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Tissue Plasminogen Activator: A Case Study In Pharming


A Case Study In Pharming Timothy G. Standish, Ph. D. What is Tissue Plasminogen Activator (t-PA)? t-PA is an enzyme that serves in the cascade of events leading to ... – PowerPoint PPT presentation

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Title: Tissue Plasminogen Activator: A Case Study In Pharming

Tissue Plasminogen ActivatorA Case Study
  • Timothy G. Standish, Ph. D.

What is Tissue Plasminogen Activator (t-PA)?
  • t-PA is an enzyme that serves in the cascade of
    events leading to dissolution of blood clots

Damaged Tissues
t-PA Has Been Developed As A Drug By Genentech
  • The biotechnology company Genentech has cloned
    human t-PA for use in treating unwanted or life
    threatening blood clots
  • Activase (Alterplase recombinant) is the trade
    name of Genentechs t-PA
  • Activase is useful in treating heart attacks and
    strokes when administered within 5 hours of
    thrombosis formation or embolism lodging in the
    heart or brain
  • The FDA approval in 1987 and medical use of
    Activase has a very interesting history

Production of t-PA
  • Scientists at Genetech took human mRNA coding for
    t-PA from a human myloloma cell line
  • The mRNA was converted into cDNA
  • Human t-PA coding cDNA was inserted it into
    Chinese hamster ovary cell lines
  • When grown in culture the CHO cells excrete human
    t-PA into their growth medium
  • Activase is produced by isolating t-PA from the
    growth medium
  • This is an expensive and difficult process

Growing t-PA In CHO Cells
  • Because production of t-PA in cell culture is a
    difficult and expensive process, t-PA is an
    expensive drug
  • t-PAs main competition in the thrombolytic (clot
    busting) market is streptokinase
  • Streptokinase costs 1/10th the price of t-PA and
    seems to do an equivalent job
  • A cheaper way to produce t-PA would be beneficial
    (unless you are a streptokinase manufacturer)
  • Pharming offers the promise of cheap production
    of a wide variety of proteins including t-PA
  • T-PA was the first viably produced protein using

What Is Pharming?
  • Pharming is the use of recombinant domestic
    animals to produce proteins and other bioactive
  • One of the most common strategies in pharming
    involves engineering mammals to produce desired
    proteins in their milk
  • This strategy was first used to produce t-PA in
    the milk of goats
  • It is not coincidental that this work was done at
    the Roslin Institute in Scotland, the same
    institute that cloned Dolly.

Making Recombinant Goats 1Vector Construction
  • The murine (mouse) way acid protein promoter
    signals for expression of the gene in mammary
    cells as part of milk
  • LAtPA cDNA codes for a point mutated form of tPA
    (asn-gtglu at AA 117) that is glycosylated
    differently resulting in longer acting (LA) tPA
  • SV40 is a virus that provides the poly A signal
    telling cells mRNA is ready for expression

Making Recombinant Goats 2Vector Insertion
Making Recombinant Goats 2Vector Insertion
Making Recombinant Goats 2Vector Insertion
Most copies of the vector are broken down
Making Recombinant Goats 2Vector Insertion
Making Recombinant Goats 2Vector Insertion
Making Recombinant Goats 3Making Kids
The 1987 Trials Of Genentech
  • March
  • Japanese patent for tPA awarded to Genentich
  • Several companies file objections
  • June
  • FDA refuses to license tPA - Genentech stock
    loses 1,000,000,000 or 11.50 per share
  • Wellcome challenges Genentechs UK tPA patent

The 1987 Trials Of Genentech
  • July
  • Genentech looses to Wellcome but appeals - Stock
    loses 1.375
  • tPA is on the market in New Zealand, The
    Philippines, and France
  • November
  • FDA approves tPA for human use
  • tPA is on the market in Austria, West Germany and
    South Korea
  • December
  • In the last 6 weeks of 1987, US sales of tPA
    total 58,000,000

Genentech Stock Prices 1987
Loss of patent Infrigngment suit
The 1988 Trials Of Genentech
  • January
  • 20,000,000 in US tPA sales
  • March
  • Genetech stock is listed on the NYSE
  • A study reveals tPA reduces mortalitiy two weeks
    after acute myocardial infarction
  • Sales of tPA drop to 11,000,000 for February
    and March
  • 2,000 patients a week are treated with tPA
  • April

The 1988 Trials Of Genentech
  • April
  • Ontario Medical Association recommends using
    streptokinase instead of tPA because of the
    expense of tPA
  • Medicare refuses to pay for tPA
  • Genentech stock drops 18 in two weeks
  • June
  • US patent for tPA is granted to Genentech, but
    only covers the purified form and does not
    exclude others from filing patents
  • In a suing-o-rama, Genentech sues Burroughs
    Welcome and Genetics Institute for their tPA
    collaboration, Abbott sues Genentech for patent
    infringement, Genentech fails to win a
    restraining order to prevent clinical trials of
    tPA produced by Toyobo under license from
    Integrated Genetics in Japan

The 1988 Trials Of Genentech
  • September
  • Genentech is issued a US patent on its human
    recombinant version of tPA
  • On the basis of the new patent Burroughs Wellcome
    and Genetics Institute are sued again
  • November
  • Genentech looses its appeal of a lower court
    decision to void its patent for being to broad in

  • March
  • An Italian study shows streptokinase to be
    equally effective as tPA for long term survival
    of heart attacks

Genentech Stock Prices 1988
Current Genentech Stock Prices
Ethical Issues
  • Is production of recombinant organisms ethical?
  • Do the risks of recombinant organism production
    outweigh the benefits of recombinant products?
  • Is use of organisms as tools to make products
    purely for human benefit ethical?
  • Is introduction of animal products into humans
    for therapeutic purposes ethical?
  • Is the cost of making recombinant products the
    most productive use of health care resources?
  • Is it ethical to withhold treatment using
    expensive recombinant products from the poor so
    that investment can be recouped and reinvested?

Ethical Issues Cont.
  • Is it ethical to produce high tech/high cost
    health care products that are only marginally
    better than lower tech lower cost products?
  • Is it possible to own (patent) a naturally
    occurring human gene?
  • Is it product infringement when another company
    produces a comparable product that has identical
    activity and other properties, but differs
    structurally from the original?

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