RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Answer about the linker Of course not. I merely suggested he go to the source to get an answer to his confusion on the linker. On the contrary, I am suggesting Marsolais not only has the answer but can explain the rationale or the fact it's standard and well tested, etc. Heceill no doubt clear up the confusion .
palinc2000 wrote:
Wino
Are you serious? You want Jfm to tell Mardolais and all which linker they should use....You have more confidence in Jfm than in the scientific team and advisors at Thtx ....
Wino115 wrote:
Yes, of the unknown factors presenting risk in the human trial, the linker is a significant one. I would suggest given your background you should ask Marsolais directly, or via Leah. That is all public info so a valid investor question. I would bet if you compose the right question he will respond via email and clear it up. You would understand his explanation best given your background .
jfm1330 wrote: Thank you SPCEO,
I got the document. Now I have to agree with you, this was poor communication from Thera. They show the linker in TH1904 section, and I assumed it was the same for TH1902, which it now seems it was not. But why have they published the linker of TH1904 and not the linker of TH1902, especially if it is really different?
If they really use two different linkers, now I would like to understand why. Why the dimethyl glutaryl linker is good for TH1904, but not good for TH1902? It"s a very important thing to understand since it can make or break the success of this trial on TH1902. They never sais a word about linker selection, and again, it's a critical decision and now I am totally lost
For those who would think I am exagerating zoptarelin (Zoptrex) a PDC based on a small peptide agonist of LHRH receptor likely failed because of not being stable enough in the human bloodstream. Aeterna Zentaris also dropped another promising PDC (AN 207) because it was not stable enough in the bloodstream, both were using the glutaryl linker (not the dimethyl glutary), but the succinyl linker is very similar to the glutaryl linker, just one carbon (CH2) shorter. So I would like to know its relative stability versus the glutaryl linker.
Just to show why explainations about the linker would be a necessary thing to have for us investors, is the fact that chosing the right linker is not that simple. You need to take into account multiple factors. The main factor is related to the speed of internalization of the PDC inside the cells. If the internalization speed is very high, it means the stability of the linker is less of a concern because the PDC will enter the cell before a possible cleavage outside the cell, in the bloodstream. If the speed of internalization is on the slower side, then stability of the linker can be an issue, you need it to be stable enough in the blood. Also, the chemical structure of the two drug molecules loaded on TH19P01 can have an influence on the speed of cleavage by esterases enzymes. In other words, these two molecules can be in the way of the enzymes to do their job and as a result, slow down the process. Another key factor, is the difference in esterase level and activity in the mice blood and the human blood. As it was reported for zoptarelin, the ester bond half-life was much longer in human serum (126 min.) compared to mouse serum (19 min.). But as we know if there is esterase differences between the two species, there can also be differences in receptor expression and activity, also an enormous difference in tumor size, so a big difference in penetration time. So there are many factors to take into account concerning the linker choice and how it will behave in humans in a specific PDC. I think it's a critical aspect that was not explained at all by Beliveau or Marsolais. It's kind of taken for granted that because it works in xenograft mice on minuscule selected tumors, it will work as well in real patients on big complex tumors. I hope they will explain their linker rationale during the next investor day in mid-September.