Twinter, I ran across an article a while back than might answer some of your questions. At least the RO questions, which clearly differentiate leronlimab from maraviroc. It describes the work done developing the CCR5 receptor occupancy array that the crew out of OHSU did back in 2020-21 and published in Frontiers in Immunology, Nov 2021. It looks to be some pretty fundamental work. The lead author is Xiao Chang, but in the list of co-authors are some familiar names, like Helen Wu, Gabriela Webb, and as you might expect, Jonas. It's very dense and scientific, but lots on RO and half-life. Their research is based on a lot of monkey business, and I can see why people are worried about the shutting down of primate work at OHSU. I don't pretend to understand it all, and my eyes glaze over at a certain point trying to understand what's going on. But you and others on the board might find it a worthwhile read this weekend. Here's a taste:
"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..."
After reading the abstract and intro, I skipped ahead to the Results section. Bingo! Something quite relevant I think:
"In samples without Leronlimab, we observed CCR5 internalization in response to MIP-1α, MIP-1β, and RANTES (Figure 1B). Following treatment with Leronlimab, we found increased frequencies of CCR5+CD4+ T cells where CCR5 was resistant to internalization following treatment with all three CCR5 ligands, indicating that 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."
So, if I'm reading this right, leronlimab's ability to to stabilize surface expression of CCR5 and prevent it's internalization is what makes it more effective than maraviroc. And the way my Neanderthal brain works--stable CCR5 expression Good!... preventing internalization Good! But why is preventing internalization good? I'd have thought that internalizing CCR5 would limit RANTES and the other ligands from activating the CCR5/CCL5 axis, but clearly, I'm missing something here. Ohm... can I ask you to clarify?
The IH website wouldn't let me paste the RO equations they developed without mangling them, but they are pretty wild. Lots of cool graphics in general. If you like pictures.
Here's the link:
https://www.frontiersin.org/journals/immunolo...nology#B23
"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..."
After reading the abstract and intro, I skipped ahead to the Results section. Bingo! Something quite relevant I think:
"In samples without Leronlimab, we observed CCR5 internalization in response to MIP-1α, MIP-1β, and RANTES (Figure 1B). Following treatment with Leronlimab, we found increased frequencies of CCR5+CD4+ T cells where CCR5 was resistant to internalization following treatment with all three CCR5 ligands, indicating that 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."
So, if I'm reading this right, leronlimab's ability to to stabilize surface expression of CCR5 and prevent it's internalization is what makes it more effective than maraviroc. And the way my Neanderthal brain works--stable CCR5 expression Good!... preventing internalization Good! But why is preventing internalization good? I'd have thought that internalizing CCR5 would limit RANTES and the other ligands from activating the CCR5/CCL5 axis, but clearly, I'm missing something here. Ohm... can I ask you to clarify?
The IH website wouldn't let me paste the RO equations they developed without mangling them, but they are pretty wild. Lots of cool graphics in general. If you like pictures.
Here's the link:
https://www.frontiersin.org/journals/immunolo...nology#B23
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