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Membrane-anchored b-glucuronidase Steve Roffler Institute of Biomedical Sciences Academia Sinica Taipei, Taiwan Memzyme activation of imaging or therapeutic agents Glucuronide probe or drug glucuronide glucuronide glucuronide glucuronide ß-glucuronidase B7 TM Transgene Expression MEMzyme Transgene Potential advantage: Signal amplification due to enzymatic hydrolysis of glucuronide probes or drugs Potential advantages of a ßG reporter ßG in lysosomes – inaccessible to glucuronides Low serum ßG – little systemic activation Low toxicity Fast renal clearance – rapid imaging Endogenous - low immunogenicity Many possible glucuronide probes and drugs In vitro imaging of gene expression red = enzyme expression green = activated probe accumulation Fluorescent probe can be activated and accumulate at cells that express enzyme Imaging of adenovirus memzyme expression Kodak IS2000MM Sites of Ad transgene expression could be imaged In vitro activation of HAMG HAMG Glucuronide prodrug pHAM Active drug COOH O 3 H-thymidine incorporation (% control ) HO HO Cl O N OH HO Cl N Cl Cl 125 100 75 EJ-pHAM EJ-HAMG 50 EJ/mbG-pHAM EJ/mbG-HAMG 25 0 0.1 1 10 100 1000 Concentration(nM) HAMG can be activated at EJ/mßG cells HAMG prodrug toxicity to mice HAMG is well tolerated by mice Prodrug therapy of EJ tumors (150 mg/kg HAMG on days 15 and 19) Tumor volume (mm3) 2000 EJ PBS EJ HAMG EJ/mßG PBS EJ/mßG HAMG 1000 0 0 10 20 30 40 50 Days HAMG displayed selective activity against EJ/mßG tumors Summary Surface enzyme allow both imaging and therapy Immunogenicity is low but selectivity is high May possess advantages for cancer gene therapy Surface expression Tang-Bi Liu T cell activation Shih-en Chang Wen-Jun Chung Dr. Tian-Lu Cheng Kaohsiung Medical University Chin-Chuan Chen Pei-Yu Wu Yi-Hsuan Chiang Chien-I Su Dr. Hsin-Ell Wang National Yang Ming University Dr. Yu-Ling Leu Chia-Nan College of Pharmacy and Science Surface scFv Dr. Kuang-Wen Liao Shey-Cherng Tzo Bing-Mae Chen Dr. Ji-Wang Chern National Taiwan University http://www.ibms.sinica.edu.tw/~sroff/sr_refs.html