Replies to post #4264 on GTC Biotherapeutics (fka GTCB)

[DewDiligence]

||You suggested that GTC’s drug candidates have a greater likelihood of immunogenicity than recombinant drugs produced by other means.||
>I never once said anything close to that.<

I guess we disagree on what constitutes a suggestion. In msg #4256, you said:

“Lack of glycosylation can promote faster renal clearance, depending on the molecular weight of the protein. For AAT and Factor VII, their molecular weights fall into the range that makes me worry. In addition to my half-life concerns, some aglycosylated proteins (proteins that are normally glycosylated but manufactured in a non-glycosylated form) sometimes have a tendency to be more labile to proteolysis, aggregation, and immunogenicity.”

[DewDiligence]

>the reason why I ignored your claim that GTC Researchers can simply "engineer in" post-translational modifications is because its not that easy. Trust me, Ive engineered-in and engineered-out N-linked glycosylation signatures on multiple scaffolds. I would gather that its especially dicey for a metastable protein like a serpin, which is basically a molecular mousetrap waiting to catch a protease.<

If it’s hard to do, that plays right into GTC’s competitive strength, IMO. Scientific brainpower is clearly one thing that GTC does not lack.

[aslan2772]

"GTC Researchers can [not] simply "engineer in" post-translational modificiations is because its not that easy. "

For the sake of argument, if GTCB wanted to produce exclusively antithrombin alpha, all they would have to do is make a point mutation, converting serine 137 to a threonine, creating a NXT consensus sequence. This would most likely work just fine.

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=7599134&dopt=A...

The degree to which Asparagine 135 is glycosylated is perhaps more likely to be a tissue issue (breast tissue may be less efficient at glycosylating NXS sequences in this case) than a species issue. Some deeper research may shed some light on this.

In any case, it is uncommon for two functionally distinct isoforms of a protein to result from differential glycosylation. As far as antibodies go, the glycosylation issue is less likely to be critical, IMHO. Differential glycosylation of antibodies may influence stability and affinity (for better or worse), but how could it dramatially alter function? Furthermore, human allergy to goat proteins is fairly uncommon, much less than for cow and rodent proteins. Comparing Hampsters (CHO), Goats and modified yeast (Glycofi), I don't see glycosylation being a show stopper for GTCB. I think the key factors will be price and production speed.

On that note, the in vitro technologies do have the advantage of rapidly and easily producing small amounts of protein for pilot studies and preclinical work. Perhaps GTCB could address this advantage by offering their own in vitro system (cultured goat breast cells -- I'm not kidding -- the Donaldson cell culture nanofiber substrate, now sold by Corning, just so happens to be an excellent growth substrate for the notoriously difficult-to-culture breast cell. In fact T47D cells exhibit a multicellular spheroid morphology with the presence of a central luminal cavity on this substrate). But I digress...