Replies to post #2013 on GTC Biotherapeutics (fka GTCB)

[DewDiligence]

Biowatch’s assertion about improved cell-culture yields is correct, especially with respect to mAbs. Cell-culture production has closed the gap relative to transgenic production to some degree. However, there are many proteins that express poorly or not at all in cell culture (e.g. antithrombin and Merrimack’s MM-093 alphafetaprotein). In any event, the improvement in cell-culture yields hardly justifies the 10X reduction in valuation that GTC has experienced since 2000. Regards, Dew

[dewophile]

I know this was addressed to Dew, but I thought I would chime in (I am not an expert in this area, but have done some basic research in the past and have some basic understanding of molecular biology)

First, as Dew has correctly stated, it is imprtant to separate proteins that require eukaryotic expression from bacterial expression for activity. Bacteria can produce huge quantities of material intracellularly. Eukaryotic proteins are generally secreted extracellularly in much smaller quantities, but the cellular machinery is able to glycosylate the proteins (this happens after translation of the RNA into protein, which bacteria cannot do). So glycoproteins must be produced in eukaryotes.

The improvements over the years to improve yeilds include development of large-scale bioreactors, strains of eukaryotic cells that are efficient at secreting these proteins (companies have proprietary cell lines established), refinements in purification to increase yields, just to name a few.

"post-facto modify glycosylation" is a strage term to me. I think what is meant (but could be wrong) is the ability to modify the constituents of the carbohydrate side-chains to (generally) alter pharmacokinetic parameters of proteins. a few examples include amgn's long-acting erythropoietin analogue created by adding N-linked glycosylations, and organon's FSH-CTP in phase III created by linking the CTP of hCG to FSH to increase half-life (the CTP contains 4 O-linked sugars)
these modifications are inserted into the vector, so i'm not sure what is meant by "post-facto", although other modifications can be made to the purified material, like deglycosylating with enzymes, hydrogen fluoride, etc. (deglycosylating often renders a protein inactive, but may still have clinical utility as an antagonist by retaining receptor binding)

at the end of the day, with all the refinements over the years, in the best of circumstances yields remain orders of magnitude lower than what gtcb's transgenic platform provides
(I would have to do digging to give you quantitative comparisons, but as a generalization this holds)