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Antibody and prodrug therapy of cancer
Steve Roffler Institute of Biomedical Sciences Academia Sinica
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Overview Cancer drug therapeutic index
Antibody targeted prodrug activation 9ACG - new glucuronide prodrug Surface expression of proteins scFv activation of T cells Membrane suicide gene therapy
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Effective medicines require a therapeutic index > 1
Toxic drug concentration Therapeutic concentration Property of tumor cells Unique or over-expressed target in cancer cells Relative resistance of normal cells Tumor targeting
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Alkylating agents kill dividing cells
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Basis for cancer drug therapeutic index
Property of tumor cells Unique or over-expressed target in cancer cells Relative resistance of normal cells Tumor targeting
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Nature Reviews Drug Discovery 1: 493-502, 2002
Gleevec Nature Reviews Drug Discovery 1: , 2002
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Topoisomerase I inhibitors
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Basis for cancer drug therapeutic index
Property of tumor cells Unique or over-expressed target in cancer cells Relative resistance of normal cells Tumor targeting
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Cyclophosphamide metabolism
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Basis for cancer drug therapeutic index
Property of tumor cells Unique or over-expressed target in cancer cells Relative resistance of normal cells Tumor targeting
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Antibody-targeted cancer therapy
Nature Cancer Reviews 1: , 2001
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Nature Cancer Reviews 1: 118-129, 2001
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Antibody-directed enzyme prodrug therapy
∆ Flexibility ∆ Amplification step ∆ Bystander killing
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ADEPT
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Summary of previous findings
BHAMG times less toxic than pHAM in vitro Mechanism of low prodrug toxicity Produces strong bystander effect in vitro and in vivo Clearance of immunoenzyme improves tumor localization Cured rat hepatocellular carcinoma tumors
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Immunoenzymes for human cancer therapy
+ mAb B72.3 against TAG-72 + on colon, breast, ovarian, lung cancers + employed for imaging in over 1000 patients + TAG-72 in not internalized
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Immunoenzyme localization
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ADEPT therapy of human colon xenografts
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ADEPT therapy of rat malignant ascites
Day 0 Inject 1.5x107 ADS-30D cells Day 1 Inject 1.5x107 AS-30D cells Day 7 Inject RH1-bG immunoenzyme Inject BHAMG prodrug
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In vivo depletion of immune cells during ADEPT
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T cells are important for control of metastasis during ADEPT
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Glucuronide prodrug of camptothecin
- poor water solubility - converted to inactive form in vivo - high toxicity
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9ACG 9-aminocamptothecin glucuronide
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Properties of 9ACG - 100 to 2000 times more soluble than 9AC
- stable in human serum for >72 h Km = 31.0 µM Vmax = 10.9 µmole/µg-min
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9ACG activity against human lung cancer
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Low dose 9ACG vs. topotecan
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Mechanism of 9ACG activation
9ACG activated by ß-glucuronidase at tumor? Source of ß-glucuronidase - tumor or immune cells? anti-mouse ß-glucuronidase anti-human ß-glucuronidase ß-glucuronidase KO tumor ß-glucuronidase KO mice
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