This is an excellent effort to make sense of the Yang findings which conflict with the original understanding of LL's MoA.
Hope some of my betters here will discuss and evaluate.
My Thoughts on the Recent Long Hauler's Trial and the Implications
The recent news on the weekly administration of 700mg sub-q Leronlimab to Long Hauler patients that resulted in increasing numbers of CCR5 was an unexpected and significant finding. My understanding and interpretation, I make here.
Essentially, the researchers that conducted the study seem to feel that patients who have long haulers have it because their immune systems had been weakened by the Covid 19 disease and that the weakening brought their CCR5 levels down. I would agree that fighting Covid 19, puts your immune system through hell and that it "ages" many of your Immune fighting T-Cells & B-Cells and certainly may down regulate the number of CCR5 receptors found on the cell's surface. The doctors found that in the Leronlimab treated arm, those patients were found to have and increased number of CCR5 while those who were in the Placebo treated arm, did not have an increase in their CCR5 cell surface count. The researches concluded that Leronlimab may "normalize" CCR5 levels if they were abnormally low. But they did not give a means by which that happens.
I am thinking that this mechanism is along the lines of a bodily reaction; sort of like a reflexive response to the drop in required communication & signaling which was resulted with every new administration of weekly Leronlimab. In general, based on the stimulus level or the disease level, there ought to be a certain level of communication and messaging being performed by the CCR5 receptors. As the stimulus of disease increases, the body would upregulate CCR5 to increase the level of signaling, communication messaging and when the stimulus of disease decreases, the body would tone down CCR5 quantities which perform that messaging. However, in Long Haulers, although there was a significant stimulus of disease, there wasn't sufficient messaging being performed, and researchers believe that CCR5 levels were down because the Immune System was fatigued from overwork fighting Covid 19 and now Long Haulers, but when Leronlimab was added, the CCR5 messaging increased and the patient's immune fighting capacity was ramped up.
Here is how I see it: When the patient's received their Leronlimab injection, Leronlimab bound to CCR5 with a strong affinity. This binding disabled only a portion of the CCR5 functionality, not all of it's functionality. Specifically, Leronlimab blocks CCR5's capacity to message the Innate Immune System which is the "Acute Immune Response to invasion or to infection". This Innate Immune Response entails messaging to the Macrophages (which increase in bacterial infection), to the Eosinophils (which increase in number in allergic response), to Basophils, Dendrites and Natural Killer Cells all of which are extremely inflammatory. However, the binding of Leronlimab to CCR5 does not impact CCR5's capacity to message the cells which comprise the Adaptive Immune Response, (which is the response produced by the body for chronic diseases, and therefore, the response which happens over time). The white blood cells that entail the Adaptive Immune Response are the Lymphocytes (which increase in chronic infection or viral attacks), monocytes (increasing in chronic inflammatory disease, parasitic infections), the T-Cells and the B-Cells (which are responsible for the manufacturing of antibodies and the memory of these antibodies).
So my theory is that as these Long Hauler patients received the series of Leronlimab injections, the Leronlimab bound to the CCR5 receptors, thereby disabling the patient's Natural Innate Immune Response. The messaging & signaling of the macrophages, eosinophils, basophils, Dendrites and Natural killer cells were all shut down. The body quickly recognized the loss of cellular chemical communication in this respect and therefore produced more CCR5 as a "reflex", almost like a PID controller, (Proportional, Integral, Derivative controller). When the return of the signaling and messaging went back as feedback to the PID Loop Controller, to what the "set point" asked for, given the current disease state and level of stimulus, the controller was satisfied and since Leronlimab was not around to take away CCR5 communication, the controller went into homeostasis and maintained current setpoint / output.
The next week comes along and the patient received the 2nd Leronlimab injection. Again, Leronlimab has such strong affinity to CCR5, with which it bound 100% to CCR5 and again, the signaling and messaging in the Innate Immune Response became zilch. The body's PID loop controller picked that up as negative feedback and produced a derivative signal for more CCR5 receptors in response. The Innate Immune Response was ramped back up to what was expected and since the CCR5 molecules were produced after the Leronlimab injection, those CCR5 receptors were not bound to Leronlimab, and signaling and messaging communication was re-established.
