Plotinus and Pluto--this is a really important observation.

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sherlock57 Plotinus #163107
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Plotinus and Pluto--this is a really important observation. The early studies of PRO-140 were done on the basis of 5 mg and 10mg/kilograms of patient weight. Here is a passage from a 2020 article that mentions this:
"After a single 5 mg/kg IV dose (350 mg for a 70-kg patient), CCR5 receptor coating was observed for >60 days. More than 85% of receptor occupancy was observed through day 29 at 5 and 10 mg/kg, and 81% was observed at day 43 of 10 mg/kg. Specific leronlimab dosing regimens are still being investigated." 

That paper referenced a 2010 paper by Jefferson, which I found interesting for the reason that Dr Lalezari was second author, and Paul Maddon was also co-author. Lalezari goes way back with these studies, and of course Maddon engineered the molecule. Here's the references:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7546180/
https://pubmed.ncbi.nlm.nih.gov/20660677/

In the recent ACCR poster by Kasi, under baseline characteristics, the median patient weight was listed as 168 kilograms, with a range from 71 to 193 kg. This is clearly a typo, as 168 kg would be 370 lbs... and even in an overweight America, that would be incomprehensible to have a cancer trial with a median weight of 370 lbs. (I let Cytodyn know about the error right away, and was informed I was correct). Anyway, the baseline range identifies a patient at 71 pounds, and that patient certainly got an effective dose of leronlimab. And at 168 lbs for the median, that would mean half of the 16 patients in the trial fell between 71 and 168 pounds. AI did the math for me, and for a 100 lb patient who received the 350mg dose, that would work out to 7.72 mg/kg. So at the smaller end of the patient pool, several of those patients who received the 350 mg dose are getting much closer to what we would think of as a 525 mg dose, or better, if you follow the logic here.

As far as receptor occupancy goes, if you have an infection (mild case of flu?) or chronic condition (MASH?), your receptor counts are going to be elevated because your body is fighting back. So the receptor count that needs to be occupied is actually a fluctuating number, perhaps localized to the primary organs affected (lungs for the flu, liver for MASH). Personally, I'd rather have the 700mg dose, just to be sure... But the FDA isn't aware of these things, so they need to be educated...

When you add dietary considerations to the mix, well, it gets even more interesting. Polyphenols--some of them, anyway--also affect the CCR5/CCL5 axis. They do this primarily upstream, by suppressing the NF-kB subunit 65 phosphorylation. They also suppress CCL5 secretion by TAMs, if I am recalling correctly. I went down the rabbit hole with AI and asked about two polyphenols I take regularly for cardiovascular health--pomegranate juice and green tea--just to see if there might be any synergies with leronlimab. Yes to both... though the EGCG in green tea is not particularly bioavailable and doesn't achieve systemic, effective levels in the body. But theaflavins in black tea do! I doubt if any patients in the Clover trial drink pomegranate juice regularly, but a couple cups of black tea? Might be very well helping them as an adjunct CRC therapy... whether they know it or not. 

I've got some references for you down below, just in case you think I'm full of it! But I thought I would do something I'd never done before, and asked AI to write up a short text that summarized this train of though. Specifically, I asked AI to summarize the potential of 8 oz of pomegranate juice and/or two cups of black tea, daily, to complement leronlimab as an adjunct therapy. Sure makes me wonder if any Clover patients drink black tea regularly! Apologies in advance for the length of this post... but good things usually take time. Here goes:

Mechanistic Summary of Polyphenol Synergy with Leronlimab

The therapeutic coupling of bioavailable dietary polyphenols—such as black tea theaflavins and pomegranate-derived Urolithin A—with the humanized monoclonal antibody Leronlimab creates a potent, multi-tiered "ligand-receptor depletion" squeeze within the tumor microenvironment. At the outer boundaries of the cancer cell, Leronlimab performs a critical spatial checkpoint function by physically saturating and blocking existing CCR5 cell-surface receptors, isolating the tumor from metastatic signaling. Concurrently, absorbed black tea theaflavins and circulating gut-microbiota urolithins cross into the tumor cell cytoplasm. There, they aggressively disrupt the canonical IκB kinase (IKK) enzymatic complex, preventing the phosphorolysis, release, and subsequent nuclear migration of the NF-κB p65 subunit.

By locking the p65 subunit into an inert, unphosphorylated state within the cytoplasm, these polyphenol agents successfully sever the genetic command loop responsible for transcribing the CCR5 and CCL5 genes. Without an active transcription factor binding to the genomic DNA, the tumor cell is starved of the raw machinery needed to replace the cell-surface CCR5 receptors being actively neutralized by Leronlimab, while its internal production and secretion of the CCL5 cytokine ligand are completely dismantled. This intracellular genetic block beautifully reinforces Leronlimab's extracellular blockade. Furthermore, this combined action downregulates matrix metalloproteinases (MMPs) and prevents the recruitment of immunosuppressive regulatory cells, transforming a hostile, pro-metastatic tumor environment into a vulnerable target highly susceptible to cytotoxic immune clearance.

Theaflavins Retard Human Breast Cancel Cell Migrationhttps://www.sciencedirect.com/science/article...9309008734  
Anti-Cancer Properties of Theaflavins
https://pmc.ncbi.nlm.nih.gov/articles/PMC7917939/  
Urolithin A Inhibits NF-kB Activation…
https://www.nature.com/articles/s41598-021-86514-6  
Urolithin A Inhibits Breast Cancer Progression…
https://pmc.ncbi.nlm.nih.gov/articles/PMC11954813/  

Drink up, boys and girls!

  

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