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Posted On: 05/06/2025 11:44:03 PM
Post# of 152642
Not sure if they ever disclosed receptor occupancy versus dosage or LL concentration curve, have they?
In order to get 100% CCL5 blockage, in mouse model of PA14 need 60 ug/mL concentration, per Figure 3 of https://journals.asm.org/doi/full/10.1128/jvi...-4155.1999.
In human HIV PK study, a single 324mg SC dose of LL resulted in peak of only ~12 ug/mL in human plasma, versus just 4 ug/mL for half that dose. Would 700mg get up to 60 ug/mL plasma concentration to give complete CCL5 blockage? or maybe in humans, lower plasma concentration is needed for 100% CCL5 blockage?
https://pmc.ncbi.nlm.nih.gov/articles/PMC2856743/ Figure 2 shows SC PK of LL.
LL seems to bind at the ECL2 loop of CCR5:
ECL2 binding antibodies do a better job of blocking RANTES/CCL5 and MIP2/CCL2 than those ABs binding to N terminal or other (multi)domains:
https://www.jbc.org/content/274/14/9617.long
That's why 2D7 worked so well:
https://www.jbc.org/article/S0021-9258(19)87297-6/fulltext
Just for fun, here's another paper on LL epitope binding:
https://pubs.acs.org/doi/10.1021/bi401289p
Mechanics of where and how well LL binds to the CCR5 receptor is complicated. I'm not convinced we are getting 100% blockage of CCL5 with the dosages we are using.
In order to get 100% CCL5 blockage, in mouse model of PA14 need 60 ug/mL concentration, per Figure 3 of https://journals.asm.org/doi/full/10.1128/jvi...-4155.1999.
In human HIV PK study, a single 324mg SC dose of LL resulted in peak of only ~12 ug/mL in human plasma, versus just 4 ug/mL for half that dose. Would 700mg get up to 60 ug/mL plasma concentration to give complete CCL5 blockage? or maybe in humans, lower plasma concentration is needed for 100% CCL5 blockage?
https://pmc.ncbi.nlm.nih.gov/articles/PMC2856743/ Figure 2 shows SC PK of LL.
LL seems to bind at the ECL2 loop of CCR5:
ECL2 binding antibodies do a better job of blocking RANTES/CCL5 and MIP2/CCL2 than those ABs binding to N terminal or other (multi)domains:
https://www.jbc.org/content/274/14/9617.long
That's why 2D7 worked so well:
https://www.jbc.org/article/S0021-9258(19)87297-6/fulltext
Just for fun, here's another paper on LL epitope binding:
https://pubs.acs.org/doi/10.1021/bi401289p
Mechanics of where and how well LL binds to the CCR5 receptor is complicated. I'm not convinced we are getting 100% blockage of CCL5 with the dosages we are using.
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