Antibody and prodrug therapy of cancer
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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.

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Antibody and prodrug therapy of cancer
Antibody and prodrug therapy of cancer

Steve Roffler

Institute of Biomedical Sciences

Academia Sinica


Overview
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


Antibody and prodrug therapy of cancer

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



Antibody and prodrug therapy of cancer

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 and prodrug therapy of cancer

Gleevec

Nature Reviews Drug Discovery 1: 493-502, 2002



Antibody and prodrug therapy of cancer

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 and prodrug therapy of cancer

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 and prodrug therapy of cancer

Antibody-targeted cancer therapy

Nature Cancer Reviews 1: 118-129, 2001



Antibody directed enzyme prodrug therapy
Antibody-directed enzyme prodrug therapy

∆ Flexibility

∆ Amplification step

∆ Bystander killing



Summary of previous findings
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
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




Adept therapy of rat malignant ascites
ADEPT therapy of rat malignant ascites

Day 0Inject 1.5x107 ADS-30D cells

Day 1Inject 1.5x107 AS-30D cells

Day 7Inject RH1-bG immunoenzyme

Inject BHAMG prodrug




Glucuronide prodrug of camptothecin
Glucuronide prodrug of camptothecin

- poor water solubility

- converted to inactive form in vivo

- high toxicity



Properties of 9acg
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




Antibody and prodrug therapy of cancer

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