RE:RE:RE:RE:News: Lymphing along to better days...Links Crazy busy day. Finally got this post done.
BearDownAZ asked, "Why would you expect target engagement and cancer naivety to be the explanation for lack of brain accumulation but not hold the observed peripheral accumulation to the same standard?"
Let's define some terms first.
TZM : trastuzumab, scientific name for Roche/Genentech's Herceptin.
NHP : Non Human Primate
xB3 : Trade name for the Bioasis drug/BBB transport technologies
xB3-001 : Bioasis' name for its xB3-TZM fusion protein, which is a molecule of TZM with one or more xB3 peptide structures fused to it for BBB transportation purposes.
xB3/Transcend Construct : Any therapeutic that has either the xB3 peptide or the full p97 molecule attached to it, either fused or conjugated, for the purpose of transportation across the BBB.
xB3 Platform : The set of Bioasis peptide sequences and associated linkages, IP protected, that can be attached to therapeutics for the purpose of transporting them across the BBB and into the brain (and entire CNS, actually).
Periphery : All of the body OUTSIDE of the central nervous system (and brain).
My understanding, BearDownAZ, goes like this. (I suspect our scientists may call for my lynching when they read this, but they're free to correct me if I'm taking too many liberties. Also, some of this you already know but I'm posting for everybody.)
The brain has a much lower tolerance of foreign substances than the periphery does. Besides the BBB, the first line of defence, it has other mechanisms. We could get into the mechanisms, immune system, protease enzymes, efflux pumps and such, but the details are more advanced than I ever cared to pursue. All I'm interested in is the xB3-001 that stays in the brain and treats brain tumours.
It's been discussed by Bioasis and on this forum in the somewhat distant past that UNLESS Herceptin (trastuzumab or TZM), or a Transcend or xB3-TZM construct, attaches to a target receptor in the brain (an HER2+ tumour cell, essentially), then the brain's defences will boot the Herceptin (or Transcend/xB3 construct) out. That's old news. Talked with RH about it in older times. It's been posted here. When I say "booted," the reader should consider that the science is more complicated than "booted" but the effect is pretty much the same.
On the other hand, if the Herceptin DOES find targeted HER2+ tumour cell receptors in the brain, then its life in the brain is extended from a couple of hours to a previously reported half-life of up to 14 days. I would imagine that the xB3-001 attachment to the receptor causes biochemical reactions (signals) that tell the brain's protective mechanisms to leave this molecule alone. Not a very scientific way of saying it but that's the end result. Since the naive NHPs in this peripheral study do not have brain tumours, they therefore do not have TZM-targeted receptors and the brain's defences boot the TZM construct out.
THIS STUDY WAS INTENDED TO PROVIDE BIOASIS WITH INFORMATION ABOUT WHERE XB3-001 LOCATES ITSELF IN THE PERIPHERY, NOT IN THE BRAIN. BRAIN EXPOSURE WAS NOT STUDIED.
And in the process of the study, we got a surprise, a damn good one; xB3-001 can penetrate the lymph system.
No, BFW, I don't think we're getting xB3-001 draining from the brain via the lymph system into the groin area. I don't think the expulsion of xB3-001 from the brain is as simple a whole molecules being expelled. Protease or other enzymatic processes could be involved, that the molecule could be broken down in some natural way. I suspect Bioasis will nail that down, if they haven't already. Some pretty smart people directly and indirectly contributed knowledge that resulted in this PR. They're not going to hang themselves out to dry.
To my knowledge, the study was never intended to produce news. There were no real thumbs-up or thumbs-down elements to the study. It was meant to provide insight into where xB3-001 went in the body. But surprise, surprise, it did produce news, good news, and that's why the PR went out.
Any nonsense, and I've heard a lot of nonsense today, that things didn't work out, that we had problems with the study, are just that - NONSENSE!
Implicit in some questions on various forums is a misunderstanding of what is being tested when we talk about xB3, the xB3 Platform and xB3-001. I can't imagine Bioasis testing an xB3 peptide all by itself. It would be like a tow truck driver disconnecting the hook from his cable, attaching the hook to the car and then starting to pull the cable. All hook, no cable. xB3 peptide - all hook, no drug. Not worth testing. Waste of money. Nothing to be learned. Everybody is interested in whether xB3 fusion proteins work, and those are what will be studied, just like any other new drug.
Also, judging from the questions about this study, maybe a little refresher is needed. Not all studies will be newsworthy. In many cases, Bioasis is just gathering data that you can't look at unless you sign a non-disclosure agreement. Only potential licencees and partners can see the data. Take a look at my July
post about target engagement. It explains quite a bit about the types of studies that are needed.
So, Dan-O-
Mite, 2005, turned his tail from the wind and his face into it and spit all over himself with a ridiculous, completely uninformed post. Dan, don't spit into the wind! Your post was nonsense. Not worthy of further response.
jdstox