The 3rd injection of Leronlimab again boosted CCR5 levels. It was given and again all the CCR5 in the body became 100% bound with Leronlimab and again the body became deficient in the Innate Immune Response. The body's PID loop controller ramped up the production of CCR5 until Innate Immune communication came up to par. This cycle happened over and over until the 8th injection which resulted in an overall increased numbers of CCR5.
All of this may have happened because of the stimulus or the call for the Innate Immune Response to ramp up due to the invader which was likely the spike protein from Covid or the spike protein from the vaccination. The invader was the stimulus which caused the Immune Response to call for the Macrophages, Eosinophils, Basophils, Dendrites and Natural Killer Cells to rise, increase in number and attack the invader, all of which are extremely inflammatory. However, with every dosage of Leronlimab, this communication, signaling and messaging capacity of CCR5 was toned down, thereby reducing inflammation, but the Adaptive messaging continued.
However, with the ever increasing number of CCR5, the capacity of CCR5 to message and communicate with the Adaptive Immune Cells including the Lymphocytes, monocytes, the T-Cells and the B-Cells went up with every injection of Leronlimab. Not because Leronlimab augments this communication in any way, but rather because the body produced more CCR5 in response to the binding effects Leronlimab had on CCR5, (the loss of communicative capacity in the Innate system). Since Leronlimab did not impair the messaging and signaling upon the cells of the Adaptive Immune Response, the long term cure for the disease could be made faster and better with more messaging and communication with the increased numbers of CCR5.
Given that Long Haulers is a disease with many varied symptoms (heterogenous), the body is dealing with an attack by a pathogen it hasn't ever dealt with. In addition, these patients have lived with the disease for months. Therefore the disease is chronic. The patient also has not yet developed a means to cure him/herself of the disease, (Adaptive Response is poor). This means the patient is immuno-compromised, at least for this disease, he is. He / She has a disease which they are unable to cure themselves of and that makes them immunocompromised. Leronliimab comes on board and effectively gives them the necessary tools to overcome their problem, an increase in the communication and messaging of the Adaptive Immune System. Therefore, we can claim that Leronlimab ramps up the immune system if it is abnormally suppressed.
What implications could that point to? Immunosuppression is common in many disorders, especially cancer and diabetes. Especially those who require chemotherapy. Chemotherapy acts like a poison. What do you think that does to someone's immune system? Their entire immune system, both Innate and Adaptive are both probably dead from the chemo itself. All white blood cell lines fatigued to the point of exhaustion trying to fight off the chemo. How low do you think the CCR5 count is in chemo patients? Probably zero. Many elderly too are immunosuppressed. Somehow, they are unable to mount the appropriate response when they become infected. Could they have low CCR5 levels as they age? Diabetics who have difficulty with glucose control tend to be immunosuppressed. Could higher sugar levels have an effect on CCR5 surface expression? And what about those who require long stents of and large doses of prednisone and cortisone. Their immune systems are suppressed. Could cortisone itself interact with CCR5 and disable it? Many auto-immune patients see rheumatologists are prescribed cortisone and other anti-inflammatory medications, many of which are called DMARDs which are Disease Modifying Anti-Rheumatic Drugs. These medications suppress select portions of the immune system so the patient no longer suffers from diseases which attack the person him/herself, which are auto-immune disorders.
By this extrapolation, we can see that it is feasible that Leronlimab be added in conjunction with any/all of these disorders to boost patient's immune system capacity so they do not develop life altering diseases such as pneumonia, influenza, cellulitis, hard to treat infections of the body and brain, diseases of the organs, etc, etc... while they are immunocompromised or immunosuppressed either alone or in combination therapy with their treatments.
I tend to think that if Leronlimab is given to a patient, and if the patient is healthy, say there is no underlying disease, then, yes, Leronlimab will bind to 100% of CCR5, but since there is no underlying disease, the body does not subsequently call for an activation of the Innate Immune Response and therefore there is no call for an increase in number of CCR5. If that patient, while on Leronlimab therapy, develops a disease, then the body will call for the Innate Immune Response, but will find that none was issued, because it was blocked by Leronlimab, then the body will immediately call for more CCR5 to be manufactured and expressed on the cells surface. When the body has reached homeostasis, as determined by the PID Loop Controller, then the number of CCR5 will normalize in accordance with the disease level of that stimulus.
