RE:RE:RE:RE:A Q on The A ForumTo my knowledge, MineDigger, Bioasis has not discussed the drug structure and manufacturing details of the xB3-004 (xB3-IL-1Ra) construct used in the multiple sclerosis study that was the subject of a
recent press release.
In my opinion, there was a mistake in that press release. Concerning the MedImmune study, Bioasis stated that "
a recombinant fusion protein of Bioasis’ proprietary xB3™ peptide with an interleukin-1 receptor antagonist (xB3™-IL-1RA) demonstrated efficient delivery of effective concentrations of IL-1RA to the brain eliciting analgesia in a neuropathic pain animal model."
The scientific paper from MedImmune/Bioasis stated, "
3D confocal fluorescence microscopic analysis demonstrated brain parenchymal localisation of a fluorescently labelled antibody (NIP228) when chemically conjugated to either the MTf peptide or full-length MTf protein."
And then in the next sentence the paper calls them fusions. But there are two sections in the paper with the titles, "
Chemical conjugation of MTf or MTfpep to NIP228 mAb for confocal fluorescence microscopy" and, "
Chemical conjugation of MTfpep-NIP228 mAb constructs." (Note that MTf is p97 and MTfpep is the xB3 peptide.)
So, the structures in the study were chemical conjugates, as BT2111 was. The only thing "recombinant" was the p97 that was used, in this case meaning that the p97 was a man-made. But then the "recombinant" p97 was chemically conjugated with IL-1Ra and the other monoclonal antibody (NIP228) to make make one of the tested constructs in the study.
We don't know whether the xB3-004 is a chemical conjugate or a fusion protein. With all fusion proteins, the first molecule is the most expensive. You can't make it without gene modification in a living cell in which the fusion protein is then expressed. Cells divide to make more little drug manufacturing cells.
The point is that it's not likely worth the expense to make fusion proteins for early preclinical work when chemical conjugates make far more economic sense. There could be reasons in some instances where fusions are needed, but I am not aware of any. Also, the technologies involved in the genetic modification of living cells is advancing at ridiculous speeds. This is causing costs to come down, but manufacturing cost remain high.
On balance, I woulkd say that Bioasis and its several partners would be using chemical conjugates for early proof-of-concept work, with the switch to fusions talking place when the decision is made that the drug is worth submitting and IND application to the FDA. There has no announcement made that Bioasis or its partners and licensees have reached the stage where the switch to fusions is needed. However, everything is secret with partners and licensees so I wouldn't be surprised if somebody hasn't reached that state, possibly Prothena. I'm not confident that Chiesi has reached that point, and certainly Aposense and Oxyrane can't be expected to be there yet.
But, Bioasis has entered that stage with xB3-001 where fusions are required to move forward. I'vestated my views previously about WuXi and Protalix. xB3-004 (IL-1Ra) is getting to thatpoint. If the xB3-009 (progranulin) study is done or nearly so, then it's getting closer also.
This is where it makes sense to me for Bioasis to choose a partner that can manufacture fusion proteins where the partner can pay (in kind) for some of the up front partnership fees by manufacturing the dusion proteins. I like Protalix as a partner for xB3-001, xB3-004 and xB3-009. I suspect Protalix can't do Gaucher's because of its relationship with Pfizer and that could be why Bioasis may have taken xB3-007 (Gaucher's) to Oxyrane with its yeast manufacturing technologies. And it does show that Bioasis is willing to forego mammalian cell fusion production for other process like yeast (Oxyrane) and, possibly, plant cells (ProCellEx at Protalix).
Finally, with respect to your question about whether Herceptin is droppped into the fusion protein manufacting process, the answer is no. The cells producing xB3-001 fusion proteins would be genetically capable of producing the fusion protein as a unit, the complete building of the herceptin molecule from scratch with the xB3 a part of it as though it was just another part of the natural protein. It's a beautiful thing.
Ok, that's enough. Great questions.
jd