RE:RE:RE:RE:RE:RE:RE:RE:RE:What's our Oncology Option Worth?It is good. Imagine a big cargo ship on which you can only load 8 containers and a ship a 100 times smaller on which you can load 2 containers, the exact same containers. So you need four small ships to deliver the same number of container. These smaller ships are agile, arriving at the harbor they can easily find a fast way through much bigger ships, and it is much easier for them to berth at the pier for fast unloading. Also, the ease to send a much higher number of highly loaded small ships will in the end mean a higher delivery capacity because the harbor is not big enough to accomodate a very high number of very big cargo ships with si little freight on it.
This is an analogy, but the big theoretical advantage is speed and delivery effectiveness. Another theoretical advantage is to send fewer "small ships" or inject less PDCs and the ease of adjusting the number, or dose, to get just enough at the target. A good PDC would, in theory, allow to reach a higher intracellular concentration of the cytotoxic drug vs ADC. I always say in theory, because the much smaller size of a PDC vs ADC is only one variable of a multi-factor equation. To have the size and high loadability on your side is not enough, you need to have all the other factors right for the whole thing to work.
SPCEO1 wrote: Sorry to be so ignorant, but is that good or bad?
jfm1330 wrote: I made a huge mistake here. Thera's peptide is not 15 kDa, but around 1.5 kDa. So it is around 100 times smaller than a monoclonal antibody like those use in ADCs, so it's 7.6 drug molecules for a ADC like Trodelvy versus 760 drug molecules, on mass basis, for Thera's peptide, linker weight excluded. Including the linker weight, the difference would be more like 500 times. By chance I am rereading myself...
jfm1330 wrote: I did not research ADCs a lot, but what I know is that rate of internalization vary a lot depending on the targeted antigen and this process is much slower than with PDCs. In the case of Sortilin, it is a receptor whose role is to internalize what is binding to it, they call it a scavenger receptor. So the rate of internalization is likely to be much higher and faster when compared with ADCs. Also, having two drug molecules on a 15 kDa peptide, is a much higher ratio that having 7.6 drug molecules on a 150 kDa protein.
One important thing I found about ADCs is this:
It is critical to consider that in the patient, the distribution of the target antigen in tumors, as determined by currently available immunohistochemical assays, are often quite different from preclinical models. Most preclinical host animals do not express the target antigen, so the delivery of the ADC to the implanted tumor is not confounded by biodistribution of the ADC to normal host tissues. Furthermore, in patients, the expression of target antigen on the membrane surface of tumor cells has important characteristics that can affect delivery and the binding of the ADC. These include relative membranous and cytosolic expression, the orientation and polarity of the target antigen, and disparate expression on apical, basal lateral, or circumferential cellular surfaces, depending upon the antigen. Moreover, there exists a noteworthy heterogeneity of target antigen expression among adjacent tumor cells, and this can meaningfully affect antitumor activity. The assay selection and cutoff values for scoring potentially sensitive tumor cells is a science unto itself and requires sophisticated input from pathologists experienced in this field before it can be scaled up for clinical trials or validated as a companion diagnostic. For most tumor target antigens that are targets for ADCs, the antigen must be present for antitumor activity, but expression alone does not predict antitumor activity. This has been observed in countless preclinical models and clinical studies. As discussed in the following, the selection of the payload is inextricably related to the tumor indications that express the target antigen.