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

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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

Alkylating agents kill dividing cells


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

Topoisomerase I inhibitors


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

Cyclophosphamide metabolism


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 and prodrug therapy of cancer

Nature Cancer Reviews 1: 118-129, 2001


Antibody directed enzyme prodrug therapy

Antibody-directed enzyme prodrug therapy

∆ Flexibility

∆ Amplification step

∆ Bystander killing


Adept

ADEPT


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


Immunoenzyme localization

Immunoenzyme localization


Adept therapy of human colon xenografts

ADEPT therapy of human colon xenografts


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


In vivo depletion of immune cells during adept

In vivo depletion of immune cells during ADEPT


T cells are important for control of metastasis during adept

T cells are important for control of metastasis during ADEPT


Glucuronide prodrug of camptothecin

Glucuronide prodrug of camptothecin

- poor water solubility

- converted to inactive form in vivo

- high toxicity


9acg 9 aminocamptothecin glucuronide

9ACG 9-aminocamptothecin glucuronide


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

9ACG activity against human lung cancer


Antibody and prodrug therapy of cancer

Low dose 9ACG vs. topotecan


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


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