Does anyone recall the mention of "CCR5 Clusters" or "CCR5 Dots" from the recent Pestell TNBC paper? I missed the significance of that, and surely wasn't the only one, as I don't recall anyone else posting about it. But, apparently, leronlimab causes the CCR5 receptors to shape-shift and internalize (endocytosis is the biological/medical term). This reduces the number of receptors needed to be occupied. Now this is entirely AI generated, and right now I want to watch Brazil at the World Cup... so I don't have the time double-check this, like I usually do. So this may be an hallucination, for all I know. But it would certainly answer the question about why sub-optimal doses of leronlimab are working so well in the Clover trial... Fascinating stuff:
Data presented at the AACR Immuno-Oncology Conference revealed that leronlimab does not need to saturate 100% of all systemic receptors to halt tumor shielding. Upon binding at a 350 mg threshold, leronlimab induces the formation of "CCR5 Dots"—internalized, aggregated receptor pools within Cancer-Associated Macrophage-Like cells (CAMLs). This signaling shutdown occurs at a cellular level, disrupting macrophage recruitment before the drug is entirely depleted.
The Direct Relationship to Receptor Occupancy
The formation of these cluster dots fundamentally changes how receptor occupancy operates, explaining why positive biomarker signs can appear even at a sub-optimal 350 mg dose:
Inducing Spatial Shutdown: When leronlimab forces receptors into these concentrated dots, it changes their shape. This structural alteration prevents inflammatory chemokines (like CCL5) from binding to any receptor within that cluster, effectively shutting down signaling across the entire aggregate.
Triggering Internalization: Once these dense cluster dots form on the cell wall, the cell recognizes the abnormality and pulls the entire cluster inside itself (a process called endocytosis or internalization).
[color=var(--text)]Bypassing the Liver Sink Calculation: This internalization loop means that a 350 mg dose can achieve a much higher functional receptor occupancy than traditional math would suggest. Instead of needing enough drug molecules to individually block every single receptor in the liver sink, a smaller amount of leronlimab can trigger a cascade that clumps multiple receptors together and removes them from the cell surface entirely.[/color]
Sherlock here, with an additional comment. I don't think the Natera assay could have told us this. This is a CreatvBio-derived insight, based on their filter-system that can trap those big CAMLs and reveal the CCR5 Clusters, which appear as "dots" when they are stained with a florescent dye. Oh, and the "liver sink" that is mentioned refers to the large numbers of CCR5 positive cells in the liver that would otherwise need to be occupied...
How much does this help shut down the CCR5/CCL5 axis? I have no idea about quantifying any of this... I'll let others look deeper into that; I've got a second half of the Brazil-Haiti match to watch.
Data presented at the AACR Immuno-Oncology Conference revealed that leronlimab does not need to saturate 100% of all systemic receptors to halt tumor shielding. Upon binding at a 350 mg threshold, leronlimab induces the formation of "CCR5 Dots"—internalized, aggregated receptor pools within Cancer-Associated Macrophage-Like cells (CAMLs). This signaling shutdown occurs at a cellular level, disrupting macrophage recruitment before the drug is entirely depleted.
The Direct Relationship to Receptor Occupancy
The formation of these cluster dots fundamentally changes how receptor occupancy operates, explaining why positive biomarker signs can appear even at a sub-optimal 350 mg dose:
Inducing Spatial Shutdown: When leronlimab forces receptors into these concentrated dots, it changes their shape. This structural alteration prevents inflammatory chemokines (like CCL5) from binding to any receptor within that cluster, effectively shutting down signaling across the entire aggregate.
Triggering Internalization: Once these dense cluster dots form on the cell wall, the cell recognizes the abnormality and pulls the entire cluster inside itself (a process called endocytosis or internalization).
[color=var(--text)]Bypassing the Liver Sink Calculation: This internalization loop means that a 350 mg dose can achieve a much higher functional receptor occupancy than traditional math would suggest. Instead of needing enough drug molecules to individually block every single receptor in the liver sink, a smaller amount of leronlimab can trigger a cascade that clumps multiple receptors together and removes them from the cell surface entirely.[/color]
Sherlock here, with an additional comment. I don't think the Natera assay could have told us this. This is a CreatvBio-derived insight, based on their filter-system that can trap those big CAMLs and reveal the CCR5 Clusters, which appear as "dots" when they are stained with a florescent dye. Oh, and the "liver sink" that is mentioned refers to the large numbers of CCR5 positive cells in the liver that would otherwise need to be occupied...
How much does this help shut down the CCR5/CCL5 axis? I have no idea about quantifying any of this... I'll let others look deeper into that; I've got a second half of the Brazil-Haiti match to watch.
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