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

  2. 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

  3. 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

  4. Alkylating agents kill dividing cells

  5. 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

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

  7. Topoisomerase I inhibitors

  8. 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

  9. Cyclophosphamide metabolism

  10. 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

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

  12. Nature Cancer Reviews 1: 118-129, 2001

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

  14. ADEPT

  15. 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

  16. 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

  17. Immunoenzyme localization

  18. ADEPT therapy of human colon xenografts

  19. 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

  20. In vivo depletion of immune cells during ADEPT

  21. T cells are important for control of metastasis during ADEPT

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

  23. 9ACG 9-aminocamptothecin glucuronide

  24. 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

  25. 9ACG activity against human lung cancer

  26. Low dose 9ACG vs. topotecan

  27. 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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