RE:RE:RE:RE:RE:RE:What's our Oncology Option Worth?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. Wino115 wrote: Verification you're idea is on to something. Perhaps shows if you establish the validity of your
linker and homing receptor, you can spend loads of time and money experimenting around
with your platform in subsequent years. That's the massive value-add of these whole ADC/PDC
approach and why the valuations and take-out valuations are astounding.
Question, are you saying that TH1902 will have a higher payload of the treatment on an apples-to-apples
basis delivered into the tumor cell than Trodelvy? One thing seems clear from pre-clinical, TH-1902 crushes
Trodelvy on their Phase 3 neutropenia effect. I know, it's not humans, but it's looking good in little critters!
jfm1330 wrote: Took a look at Trodelvy.
They use a huge linker, a proprietary linker that is linked to the mAB through disulfide bond on cysteine.
The ratio of drug molecules vs mAB is 7.6. Which on a molecular weight basis is much lower than Thera's PDC.
Interserstingly, they are now testing the mAB of Trodelvy with Lu177...