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DewDiligence

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DewDiligence

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Re: Pre_Clinical post# 4245

Monday, 07/23/2007 12:38:12 AM

Monday, July 23, 2007 12:38:12 AM

Post# of 19309
Re: GTC’s technology and product purity

>So let me see if have this right- the glycosylation profile of the transgenic goat produced antithrombin leads to a decreased half-life for the protein.<

No—GTC has not made that claim. Rather, it is thought to be the proportion of the two isoforms of AT that accounts for the difference in half-life between ATryn and plasma-derived AT.

>To me this company's platform is reminiscent of the pichia pastoris expression system - this particular yeast organism can grow to extremely high cell densities but the high mannose N-linked glycosylation profile promotes rapid clearance from the bloodstream and uptake by the liver (IIRC). You can make buckets of the recombinant protein, but its inferior to the naturally occurring molecule.<

On what do you base this assertion? It seems to me that the recombinant protein produced by GTC will sometimes be better than the corresponding endogenous protein, sometimes be worse than the endogenous protein, and sometimes be sufficiently similar to the endogenous protein that it is identical for practical purposes. Each drug candidate produced by GTC’s platform will have to be considered on its own merits.

>I would like to read more about GTC's claims of improved ADCC profiles in their Abs and how consistent/inconsistent it is with the Atryn pk data and specifically what the clearance rate of Abs produced from goats is.<

Again, the short half-life of ATryn is thought to be related to the proportion of AT isoforms in the product. I do not see how this is related to the potential benefits of enhanced ADCC in GTC-produced mAbs.

>The other concern that I have is while this material is "recombinant", its still produced in goats, which is far different from recombinant proteins produced in microbes or CHO cells. All of the potential concerns of contamination, ie virus (and who knows what else) are present in this expression system.<

That’s what GTC has spent a couple of decades perfecting! For ATryn, the amount of goat material in the final product is <5 ppm, which is roughly the level of detection of the most sensitive assays. You may find this exchange from GTC’s Feb 2006 CC helpful (#msg-9856708):

>>
Roy Friedman:

I'd like to focus on the five ppm of impurities. Do you have any sense that you have to get that down to a specific number like three or four ppm in order to satisfy the regulators on this? Does the additional filtration step affect this number at all?

Dick Scotland – VP of Regulatory Affairs:

Based on the data that we have right now, that 5 ppm is basically the maximum. It could be up to 5 ppm. But often times, based on the types of analytical tools that we are using, the actual value would be below that. In fact, sometimes we are below the limits of detection of the assays. So that 5 ppm is on the upper end. We say “not more than” simply because if one used the limited detection for all the assays, the total of the numbers based on the number of assays, we could be up to 5 ppm. However, I would say that based on the immunologic assessments that we have done to date, we have not seen any immune response either in patients or in normal healthy volunteers that have been treated. We do not, in my mind, at the moment need to reduce those levels any further based on available data.

Geoffrey Cox:

We have not received any communication, that I am aware of, back from the CHMP that that is a requirement for us… There hasn't been a request that we need to modify our process in any fashion. It was a process that we have used over a long period of time and produced this very pure product.

Roy Friedman:

But just to rephrase what you are saying: it's not that you have actually observed 5 ppm. But that would be the limit of the detection assays so that you are saying 5 ppm in order to allow for that. Is that a fair statement?

Geoffrey Cox:

That's correct.
<<

I see no reason to suppose that the above won’t apply with equal force to other products produced using GTC’s technology.

>…ZGEN is producing yeast derived thrombin as a counter to bovine sourced material. How different are goats from cows?<

The main benefit of ZGEN’s thrombin is not that the competing products are derived from animals, but is rather that the competing products are derived from plasma. I think you may be missing the forest for the trees! Regards, Dew

“The efficient-market hypothesis may be
the foremost piece of B.S. ever promulgated
in any area of human knowledge!”

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