Agree it's good to see some basic science on how leronlimab works, especially as compared to other CCR5 antagonists in preclinical models of breast cancer metastases.
The original Olson and Maddon work on PA14/PRO140/LL in 1999 DID show that PA14 blocks CCL5, CCL4, and CCL3 binding in mouse L1.2 cells. It's good to get confirmation that the same holds for human breast cancer cells.
Olson and Maddon paper:
https://jvi.asm.org/content/73/5/4145.long
Maddon ignored this relatively "weak" blocking of chemokines and claimed that there was no blocking, that this was a good thing, and that this is why there was no toxicity with PA14/PRO140/LL.
As NP explained:
Thankfully, NP did not listen to the inventor! He went ahead on his own based on *some* blockage of chemokines, and had the fantastic preclinical result in GvHD.
So, all the early HIV related material from CYDY falsely claimed that PRO140 did not block chemokines CCL3, CCL4, and CCL5 from binding to CCR5, and that's why there was no toxicity (compared to maraviroc). That was clearly false information from Progenics, as blocking chemokines is how LL works for cancer and Covid and all these autoimmune diseases. Progenics had a potential gold mine but didn't realize it!
Which brings us back to other CCR5 antagonists. Why *does* maraviroc have a black box warning of liver toxicity but LL does not seem to have that problem? Aplaviroc also had severe liver toxicity in humans and was abandoned. The best answer we've gotten is that MVC may have toxic metabolites or interfere with Cytochrome P450 system. Could it be that the relatively "weak" blockage of other chemokines by LL compared to other CCR5 antagonists is actually the reason for the apparent improved safety?
Unfortunately for us CYDY investors, I'm not sure that is the case that MVC can't be used safely for the same immunomodulatory indications as LL. Likewise for the other CCR5 small molecules in development, vicriviroc, cenicriviroc (blocks CCR2 and CCR5), and Orion's OB-002, which is 5P12-RANTES, a CCR5/RANTES chemokine analog.
From the Pestell paper, maraviroc and vicriviroc seemed to do the same things that leronlimab could do. MVC is a cheaper oral drug (compared with LL mAB). So why would people want to use a more expensive shot (does have advantage as once weekly dose)?
As with everything in biotech, there will always be competition when there are big markets at stake. Leronlimab should be a big winner, even if there may be other CCR5 antagonists in development, but our moat may not be as big as we want. Will have to see what the clinical trials show with different CCR5 antagonists for different indications. For sure, LL is better for HIV due to the problem of resistance forming from MVC, but not for LL. Will its apparently stronger safety profile be a winner in cancer and immunomodulatory diseases like Covid? Stay tuned. There are lots of CCR5 antagonist trials running for lots of different indications. Maraviroc has ongoing trials for Covid, stroke, and liver disease. I still really like our horse in the race, just hope that the Covid results are as good as anticipated so we can run a little faster for all the other indications.
The original Olson and Maddon work on PA14/PRO140/LL in 1999 DID show that PA14 blocks CCL5, CCL4, and CCL3 binding in mouse L1.2 cells. It's good to get confirmation that the same holds for human breast cancer cells.
Olson and Maddon paper:
https://jvi.asm.org/content/73/5/4145.long
Quote:Chemokine signaling in the presence of anti-CCR5 MAbs.Chemokine receptor-binding agents can be antagonists or, more rarely, agonists of receptor-mediated intracellular signaling. Alternatively, they could have no effect on signaling. CCR5 is able to bind three CC-chemokines, RANTES, MIP-1α, and MIP-1β, and transduce a signal that modulates cytosolic calcium levels. We therefore tested the agonist-antagonist activity of various concentrations of MAbs PA8 to PA12, PA14, and 2D7. Changes in intracellular calcium concentrations, [Ca2+]i, were measured in Indo-1-loaded L1.2-CCR5+ cells. None of the MAbs stimulated a change in [Ca2+]i, indicating that they are not agonists for CCR5. PA8 to PA12 were also unable to inhibit Ca2+ fluxes induced by RANTES (Fig.3a and data not shown), even at concentrations as high as 100 μg/ml, showing that they are not antagonists either. These concentrations provide saturating binding of the MAbs to L1.2-CCR5+ cells, as shown by flow cytometry and the gp120-CCR5 binding assay (Fig. 3d and data not shown). MAbs PA14 and 2D7, however, blocked calcium mobilization induced by RANTES, although with different potencies (Fig. 3a and b). The 50% inhibitory concentration (IC50) for PA14 calcium influx inhibition was 45 μg/ml, which was approximately eightfold higher than the IC50 for 2D7 (Fig. 3b). RANTES-, MIP-1α-, and MIP-1β-induced calcium fluxes were each inhibited by similar concentrations of PA14 (data not shown).
