RE:Pharmacokinetics and the fate of TH1902 in the body Christain said the half life was one hour. He didn't say if that was from animals or patients, I was assuming animals.
Christain also made half a point but didn't finish the idea. He pointed out that docetaxel gets taken up by every cell in the body. The point he didn't go on to make was that that process does not lead to a toxicity signal in every cell or tissue. If it did you would have might sick people. The drug only affects actively dividing cells and it's in those areas where toxicity is seen. So white blood cell are derived from actively dividing cells, this gets affected and that's why you get neutropenia and infections. The gut wall is under constant attack from stomach acid and gut contents, that needs constant replacement and that process gets impacted by docetaxel. Also gut bacteria are actively dividing, these take up docetaxel and get killed and the micro flora in the gut gets disturbed leading to gut problems as well. There are some other sites that are actively dividing as well. So if you think about off-cancer targeting of the PDC you have to fulfill two criteria to get toxicity. First there has to be Sortilin on the surface to take up the peptide. Second the cell has to be part of an actively dividing tissue to produce a toxic signal. The chances of fulfilling both criteria are quite small.
With other ADCs they can be carry different payloads than docetaxel. The MOA of those chemo can be much more generally toxic to cells, having a negative impact on many more cells. In that scenario off-cancer targeting can lead to more problems cause it's much more likely that the targeted healthy cell will produce a toxic signal.
I guess an analogy would be an ADC carrying a generally toxic chemo you only need throw one dice and get a six to get toxicity. Where 6 represents the presence of the target on a healthy cell.
With Th1902 you need to throw two dice and both dice land on 6 to get a toxic signal. The first dice being target on a healthy cell and the second being that cell being part of an actively dividing tissue.
Docetaxel was criticized by some as a less than perfect chemo but in some respects it might turn out to be exactly the right choice.
jfm1330 wrote: This is one area where Thera did not disclosed much data obtained on animals for their IND submission, and now they are collecting pharmacokinetic data on humans. That being said, we know the pharmacokinetics of free docetaxel in humans and it is helpful to guess what is the fate of TH1902 in the human body after injection.
Free docetaxel is a molecule with very low solubility in water, so much that it needs to be formulated with polysorbate 80, which is a surfactant or emulsifier. Like soap, it is a molecule that allows the dissolution of hydrophobic molecules in an aqueous solution. On top of formulating docetaxel with polysorbate 80, they dissolve the drug in an aqueous solution containing 13% ethanol. This alcohol helps solubilizing hydrophobic molecules in water based solutions. Docetaxel is so poorly solubule in water that in plasma, as soon as it enters the bloodstream, 98% of it binds to albumin and other proteins through hydrophobic interactions. But molucules that are poorly soluble in water are highly soluble in lipids. So that allows docetaxel to passively enter the cells everywhere in the body, except the brain, since the membranes of the cells are mainly made of lipids.
The poor solubility of docetaxel in water means that less than 5% will be eliminated in the urine by the kidneys. More than 80% of it is eliminated in the feces, after enzymatic degradation in the liver and elimination in the bile. For that reason, docetaxel can be very toxic for patients with liver problems because they will have a slower degradation and elimination rate. Docetaxel is clearing the bloodstream very quickly, with a bloodstream half-life of around 5 minutes. Then, once distributed around in all the tissues, my understanding is that it slowly diffuse back to the bloodstream, and over time the liver is catching it, degrading it and eliminating it. The overall half-life of docetaxel in the body is 12 hours. This is the time to eliminate half of what was injected. So to clear it totally from the body will take a few days.
We don't have any data on the pharmacokinetics of the peptidic part of TH1902. But in the last presentation, Dr. Beliveau showed the results of an experiment with progranulin showing that half of the peptide linked to the surface membrane is internalized within 4 minutes. This is followed by monitoring the decrease of cell surface fluorescence intensity. It uses peptide labelled with a fluorescent marker like biotin. This shows that the internalization of the peptide is very rapid, but to my undestanding, the experiment showed by Dr. Beliveau was not an in vivo process. So I guess they decided to put that slide in the presentation to show that the internalization process is rapid when the peptide is linked to sortilin, but we don't have any data on the half-life of TH1902 in the bloodstream, or how fast it interact with sortilin and what percentage is taken up by cells expressing sortilin, and what percentage of TH1902 is degreded by peptidases/proteases before being able to be taken up by cells expressing sortilin. Remember, as long as docetaxel is linked to TH19P01, it can only enter cells expressing sortilin. So either it enters those cells, or it stays in the bloodstream facing enzymatic degradation. One basic principle behind TH1902 is that a good part of it can enter the cells expressing sortilin before the PDC being degraded by peptidases. This a key principle to understand and one that Thera did not really explained.
All that being said, to me it seems clear that TH1902 can either be taken up by cells expressing sortilin, or having its peptidic part being degraded in the blood stream before entering cells. Once the peptide structure is broken, it can no longer interact with sortilin, and then the peptide will be fully degraded, releasing free docetaxel, and then free docetaxel will follow the fate that we know about docetaxel. it will distribute unspecifically in cells, some will be taken up by liver cells and be degraded, and so on until full elimination. As to the part of docetaxel entering the cells through TH1902, it will interact with microtubules there, staying there much longer, before ending up in the boodstream after killing the cells (apoptosis) or diffusing back in the blodstream. Very low quantity will be eliminated in the urine and most will end up in the liver.
So the fate of TH1902, and ultimately of the docetaxel that was linked to it is a very complex and dynamic process that can be modified by many factors. But from what I read, it is clear that 80% or more of it will end up over time in the liver where it will be enzymatically degraded and eliminated in the bile into the feces. My understanding, and I may be wrong on that, is that the neutropenia involved with the injection of free docetaxel is in part linked to the fact that neutrophiles are free flowing cells in the bloodstream that are more exposed to a high concentration of docetaxel during the infusion, and docetaxel will rapidly diffuse inside these cells, while cells in solid tissues in organs are not that exposed. This is just my personnal guess on that. Also, the infusion of a dose of docetaxel takes one hour, so there is a steady stream of free docetaxel coming in the blood during that hour, while I think that the infusion of a dose of TH1902 will take much less time than that. My guess is a few minutes since there is no solubility problems in this case. So when you inject TH1902 it has time to distributes to all the tissues before enzymatic degradation can have a meaningful impact, and also, Thera is claiming that the PDC is taken up by sortilin receptors quickly, so in this case, likely a good part is taken up by cells expressing sortilin, and what is degraded by peptidase is better distributed in the body when it happens, and there is relatively less of the docetaxel that end up free that goes into white blood cells like the neutrophiles.
So toxicity with TH1902 is lower for two reasons, again, my guess on that. First because a good part is taken up by sortilin inside the cells expressing it, and second, what is not taken is better distributed in the tissues when enzymatic degradation happens, then, neutrophiles are exposed to much lower concentrations of docetaxel. Then, again, with TH1902, utimately most of the docetaxel will end up in the liver, but at a much slower rate, so over a longer period of time. So all the process with TH1902 lead to much lower concentration of free docetaxel in the bloodstream, hence lower toxicity. That's my best effort at understanding and guessing what happen to TH1902 and the docetaxel it contains after injection in the body. Also, I still believe that the more overexpression of sortilin a patient has on its tumors, the less toxic a dose will be because a larger part of the dose will end up in the tumors and will stay there for a long time before being slowly realeased, either by cell death, or by diffusing back slowly at very low concentration in the bloodstream.