preclinical studies indicate that this protein variant increases the survival time of SCID mice bearing a human melanoma xenograft, while displaying no toxicity in mice (at 4mg/kg) and low immunogenicity The directed evolution of a ribosome-inactivating protein template represents a broad platform for identifying protein-based anticancer agents that are distinct from antibodies.