chazzle, You asked about receptor occupancy level
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Posted On: 03/05/2024 9:19:03 PM
Re: chazzledazzle #141544
chazzle,
You asked about receptor occupancy levels. I had bookmarked a couple of articles from Frontiers in Immunology concerning CCR5 that might be of interest.
This one is dated 1/26/22 and includes the following:
CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS.
https://www.frontiersin.org/journals/immunolo...35994/full
This one is dated 11/18/21. With regard to RO, they state the following:
Directly measuring CCR5 RO with monoclonal antibodies also presents challenges as CCR5 expression is a dynamic process that must be controlled for. Indeed, the frequency of CCR5+ cells change longitudinally in response to inflammatory and homeostatic stimuli and can be impacted by the CCR5-targeting reagent itself (39–43), leading to inaccuracies in methods that use baseline CCR5 values to calculate CCR5 RO (44). Not accounting for the ability of CCR5 expression to change over time in the CCR5 RO calculation for the anti-CCR5 antibody HGS004 resulted in baseline pre-treatment CCR5 RO values of 20% in HIV-1 infected participants (45). Thus, no robust and highly sensitive method for the calculation of CCR5 RO currently exists.
Here, we report on two sensitive methods to measure CCR5 RO by the anti-CCR5 antibody Leronlimab (PRO-140; Vyrologix). We demonstrate the sensitivity of this method to longitudinally quantify CCR5 RO on blood and tissue CD4+ T cells from Leronlimab-treated macaques and describe increased levels of CCR5+CD4+ T cells in the blood of both Leronlimab-treated macaques and humans. Finally, we translate the macaque CCR5 RO method to Leronlimab-treated, HIV-naïve human participants, demonstrating the direct use for monitoring CCR5 RO by Leronlimab in human clinical trials.
https://www.frontiersin.org/journals/immunolo...94638/full
The article discusses the development of methods for calculating RO. The authors included Scott Kelly and Jonah Sacha (and Nader).
You asked about receptor occupancy levels. I had bookmarked a couple of articles from Frontiers in Immunology concerning CCR5 that might be of interest.
This one is dated 1/26/22 and includes the following:
CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS.
https://www.frontiersin.org/journals/immunolo...35994/full
This one is dated 11/18/21. With regard to RO, they state the following:
Directly measuring CCR5 RO with monoclonal antibodies also presents challenges as CCR5 expression is a dynamic process that must be controlled for. Indeed, the frequency of CCR5+ cells change longitudinally in response to inflammatory and homeostatic stimuli and can be impacted by the CCR5-targeting reagent itself (39–43), leading to inaccuracies in methods that use baseline CCR5 values to calculate CCR5 RO (44). Not accounting for the ability of CCR5 expression to change over time in the CCR5 RO calculation for the anti-CCR5 antibody HGS004 resulted in baseline pre-treatment CCR5 RO values of 20% in HIV-1 infected participants (45). Thus, no robust and highly sensitive method for the calculation of CCR5 RO currently exists.
Here, we report on two sensitive methods to measure CCR5 RO by the anti-CCR5 antibody Leronlimab (PRO-140; Vyrologix). We demonstrate the sensitivity of this method to longitudinally quantify CCR5 RO on blood and tissue CD4+ T cells from Leronlimab-treated macaques and describe increased levels of CCR5+CD4+ T cells in the blood of both Leronlimab-treated macaques and humans. Finally, we translate the macaque CCR5 RO method to Leronlimab-treated, HIV-naïve human participants, demonstrating the direct use for monitoring CCR5 RO by Leronlimab in human clinical trials.
https://www.frontiersin.org/journals/immunolo...94638/full
The article discusses the development of methods for calculating RO. The authors included Scott Kelly and Jonah Sacha (and Nader).
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