jfm1330 wrote: OK. I foundother infos that could help a bit about the linker situation. In this article on Table 3 you will see the description of two candidate PDC.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942387/#R67
One of the two is ANG1005, and it says that it is using the succinyl linker. So who is behind this PDC, here you have it, Angiochem. Who is the founder of Angiochem? Richard Beliveau. Who is founder of Katana? Richard Beliveau.
The first article I found about ANG1005 is from 2008 and it confirms the use of the succinyl linker to load an angiopep peptide with three molecules of paclitaxel.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538693/
That being said, the problem is that 13 years later, this PDC is still in an ongoing phase III and it seems that Beliveau and his team are no longer involved in this project. I am not sure, but they are not in the long list of authors. Angiochem is still a private company and I don't know who are now the owners. Also, in the phase II study, 96% of the patients experienced an adverse event. Read that:
https://clincancerres.aacrjournals.org/content/26/12/2789
Safety
Safety and tolerability of ANG1005 was consistent with expected taxane profile. Overall, 69 (96%) of the 72 patients, who received at least one cycle of ANG1005, experienced an adverse event considered related to ANG1005; however, only a small number of patients (n = 5, 7%) withdrew due to adverse events. Twenty-four (24, 33%) experienced any level of dose reduction. Of those 24 patients, the first dose reduction occurred at the following cycle: cycle 2 in 10 patients (10, 42%), cycle 3 (7, 29 %), cycle 4 (3, 13%), cycle 5 (1, 4%), cycle 8 (2, 8%), and cycle 9 (1, 4%). Twenty-two (22, 31%) patients required dose reductions from 600 to 550 mg/m2, and one (1%) patient from 600 to 470 mg/m2. Nine patients (9, 12%) had further reductions from 550 to 470 mg/m2 and two (3%) patients had the dose reduced from 470 to 400 mg/m2.
The most common toxicities were related to myelosuppression with several hematologic toxicities seen at grade ≥3, as follows: reduced white blood cell count documented in 45 (62%) patients, neutrophil count decreased (46, 64%), lymphocyte count decreased (31, 43%), platelet count decreased (11, 15%), and anemia (9, 13%). In addition, 13 (18%) patients experienced febrile neutropenia including 12 (17%) at grade ≥3. The most frequent nonhematologic ANG1005-related toxicities included fatigue and nausea in 37 (51%) and 28 (39%) patients, respectively. Peripheral neuropathy/peripheral sensory neuropathy was reported in 28 (39%) patients. Few patients experienced grade 3 nonhematologic toxicity, including eight (11%) with grade 3 fatigue, four (6%) with grade 3 nausea, and six (8%) with grade 3 peripheral neuropathy. None of these most common nonhematologic events were seen at grade 4.
So it seems that they saw relatively high toxicity in line with usual toxicity of paclitaxel. To have this hematologic toxicity, it means the succinyl linker released good amounts of paclitaxel in the bloodstream. That being said ANG1005 is a PDC designed to cross the blood brain barrier. Probably the internalization out of the bloodstream is longer than with TH1902 and sortilin, and it gives more time for the cleavage of the linker in the bloodstream releasing paclitaxel. This next article tends to confirm that the rate of internalization can vary and that the level of the target receptor to cross the blood brain barrier is likely low compared to sortilin.
https://www.nature.com/articles/bjc2011427
So it is clear that crossing the BBB is not as easy as entering a cancer cell through sortilin, but at the same time, we can see that the succinyl linker is releasing paclitaxel in the bloodstream. So maybe they determined that internalization through sortilin will be so much faster that the relative instability of the linker won't be a problem, but again, mice and humans are very different. One thing is sure, I now have some doubts about the fact that the succinyl linker is stable enough.
One more thing about this linker confusion. Angiopep also made versions of ANG1005, called ANG1007 and ANG1009. It is based on the same peptide, but ANG1007 is linked to doxorubicin, and ANG1009 to etoposide. Interestingly, in this case, ANG1007 has doxorubicin linked to the peptide through the succinyl linker, while epotoside is linked through the glutaryl linker (not dimethyl glutaryl). So why with TH1904 doxorubicin is linked through the dimethyl glutaryl linker, and with ANG1007, they used the succinyl linker, and why the glutaryl linker with epotoside, and not the succinyl or the dimethyl glutaryl? We really would need some explainations about their rationale about linker selection. It seems relatively clear that it is a case by case process, but still, from the outside, it is far from clear. Even though it would look very bad, I still hope that TH1902 is made with the dimethyl glutaryl because it is likely more stable than the glutaryl and the succinyl linkers. That, at least, would make sense given all the infos I gathered about the glutaryl and succinyl relative instability in the bloodstream.
https://angiochem.com/sites/default/files/publications/2010%20JMC_Etoposide-doxo_Che%20et%20al.pdf