Wow. IL6 receptor blockade mabs failed again today with the Actemra-tocilizumab report. Perhaps Dr. Bruce Patterson can explain the failure of the IL6 receptor blockade mabs?
Using google scholar, I quickly found some articles that can explain, but I cannot assess these articles for likely correctness. But I was sure surprised that I so quickly found a scientific explanation for why IL6 receptor blockade might not be effective in covid19.
With today's news that Actemra/tocilizumab has failed a human clinical trial with the same 19% mortality at day 28 as placebo, I think we have new question for Dr. Bruce Patterson.
Actemra-tocilizumab is an IL6 receptor blocker.
Actemra-tocilizumab's failure comes not long after the failure of another IL6 receptor blocker, Kevzara-sarilumab.
So now both IL6 receptor blockade antibodies have failed in covid19.
Yet elevated IL6 is a common feature of severe/critical covid19 patients.
Neither of the failed IL6 mabs target the IL6 protein in the bloodstream. Both of the failed IL6 mabs target the cellular receptor on the cell and prevent the cell receptor from binding the IL6 in the bloodstream.
Perhaps two possibilities as to why IL6 receptor blockade has no effect?
First, the elevated bloodstream IL6 is merely an artifact of the primary problem (or problems) in covid10 hyperimmune response. The bloodstream IL6 is not doing anything bad, its just there because of something else happening.
Second, perhaps IL6 hits some other receptor than its primary receptor?
I don't know but even a quick google scholar search quickly turns up a few nuggets.
First, a sort of advertisement from Enzo Life Sciences, a diagnostics company, I think (https://www.enzolifesciences.com/science-center/technotes/2020/april/covid-19-and-the-cytokine-storm-the-crucial-role-of-il-6/):
IL-6 has significant pro-inflammatory properties, and it functions through two main signaling pathways: cis or trans. In cis signaling, IL-6 forms a complex with the membrane-bound IL-6 receptor (mIL-6R) and gp130 which then activates downstream the Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3). The activation of this signal cascade leads to pleiotropic effects on the acquired immune system (B and T cells) as well as the innate immune system (neutrophils, macrophages, and natural killer cells) which can contribute to CRS. In trans signaling, high circulating IL-6 concentrations bind to the soluble form of IL-6 receptor (sIL-6R) and form a complex with a gp130 dimer on most somatic cell types. The resultant IL-6–sIL-6R–JAK-STAT3 signaling is then activated in cells that do not express mIL-6R, such as endothelial cells. This severely aggravates the “cytokine storm” through secretion of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein–1 (MCP-1), IL-8, and additional IL-6, as well as reduced E-cadherin expression on endothelial cells. Secretion of VEGF and reduction of E-cadherin expression contribute to vascular permeability and leakage which participate in the pathophysiology of hypotension and pulmonary dysfunction in ARDS.
My translation:
IL6 combines in the blood with other proteins to stimulate other cells, including endothelial cells, that do not express the primary IL6 receptor (the target of the failed mabs). The stimulation of the other cells, including endothelial cells, "vastly aggravates the cytokine storm through secretion of vascular endothelial growth factor" and increases vascular problems contributing to ARDS.
And that might not be the worst of it as far as the IL6 receptor blockade mabs are concerned.
This article says that when you give a patient an IL6 receptor blockade mab, then the concentration of IL6 in the bloodstream actually INCREASES. Which means that the "trans" pathway will see increased stimulation with Actemra-tocilizumab or Kevzara-sarilimumab. Today's Actemra results showed 19% mortality for both the treatment arm and the placebo arm, Actemra was no worse. Actemra did show a mild improvement in days to get out of the hospital.
https://ashpublications.org/blood/article/112...icances-in
Is Bruce Patterson at all surprised at the difficulties with the IL6 receptor blockade mabs? I would ask him myself but no email. I will email Dr. Yo.
Before today, I knew that Kevzara-sarilumab had failed covid19 trials because I knew that it was a Regeneron product, and I knew it was not the spike protein mab cocktail that the white house and Fauci have their eyes on.
But with today's Actemra-tocilizumab failure, I learned that both are IL6 receptor blockers.
So I figured its a good question for Dr. Patterson. IL6 is elevated in many covid19 patients. Maybe Dr. Patterson can explain why blockading the primary IL6 receptor has no effect.
I was very surprised to find an answer in google scholar within moments. It took me two minutes to find an answer in google search and twenty minutes to write this post.