Maddon ignored this relatively "weak" blocking of chemokines and claimed that there was no blocking, that this was a good thing, and that this is why there was no toxicity with PA14/PRO140/LL.
As NP explained:
Quote:Nader Pourhassan: Let me tell you the most interesting part at that time. At CytoDyn we had a very strong cancer person, key opinion leader. And that person and Dr. Denis Burger both believed in the potential GvHD indication for leronlimab (called PRO 140 at that time). I wanted to do an animal study of graft versus host disease with leronlimab. When we held a key opinion meeting Dr. Paul Maddon, inventor , was on the call at my request. I had asked him to come on the call. He said no, no, no, no. There is no GvHD [graft versus host indication] for leronlimab. This was four and a half, five years ago. And he said, No, no, no, everything must stop. Maraviroc stops chemokines from binding. Leronlimab doesn't do that. And that's why we don't have any side effects or toxicity. So stop everything.
Thankfully, NP did not listen to the inventor! He went ahead on his own based on *some* blockage of chemokines, and had the fantastic preclinical result in GvHD.
So, all the early HIV related material from CYDY falsely claimed that PRO140 did not block chemokines CCL3, CCL4, and CCL5 from binding to CCR5, and that's why there was no toxicity (compared to maraviroc). That was clearly false information from Progenics, as blocking chemokines is how LL works for cancer and Covid and all these autoimmune diseases. Progenics had a potential gold mine but didn't realize it!
Which brings us back to other CCR5 antagonists. Why *does* maraviroc have a black box warning of liver toxicity but LL does not seem to have that problem? Aplaviroc also had severe liver toxicity in humans and was abandoned. The best answer we've gotten is that MVC may have toxic metabolites or interfere with Cytochrome P450 system. Could it be that the relatively "weak" blockage of other chemokines by LL compared to other CCR5 antagonists is actually the reason for the apparent improved safety?
Unfortunately for us CYDY investors, I'm not sure that is the case that MVC can't be used safely for the same immunomodulatory indications as LL. Likewise for the other CCR5 small molecules in development, vicriviroc, cenicriviroc (blocks CCR2 and CCR5), and Orion's OB-002, which is 5P12-RANTES, a CCR5/RANTES chemokine analog.
From the Pestell paper, maraviroc and vicriviroc seemed to do the same things that leronlimab could do. MVC is a cheaper oral drug (compared with LL mAB). So why would people want to use a more expensive shot (does have advantage as once weekly dose)?
As with everything in biotech, there will always be competition when there are big markets at stake. Leronlimab should be a big winner, even if there may be other CCR5 antagonists in development, but our moat may not be as big as we want. Will have to see what the clinical trials show with different CCR5 antagonists for different indications. For sure, LL is better for HIV due to the problem of resistance forming from MVC, but not for LL. Will its apparently stronger safety profile be a winner in cancer and immunomodulatory diseases like Covid? Stay tuned. There are lots of CCR5 antagonist trials running for lots of different indications. Maraviroc has ongoing trials for Covid, stroke, and liver disease. I still really like our horse in the race, just hope that the Covid results are as good as anticipated so we can run a little faster for all the other indications.
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