Potency assays for recombinant viral vaccines for cancer therapy
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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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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

Agenda

  • Introduction to Therion products

  • Challenges for Therion potency assays

  • Matrix approach to potency evaluation

  • Surrogate assays

  • Questions and Answers


Introduction to therion products

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


Complex biologic function

Complex Biologic Function


Complex biologic function1

Complex Biologic Function


Poxvirus vectors

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 ···


Vaccines express tumor associated antigens and costimulatory molecules

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


Therion biological potency assays

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


Challenges for therion potency assays

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


Statistical approach to biological assay development

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


Evolution of therion potency assays

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


Complex biologic function2

Complex Biologic Function

BIOLOGICAL ACTIVITY

PROTEIN EXPRESSON

GENETIC CODING

INFECTION


Summary of matrix assays to measure critical steps

Summary of Matrix Assays to Measure Critical Steps


How is tricom designed to work

SIGNAL 1

TRICOM

SIGNAL 2

Activation of

Antigen-Specific T Cells

How is TRICOM Designed to Work?


The in vitro tricom assay

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


Design of experiments for in vitro tricom assay

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


Surrogate assays

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)


Summary

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


Potency assays for recombinant viral vaccines for cancer therapy1

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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