Antibody and prodrug therapy of cancer

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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 gt
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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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Gleevec
Nature Reviews Drug Discovery 1 493-502, 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 1 118-129, 2001
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Nature Cancer Reviews 1 118-129, 2001
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Antibody-directed enzyme prodrug therapy
? Amplification step
? Bystander killing
? Flexibility
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ADEPT
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Summary of previous findings
BHAMG 100-1000 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 gt72 h
Km 31.0 µM Vmax 10.9 µmole/µg-min
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(No Transcript)
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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