RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:How Barclays Capital values Small Cap Oncology namesAt least, and notably in Breast Cancer, from the most recent research on the sortilin receptor, and assuming the compound does practically function as a competitive inhibitor, it has a decent shot at having a triple MOA:
1) Disruption of IL-6/Sortilin, Progranulin/Sortilin axes responsible of the activation of metastatic Cancer Stem Cell populations
2) Disruption of Vascular Mimicry leading to tumor hypoxia
3) in-cell delivery of the cytotoxic via Sortilin effected internalization
So even if the linker isn't perfect, there are still good hopes of seeing efficacy.
Isn't it fascinating?!
qwerty22 wrote: There are a few good reviews of ADC talking about the 3 pieces of the puzzle, antibody (peptide in our case), linker, toxic bomb. All 3 need to be doing their job for the whole thing to come together. When I read those reviews I get the sense there aren't any hard and fast rule. Essentially the field is learning from each new success and failure and cobbling together a fairly fluid rule book.
So if you take the linker as an example in some cases as in Startrap's example it breaks early and causes off target toxicity, in other cases it stays firmly attached and only releases in the cell, this is often described as desirable but in some cases is blamed for poor responses because another effect has been described called "bystander killing" which is where the released toxin can kill cells in the tumour without the target molecule because it gets released into the tumour micro-environment and passively enters cells. So in that case the rules shift depending on exactly what you want to optimize. If your tumour heterogenously expresses the target then a firmly holding linker might be a disadvantage but that in its self is also not a hard and fast rule. No need to get too deep into the detail here the basic point is the rules about what makes a good ADC/PDC aren't firmly fixed and that makes empirical data from patients all the more important.
Nothing that I can see points toward failure for th-1902 but nothing makes success a certainty.
Spartrap wrote:
jfm1330 wrote: One thing is sure, Thera is not using the same linker. But it is a good reminder that it is still at the research stage, that is why we need hard facts on humans.
Right, there are 2 methyl groups on that glutaryl on the TH compound IIRC, so hopefully more stable.. hopefully it makes all the difference. I agree with Wino some input from the CMO would be great
It's such a critical component, it must be mighty hard to tune.
There might be other factors too, such as the time to internalization from activating the sortilin receptor vs the LHGH receptor (is that one even triggering internalization?)
jfm1330 wrote: Also, an advantage of exploring the radioisotopes is the fact that no cleavable linker is needed with these. The isotopes don't need to be free inside the cell to emit radiations.
Wow, that's a great point indeed.. this plus the actinium 225 improvement, I'm actually starting to like your idea, inspite of the demanding supply chain!
jfm1330 wrote: Wino115 wrote: Sure, always the risk -- the human response. I'm not remotely qualified to discuss pros and cons of different cleavable links and homing receptors so will leave that up to you scientifically minded. I know the science has progressed a lot in last few years according to the PDC primer (I didn't even see a discussion on this linker), but THTX needs to prove it all up. I guess one thing I like is that each tumor type and cancer type is a bit different, expressing different chemical's and cellular structures, so while they could all fail, I still like the fact they have at least 4 shots on goal with these different tumor's, maybe a fifth if they get the melanoma study done, and then more with TH1901. But caution, as you say, is warranted.
These would be good questions to get to CMO - what is their understanding of the linker versus the failed one in Zoptarelin? If anyone checks in with him, be interested to hear an answer.
Spartrap wrote: It's a bit mean to do so today, but let me bring forward the sad story of Zoptarelin Doxorubicin, just to keep our enthusiasm in check: https://en.m.wikipedia.org/wiki/Zoptarelin_doxorubicin Passed P1 and P2 with flying colors just to miserably fail in P3. Apparently, the linker wasn't solid enough and tended to break too early within the more acidic Tumor Micro Environment.. Ended up being not superior or safer than Doxorubicin alone ;-/
Wino115 wrote: I So you may almost be able to have a 50-75% probability of success after Phase 1. This shows one of the benefits of a peptide versus an antibody approach.