I have pasted another great post from JD off the other board. I had a great conversation with him the other day and got a whole new perspective on how big BTI could really be. I was originally concerned about the possibility of Medimmune not being able to bind their drugs to the BT2111 molecule effectively. This is not an issue!
Here is JDs excellent post:
BiOasis has not directly announced BT211X, so I'm making some guesses and suppositions here that may be a little off in detail, but I doubt they're off on substance by very much. I can offer little guarantee of strict accuracy here except to say that for our purposes it should be accurate enough. We'll look at some relative molecule sizes as measured in Daltons (Da) or kiloDaltons (kDa). (1000 Da = 1 kDa). These are atomic mass units that allow us to compare sizes of molecules.
The atomic mass of Trastuzumab (Herceptin) is 145,531.5 Da or about 146 kDa.
The atomic mass of p97 (melanotransferrin) is about about 80,000 Da or 80 kDa.
To make a BT2111 molecule, a linker of, to me, unknown small molecular weight is used. The Trastuzumab (146 kDa) and the p97 (80 kDa) are conjugated (joined) together with the linker for a combined weight of about 226 kDa. There is a limited description of the linking process in the p97/PTAX/ADR paper found here on the biOasis web site. It's nasty reading!
Just below is a representation of the probable resulting size of the current BT2111 conjugate. The p97 is on top, then the linker, then the Trastuzumab. Each asterisk ( * ) equals 1000 Da or 1 kDa. (226,000 Da, total.) Bear in mind that small molecule drugs are less than 900 Da and only drugs of 300 or 400 Da and smaller can cross the BBB, depending on their solubility in water and lipids.
Aspirin, acetylsalicylic acid, C9-H8-O4, is only about 180 Da compared to Trastuzumab at 145,531 Da. That means that more than 5 aspirin molecules can fit in each asterisk in this drawing. (Also note that if more than one p97 molecule can be conjugated with a single Trastuzumab molecule, it's beyond my knowledge, but it would be big enough to see from the Space Station!)
So, here's the current BT2111.
****************
****************
**************** <---------------- p97
****************
****************
** <--------------------------------- Linker
*****************************
*****************************
***************************** <-- Trastuzumab
*****************************
******************************
That's a big molecule!
An added complication of BT2111 and building it using linkers is that there apparently is not direct control of the resulting molecular structure. In fact, p97 can link to Trastuzumab on more than one Trastuzumab location making for multiple versions of the BT2111 conjugate. And this is important - when seeking FDA approval, a specific, known and reproducible molecule must be used in clinical trials and the resulting therapies. So, another linking mechanism is needed to ensure a single conjugate structure exists and is tested. Fusion conjugates are required.
Fusion conjugation is a method of linking one molecule to another directly and always using the same binding location(s) on both molecules. Transcendpep should allow a much simpler way of creating fusion conjugates. The manufacturing process is reduced from several weeks per batch to several days. Further, because the peptide is just a few amino acids strung together, it's structure is simple and quality control is easier.
What's really important is that cost for Transcendpep plummets by over 90% compared to Transcend. The resulting conjugate is much smaller and cheaper than the original BT2111 and is a fusion conjugate, just what is needed to apply for Investigational New Drug (IND) status.
And it turns out that Transcendpep, when conjugated with Trastuzumab, results in a conjugate that is only about 1% bigger than Trastuzumab alone. (BiOasis won't reveal the size of Transcendpep but it appears to be 1% or less of the size of Trastuzumab so that means it's less than 1.5 kDa or 1500 Da in size.)
So instead of that BT2111 monster above we have a much simpler BT211X conjugate of about 147 kDa, instead of 226 kDa, that should compare like this:
* <----------------------------------- Transcendpep
*****************************
*****************************
***************************** <-- Trastuzumab
*****************************
******************************
It's that little "*" up top that hooks onto a receptor on the BBB and pulls Herceptin across the BBB. Further, Transcendpep can apparently be fused to multiple locations on a Trastuzumab molecule allowing a cactus-like BT211X molecule. This would greatly increase the likelihood of BT211X finding a receptor on the BBB, meaning that BT211X's half-life, bioavailability and ability to find receptors in nooks and crannies would be enhanced.
So, in the end, its the combination of very small size, very low cost and increased efficacy that has apparently sent BT2111 into history and should allow something much more practical and important to come forward, the new peptide version, BT211X, whatever it's might be called.
Now, you must understand that I'm making assumptions and guesses and, I hope, good logic to arrive at this description. For now, I'm going to work with these assumptions. I know that things are a lot more complicated than this, and some of the meanings and attributes may shift a little, but I think that for our purposes we can use this type of thinking.
I think we'll know soon enough. And think about that little Transcendpep. It'll do gene therapy and it should be small enough to do small molecules as well. Right now, only 2% of small molecule drugs (drugs less than 900 Da) can cross the BBB!!
Damn, this small thing is going to be big!!
jdstox
