Antibody and prodrug therapy of cancer

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Presentation transcript:

Antibody and prodrug therapy of cancer Steve Roffler Institute of Biomedical Sciences Academia Sinica

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

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

Alkylating agents kill dividing cells

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

Nature Reviews Drug Discovery 1: 493-502, 2002 Gleevec Nature Reviews Drug Discovery 1: 493-502, 2002

Topoisomerase I inhibitors

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

Cyclophosphamide metabolism

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

Antibody-targeted cancer therapy Nature Cancer Reviews 1: 118-129, 2001

Nature Cancer Reviews 1: 118-129, 2001

Antibody-directed enzyme prodrug therapy ∆ Flexibility ∆ Amplification step ∆ Bystander killing

ADEPT

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

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

Immunoenzyme localization

ADEPT therapy of human colon xenografts

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

In vivo depletion of immune cells during ADEPT

T cells are important for control of metastasis during ADEPT

Glucuronide prodrug of camptothecin - poor water solubility - converted to inactive form in vivo - high toxicity

9ACG 9-aminocamptothecin glucuronide

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

9ACG activity against human lung cancer

Low dose 9ACG vs. topotecan

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