antibody and prodrug therapy of cancer
Download
Skip this Video
Download Presentation
Antibody and prodrug therapy of cancer

Loading in 2 Seconds...

play fullscreen
1 / 28

Antibody and prodrug therapy of cancer - PowerPoint PPT Presentation


  • 353 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Antibody and prodrug therapy of cancer' - chun


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
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

slide3

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

slide5

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

slide6

Gleevec

Nature Reviews Drug Discovery 1: 493-502, 2002

slide8

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

slide10

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

slide11

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

slide28

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

ad