Wednesday, August 13, 2014

Bonus Process Wednesday: You Can't Make A Baby In One Month with Nine Women

What do you mean, we've run out?
Credit: happy otter
Mapp Biopharmaceuticals is the company that has a very experimental Ebola treatment. They've run out of manufactured supply, which is an interesting problem that was not discussed in the visual literature, i.e. the 90s movie "Outbreak.". Here's what The Hill (the paper that covers Congress) has to say about that:
It will take months to produce even a small batch of a promising new drug to counter Ebola, according to U.S. health officials. Mapp Biopharmaceutical’s drug ZMapp has shown some promise. The drug has been used to treat two Americans who have contracted Ebola. 
But the company said Tuesday it has run out of supplies. 
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases says it will take months to make more of the drug. Even in that timeframe, the company will only be able to produce less than a hundred treatment courses. 
He said the government was trying to help Mapp “scale up” so that it could produce more of the medicine. 
“Right now, when you’re dealing with Mapp Biopharmaceutical, it’s a small company of very few people, so what we’re trying to do with the government is to partner with them to help them scale up,” he said. “But it’s not going to be mass production … because the technology needs to be developed to make it faster.” 
The drug comes from the Nicotiana benthamiana plant, which health officials said takes longer than a month to grow. Substances from the plant then must go through months of processing before being made into ZMapp.
Upon looking at Mapp Biopharmaceutical's patent application (or what I could find with a 10-second Google search), I suspect that this is the relevant sentence:
Also provided herein are methods of producing antibodies or antigen-binding fragment that contain a substantially homogenous glycan composition using a plant or other eukaryotic expression system.
Here's a much, much, much better explanation from David Kroll at Forbes. "Plantibodies" - I like it.

I Am Not a Molecular Biologist, but it seems to me that this is a custom technology to manufacture pure bits of biomolecules by using plants (instead of yeast or whatever.) I somehow doubt that there is going to be enough successful technology transfer or successful research to substantially speed this process up. Mapp Biopharmaceuticals is out of ZMapp, and we'll have to wait until they can make more and there's very little the United States government can do about that. Best wishes, fellas. 

13 comments:

  1. A good friend of mine recently greeted a Nigerian (by shaking his hand) who had flown into the US last weekend.

    Seems inevitable that Ebola will hit the US; our government is too stupid to stop the people visiting from infected countries.

    Sometimes I wonder if it is for the best that 80-90% of the world is depopulated. I would imagine the Alabatrosses on Midway Island wouldn't mind.

    https://www.google.com/search?q=albatross+Midway&client=firefox-a&hs=zAd&rls=org.mozilla:en-US:official&channel=sb&tbm=isch&imgil=oe-TEaIyTi7f4M%253A%253BF2lATduCKXik3M%253Bhttp%25253A%25252F%25252Fwww.inspirationgreen.com%25252Fmidway-island-albatross.html&source=iu&usg=__wcu8lp8EYGzDf-uyftPeb2qYf-Q%3D&sa=X&ei=xZHrU9mhBcWwyASC5YH4Aw&ved=0CCQQ9QEwAA&biw=1120&bih=565#facrc=_&imgdii=_&imgrc=oe-TEaIyTi7f4M%253A%3BF2lATduCKXik3M%3Bhttp%253A%252F%252Fwww.inspirationgreen.com%252Fassets%252Fimages%252FIssues%252FAlbatross%252520Chris%252520Jordan%252FCF000478%25252019x25.jpg%3Bhttp%253A%252F%252Fwww.inspirationgreen.com%252Fmidway-island-albatross.html%3B660%3B433

    ReplyDelete
    Replies
    1. "A good friend of mine recently greeted a Nigerian (by shaking his hand) who had flown into the US last weekend."

      Why is this pertinent?

      Delete
    2. Reads like an ugly combination or racism and fear-mongering to me. You can't even contract Ebola though a handshake, you need to be in contact with their bodily fluids.

      Delete
    3. Sure, everyone's such a germophobe now that every building has hand sanitizer dispensers for no medical purpose, but if you don't shake hands with the high(er) probability plague carriers, you're a racist. Haven't you heard? Ebola's an equal opportunity killer.

      Delete
    4. Ebola doesn't spread that way. You are not ever in a million years going to get it by a handshake. If you're vomited on, sure, you're in trouble, but not from a simple handshake.

      Delete
    5. What about if the person you're shaking hands with has vomit on them?

      Delete
  2. The key here is to get the correct glycoforms (N-linked glycans) and consistent relative levels of each glycan on the MAbs by producing in genetically-engineered plant cells vs. CHO cells. N- (and sometimes O-) linked glycosylation is a critical quality attribute for MAb and therapeutic proteins biomanufacturing. For the PNAS paper cited, I wish they had put in more MS/MS data in support of the structures - I think based on retention time of the 2-AA derivatives and only nominal mass from LC-MS analysis is highly inadequate in claiming the structures of the glycans they see.

    ReplyDelete
    Replies
    1. Uh, I bow to your superior expertise. Do you think that quick transfer/scale-up would even be possible?

      Delete
    2. It depends on how well the MAb (which is a protein) is expressed and how well it purifies. I didn't pay attention to the yields/recovery in the paper but scaling up protein expression can be a very tricky business - Merck bought GlycoFi a few years back for their engineered yeast expression system which claims to work well in lab scale - I am not sure how it played out on pilot/manufacturing scale. So, the answer I think would be, no, scaling up/transfering protein production processes in engineered expression system is not going to be easy/straightforward, is always much more challenging than small molecule. And I am not even considering characterization and quality controls yet.

      Delete
    3. anon electrochemistAugust 13, 2014 at 2:52 PM

      Agree on the quadrupole data not being sufficient, although it's always been hard to draw the line on glycoforms. More data is not better data for carbohydrates. Should we ask for ammonia adduct spectra? Triple quad for quantitation, or ion trap for the MS^n? MALDI? Not everyone can block off a week of Orbitrap time.

      Delete
  3. Medicago has scaled its tabacco-based protein expression system quite well. In 2012, they produced Ten Million Doses of H1N1 VLP Influenza Vaccine in 30 days (http://www.medicago.com/English/Medicago-USA/MedicagoUSA/default.aspx)

    ReplyDelete
    Replies
    1. Huh, that's very interesting. So it's not like this sort of thing hasn't been done before, but it is worth noting that that was a vaccine and ZMapp is monoclonal antibodies? Perhaps I don't understand the biochemistry well enough to know how similar these things are at the structural level.

      Delete
  4. I love the nine women and a baby analogy. Unfortunately, I find myself using it far too often at my workplace.

    ReplyDelete