Leronlimab seems massively superior to IL6 receptor blockade mabs based on the MOA described in the articles that I found on google scholar so quickly.
Using google scholar, I quickly found some articles that can explain, but I cannot assess these articles for likely correctness. But I was sure surprised that I so quickly found a scientific explanation for why IL6 receptor blockade might not be effective in covid19.
With today's news that Actemra/tocilizumab has failed a human clinical trial with the same 19% mortality at day 28 as placebo, I think we have new question for Dr. Bruce Patterson.
Actemra-tocilizumab is an IL6 receptor blocker.
Actemra-tocilizumab's failure comes not long after the failure of another IL6 receptor blocker, Kevzara-sarilumab.
So now both IL6 receptor blockade antibodies have failed in covid19.
Yet elevated IL6 is a common feature of severe/critical covid19 patients.
Neither of the failed IL6 mabs target the IL6 protein in the bloodstream. Both of the failed IL6 mabs target the cellular receptor on the cell and prevent the cell receptor from binding the IL6 in the bloodstream.
Perhaps two possibilities as to why IL6 receptor blockade has no effect?
First, the elevated bloodstream IL6 is merely an artifact of the primary problem (or problems) in covid10 hyperimmune response. The bloodstream IL6 is not doing anything bad, its just there because of something else happening.
Second, perhaps IL6 hits some other receptor than its primary receptor?
I don't know but even a quick google scholar search quickly turns up a few nuggets.
First, a sort of advertisement from Enzo Life Sciences, a diagnostics company, I think (https://www.enzolifesciences.com/science-center/technotes/2020/april/covid-19-and-the-cytokine-storm-the-crucial-role-of-il-6/):
IL-6 has significant pro-inflammatory properties, and it functions through two main signaling pathways: cis or trans. In cis signaling, IL-6 forms a complex with the membrane-bound IL-6 receptor (mIL-6R) and gp130 which then activates downstream the Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3). The activation of this signal cascade leads to pleiotropic effects on the acquired immune system (B and T cells) as well as the innate immune system (neutrophils, macrophages, and natural killer cells) which can contribute to CRS. In trans signaling, high circulating IL-6 concentrations bind to the soluble form of IL-6 receptor (sIL-6R) and form a complex with a gp130 dimer on most somatic cell types. The resultant IL-6–sIL-6R–JAK-STAT3 signaling is then activated in cells that do not express mIL-6R, such as endothelial cells. This severely aggravates the “cytokine storm” through secretion of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein–1 (MCP-1), IL-8, and additional IL-6, as well as reduced E-cadherin expression on endothelial cells. Secretion of VEGF and reduction of E-cadherin expression contribute to vascular permeability and leakage which participate in the pathophysiology of hypotension and pulmonary dysfunction in ARDS.
My translation:
IL6 combines in the blood with other proteins to stimulate other cells, including endothelial cells, that do not express the primary IL6 receptor (the target of the failed mabs). The stimulation of the other cells, including endothelial cells, "vastly aggravates the cytokine storm through secretion of vascular endothelial growth factor" and increases vascular problems contributing to ARDS.
And that might not be the worst of it as far as the IL6 receptor blockade mabs are concerned.
This article says that when you give a patient an IL6 receptor blockade mab, then the concentration of IL6 in the bloodstream actually INCREASES. Which means that the "trans" pathway will see increased stimulation with Actemra-tocilizumab or Kevzara-sarilimumab. Today's Actemra results showed 19% mortality for both the treatment arm and the placebo arm, Actemra was no worse. Actemra did show a mild improvement in days to get out of the hospital.
https://ashpublications.org/blood/article/112...icances-in
Is Bruce Patterson at all surprised at the difficulties with the IL6 receptor blockade mabs? I would ask him myself but no email. I will email Dr. Yo.
Before today, I knew that Kevzara-sarilumab had failed covid19 trials because I knew that it was a Regeneron product, and I knew it was not the spike protein mab cocktail that the white house and Fauci have their eyes on.
But with today's Actemra-tocilizumab failure, I learned that both are IL6 receptor blockers.
So I figured its a good question for Dr. Patterson. IL6 is elevated in many covid19 patients. Maybe Dr. Patterson can explain why blockading the primary IL6 receptor has no effect.
I was very surprised to find an answer in google scholar within moments. It took me two minutes to find an answer in google search and twenty minutes to write this post.
Leronlimab seems massively superior to IL6 receptor blockade mabs based on the MOA described in the articles that I found on google scholar so quickly.
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