jfm1330 wrote: If you look closely you will see they use two types of antibodies for immunostaining, one where the antigen is a recombinant proteic sequence of sortilin, and the other is a peptide with no further details. The antibody made out of the recombinant sequence detect more sortilin. Correllation between immunostaining and quantification mRNA of sortilin (which shows level of sortilin expression) is not always good. The other thing, is that they claim the the main location of sortilin in the cell is in the Golgi appartus, the cytosol, and in third place, the celle membrane. It is in line with what Wino reported that 90% of sortilin is intracellular and 10% in the membrane.
That raises a lot of questions. Do Thera know if the 90/10 sortilin distribution is always the same? Is the ratio different in cancer cells and does this ratio change in advanced cancer. Also, the data given for overall sortilin expression vary depending on the antibody used, and we have no idea of the stage of the cancer they tested. According to Thera, expression level goes up with the stage of the cancer.
I don't understand how immunostaining can allow the detection of intracellular sortilin on a very thin layer of dead tissue that has been frozen. It is important to recall that immunostaining id done on biopsies samples, not a tissue that is still alive. So I wonder if what is seen in immunostaining is true reflection of what exists in tumors and cancer cells that are still alive in the body. That's why I repeat myself with TH19P01-DOTA-Ga68. This tool would allow to see the level of sortilin on the membrane that really binds TH19P01 in vivo in humans. That would be the ultimate tool to really understand what is going on with a PDC based on TH19P01. It would likely not be exacly the same behavior os TH1902, since the load on TH19P01 would not be the same, but it would be as close as possible.
The more I read about sortilin expression, the more I think this is a weak spot of the whole concept. The whole thing is predicated on sortilin overexpession on the membranes, not in the Golgi and not in the cytosol, so it would be critical to have a reliable way to detect the level of sortilin on cancer cells membranes to select patients. With the "all comers" inclusion criteria in phase Ia, it is likely to be a good part of the problem, and as far as I can see, immunostaining of biopsie tissues for phase Ib will not be very reliable to show the real level of sortilin on the membranes of cancer cells. The would really need an in vivo imagaing tool to see where their peptide binds in vivo in humans. Again, as soon as they have a proof of concept they should start the development work on that.