some of the paper's findings: Leronlimab both s
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Posted On: 06/02/2022 9:52:03 AM
some of the paper's findings:
shows that our Receptor Occupancy test is superior to the one used by Pfizer to verify Maraviroc's effectiveness to bind to CCR5 which uses internalization calculations.
So, yes, this likely also contributed to the increase in CCR5 on CD4 surfaces.
When CCR5 is internalized, it is no longer expressed on the surface of the cell, but when it is bound to LL, it remains expressed. Could this mean that when LL is fully dosed, it actually enters the cell, finds the internalized CCR5, dislodges the bound ligand, binds to CCR5 and then the combined CCR5+LL is expressed on the cell surface? That would increase their numbers.
Quote:
Leronlimab both stabilized surface CCR5 expression and prevented its internalization. Thus, it is critical to account for this Leronlimab-induced increase in surface CCR5 levels for CCR5 RO measurements.
Quote:
TThese results are in contrast to the commonly used MIP-1β internalization assay utilized for Maraviroc, which is associated with background levels of approximately 25% in human samples (38) and yields values in excess of 100% in maraviroc-treated and -untreated rhesus macaques (39). Higher RO percentages calculated by the MIP-1β internalization assay may be due to fluctuating CCR5 frequencies or incomplete CCR5 internalization upon MIP-1β binding. In contrast, our methods did not depend on receptor internalization and all mathematical components used were gated on CCR5+ cells, compensating for any fluctuation in CCR5 frequency and allowing for precise calculation of RO. Finally, the pre-clinical Leronlimab CCR5 RO assay was extended into human participants, demonstrating the ability to longitudinally and robustly monitor CCR5 RO.
shows that our Receptor Occupancy test is superior to the one used by Pfizer to verify Maraviroc's effectiveness to bind to CCR5 which uses internalization calculations.
Quote:
Similar to maraviroc, we found that Leronlimab stabilized surface CCR5 molecules and prevented its internalization following ligand binding. Indeed, this shared feature of both drugs likely explains their shared ability to increase frequencies of CCR5+CD4+ T cells in both humans and macaques.
So, yes, this likely also contributed to the increase in CCR5 on CD4 surfaces.
When CCR5 is internalized, it is no longer expressed on the surface of the cell, but when it is bound to LL, it remains expressed. Could this mean that when LL is fully dosed, it actually enters the cell, finds the internalized CCR5, dislodges the bound ligand, binds to CCR5 and then the combined CCR5+LL is expressed on the cell surface? That would increase their numbers.
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