This is a very interesting post, and reply. Perhaps Ohm, CTMedic, any of our smart medical guys can comment on this? From YMB:
Videoctr
Videoctr7 hours ago
This looks like an interesting puzzle piece...
Clinical Infectious Diseases, Volume 32, Issue 4, 15 February 2001, Pages 650–652,
"Patients with Active Tuberculosis Have Increased Expression of HIV Coreceptors CXCR4 and CCR5 on CD4+ T Cells"
https://academic.oup.com/cid/article/32/4/650/466467
ReplyReplies (1)16
Kevin
"It is not quite unexpected. The term might be upregulation. I cited the following in an email to CYDY, to which Dr. Recknor responded with a thank you:
Lee et alia. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages.
In vitro maturation of PBDC resulted in median 3- and 41-fold increases in CCR5 and CXCR4 ABS, respectively. We found that macrophage colony-stimulating factor caused the greatest up-regulation of both CCR5 and CXCR4 on macrophage maturation (from ~5,000 to ~50,000 ABS) whereas granulocyte macrophage colony-stimulating factor caused a marked decrease of CXCR4 (from ~5,000 ABS to <500) while up-regulating CCR5 expression (from ~5,000 to ~20,000 ABS).
Mr. Mullholland emailed that my question would be in the conference call. The moderator asked my question about half-life. I responded to Dr. Patterson on Twitter about this, too.
Think about it: T cells massively proliferate (expansion) in active adaptive immune responses. If the number of T cells greatly increase AND the number of CCR5 receptors increase (and turnover), then should this not affect the half-life of Leronlimab?
CYDY stated a half-life of 10 days without citation in one of their papers. They are dosing on 7 days. What happens if the half-life is less than:
Jacobson JM, Thompson MA, Lalezari JP, Saag MS, Zingman BS, D'Ambrosio P, Stambler N, Rotshteyn Y, Marozsan AJ, Maddon PJ, Morris SA, Olson WC. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody. J Infect Dis. 2010 May 15;201(10):1481-7. doi: 10.1086/652190. PMID: 20377413; PMCID: PMC2856743.
Serum concentrations observed during the first week of treatment are depicted in Figure 2 and were used to calculate pharmacokinetic metrics. Data for the 324 mg weekly and biweekly groups were pooled for this analysis. Peak concentrations typically were observed 32–56 h after treatment, with a mean of 6.1 and 13.8 mg/L for subjects treated with 162 and 324 mg of PRO 140, respectively. The corresponding mean terminal half-lives were 3.4 and 3.7 days, respectively.
Then again, I am not convinced that 7 days IV with 700 mg is the correct dose amount, frequency, and route to quell the cytokine storm but allow a needed immune response. CYDY appears to be shooting from the hip, but they may have data that is not public."
Videoctr
Videoctr7 hours ago
This looks like an interesting puzzle piece...
Clinical Infectious Diseases, Volume 32, Issue 4, 15 February 2001, Pages 650–652,
"Patients with Active Tuberculosis Have Increased Expression of HIV Coreceptors CXCR4 and CCR5 on CD4+ T Cells"
https://academic.oup.com/cid/article/32/4/650/466467
ReplyReplies (1)16
Kevin
"It is not quite unexpected. The term might be upregulation. I cited the following in an email to CYDY, to which Dr. Recknor responded with a thank you:
Lee et alia. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages.
In vitro maturation of PBDC resulted in median 3- and 41-fold increases in CCR5 and CXCR4 ABS, respectively. We found that macrophage colony-stimulating factor caused the greatest up-regulation of both CCR5 and CXCR4 on macrophage maturation (from ~5,000 to ~50,000 ABS) whereas granulocyte macrophage colony-stimulating factor caused a marked decrease of CXCR4 (from ~5,000 ABS to <500) while up-regulating CCR5 expression (from ~5,000 to ~20,000 ABS).
Mr. Mullholland emailed that my question would be in the conference call. The moderator asked my question about half-life. I responded to Dr. Patterson on Twitter about this, too.
Think about it: T cells massively proliferate (expansion) in active adaptive immune responses. If the number of T cells greatly increase AND the number of CCR5 receptors increase (and turnover), then should this not affect the half-life of Leronlimab?
CYDY stated a half-life of 10 days without citation in one of their papers. They are dosing on 7 days. What happens if the half-life is less than:
Jacobson JM, Thompson MA, Lalezari JP, Saag MS, Zingman BS, D'Ambrosio P, Stambler N, Rotshteyn Y, Marozsan AJ, Maddon PJ, Morris SA, Olson WC. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody. J Infect Dis. 2010 May 15;201(10):1481-7. doi: 10.1086/652190. PMID: 20377413; PMCID: PMC2856743.
Serum concentrations observed during the first week of treatment are depicted in Figure 2 and were used to calculate pharmacokinetic metrics. Data for the 324 mg weekly and biweekly groups were pooled for this analysis. Peak concentrations typically were observed 32–56 h after treatment, with a mean of 6.1 and 13.8 mg/L for subjects treated with 162 and 324 mg of PRO 140, respectively. The corresponding mean terminal half-lives were 3.4 and 3.7 days, respectively.
Then again, I am not convinced that 7 days IV with 700 mg is the correct dose amount, frequency, and route to quell the cytokine storm but allow a needed immune response. CYDY appears to be shooting from the hip, but they may have data that is not public."
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