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Potency Assays For Recombinant Viral Vaccines For Cancer Therapy

Potency Assays For Recombinant Viral Vaccines For Cancer Therapy. Kelledy Manson Sr. Director Bioanalytical Development Therion Biologics Corporation February 9, 2006. Agenda. Introduction to Therion products Challenges for Therion potency assays Matrix approach to potency evaluation

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Potency Assays For Recombinant Viral Vaccines For Cancer Therapy

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  1. Potency Assays For Recombinant Viral Vaccines For Cancer Therapy Kelledy Manson Sr. Director Bioanalytical Development Therion Biologics Corporation February 9, 2006

  2. Agenda • Introduction to Therion products • Challenges for Therion potency assays • Matrix approach to potency evaluation • Surrogate assays • Questions and Answers

  3. Introduction to Therion Products • PANVAC-VF • Phase 3 for the treatment of patients with metastatic pancreatic cancer • PROSTVAC®-VF • Phase 2 for the treatment of patients with metastatic prostate cancer Poxviruses deliver genes encoding target tumor antigens and immune-enhancing proteins

  4. Complex Biologic Function

  5. Complex Biologic Function

  6. Poxvirus Vectors • Vaccinia (V) • Replicates in multiple cell types • Replication limited by rapid host immune response • Fowlpox (F) • Replicates only in avian cells • Infects and expresses proteins but does not replicate in mammalian cells • Protein expression not inhibited by host immune response to fowlpox Administered in a heterologous prime-boost regimen V F F F ···

  7. Vaccines Express Tumor-Associated Antigens and Costimulatory Molecules • Tumor-Associated Antigens (TAA) • PANVAC-VF • CEA • MUC-1 • PROSTVAC®-VF • PSA • TRIad of COstimulatory Molecules -TRICOM™ • B7.1 • LFA-3 • ICAM-1

  8. Therion Biological Potency Assays • Measure biological activity that relates to product function • Ensure lot-to-lot consistency • Stability-indicating • Minimize variability • Include suitable reference standards

  9. Challenges for Therion Potency Assays • Complex products with multiple components • Two distinct viral vectors with different biological characteristics • One or two tumor-associated antigens • Human costimulatory molecules • Series of events required for biological activity

  10. Statistical Approach to Biological Assay Development • Statistical design of experiments • Identification of the sources of assay variability • Informs the number of replicates or doses for accuracy and precision • May lead to assay modifications and refinements • Accommodates use of multiple lots of reference standard

  11. Evolution of Therion Potency Assays DEVELOPMENT STAGE ASSAY TYPE Phase 1-2 Trials Plaque titration Biological activity Phase 3 Trials MATRIX APPROACH Critical steps required for biological function Approved Product Quantitative Surrogate

  12. Complex Biologic Function BIOLOGICAL ACTIVITY PROTEIN EXPRESSON GENETIC CODING INFECTION

  13. Summary of Matrix Assays to Measure Critical Steps

  14. SIGNAL 1 TRICOM SIGNAL 2 Activation of Antigen-Specific T Cells How is TRICOM Designed to Work?

  15. The In Vitro TRICOM Assay • Activation of human T cells in vitro • Signal 1: Non-specific • Signal 2: Poxvirus-infected cell line expressing TRICOM • T cell activation quantitated by measurement of cytokine secretion

  16. Design of Experiments for In Vitro TRICOM Assay • Sources of variability in a single experimental design: • Day-to-day • Operator-to-operator • Naïve T cell donor source • Assay plate-to-plate • Well-to-well • ELISA plate to ELISA plate • Dose-response to different multiplicities of infection • Designed to increase sensitivity to allow assessment of lot-to-lot consistency and stability

  17. Surrogate Assays Evaluating surrogate assays for biological function: • Analytical • Quantitative • More reproducible • Correlation with biological activity (e.g., use of quantitative flow cytometry to replace in vivo potency assay)

  18. Summary • Complex products require more than one assay to assess activity • Matrix of analytical assays can be used to evaluate critical steps • Statistical approach for biological activity assays is critical for development and validation • Quantitative surrogate assays can replace or supplement variable biological assays for consistency and stability assessment

  19. Potency Assays For Recombinant Viral Vaccines For Cancer Therapy Kelledy Manson Sr. Director Bioanalytical Development Therion Biologics Corporation February 9, 2006

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