Now to answer the question about what is the PID Controller in the body, that is like answering the question as to why do all the trees bloom on the same day after months of cold hibernation. Or how do all the bugs on a bush, flicker all at once, simultaneously in unison, as if there were some invisible communication between them all. Something senses the communication and something upregulates the quantity of CCR5 on the cell surface, but what that something is, it does a good job when the system is healthy, but when the person is old or cancer ridden requiring chemo, diabetic or drugged with DMARDS, then it doesn't work as well as it should.
Adding to what we already have known about this drug, Leronlimab has massive potential. I think we are only on the surface of learning everything it's capable of.
Hope some of my betters here will discuss and evaluate.
My Thoughts on the Recent Long Hauler's Trial and the Implications
The recent news on the weekly administration of 700mg sub-q Leronlimab to Long Hauler patients that resulted in increasing numbers of CCR5 was an unexpected and significant finding. My understanding and interpretation, I make here.
Essentially, the researchers that conducted the study seem to feel that patients who have long haulers have it because their immune systems had been weakened by the Covid 19 disease and that the weakening brought their CCR5 levels down. I would agree that fighting Covid 19, puts your immune system through hell and that it "ages" many of your Immune fighting T-Cells & B-Cells and certainly may down regulate the number of CCR5 receptors found on the cell's surface. The doctors found that in the Leronlimab treated arm, those patients were found to have and increased number of CCR5 while those who were in the Placebo treated arm, did not have an increase in their CCR5 cell surface count. The researches concluded that Leronlimab may "normalize" CCR5 levels if they were abnormally low. But they did not give a means by which that happens.
I am thinking that this mechanism is along the lines of a bodily reaction; sort of like a reflexive response to the drop in required communication & signaling which was resulted with every new administration of weekly Leronlimab. In general, based on the stimulus level or the disease level, there ought to be a certain level of communication and messaging being performed by the CCR5 receptors. As the stimulus of disease increases, the body would upregulate CCR5 to increase the level of signaling, communication messaging and when the stimulus of disease decreases, the body would tone down CCR5 quantities which perform that messaging. However, in Long Haulers, although there was a significant stimulus of disease, there wasn't sufficient messaging being performed, and researchers believe that CCR5 levels were down because the Immune System was fatigued from overwork fighting Covid 19 and now Long Haulers, but when Leronlimab was added, the CCR5 messaging increased and the patient's immune fighting capacity was ramped up.
Here is how I see it: When the patient's received their Leronlimab injection, Leronlimab bound to CCR5 with a strong affinity. This binding disabled only a portion of the CCR5 functionality, not all of it's functionality. Specifically, Leronlimab blocks CCR5's capacity to message the Innate Immune System which is the "Acute Immune Response to invasion or to infection". This Innate Immune Response entails messaging to the Macrophages (which increase in bacterial infection), to the Eosinophils (which increase in number in allergic response), to Basophils, Dendrites and Natural Killer Cells all of which are extremely inflammatory. However, the binding of Leronlimab to CCR5 does not impact CCR5's capacity to message the cells which comprise the Adaptive Immune Response, (which is the response produced by the body for chronic diseases, and therefore, the response which happens over time). The white blood cells that entail the Adaptive Immune Response are the Lymphocytes (which increase in chronic infection or viral attacks), monocytes (increasing in chronic inflammatory disease, parasitic infections), the T-Cells and the B-Cells (which are responsible for the manufacturing of antibodies and the memory of these antibodies).
So my theory is that as these Long Hauler patients received the series of Leronlimab injections, the Leronlimab bound to the CCR5 receptors, thereby disabling the patient's Natural Innate Immune Response. The messaging & signaling of the macrophages, eosinophils, basophils, Dendrites and Natural killer cells were all shut down. The body quickly recognized the loss of cellular chemical communication in this respect and therefore produced more CCR5 as a "reflex", almost like a PID controller, (Proportional, Integral, Derivative controller). When the return of the signaling and messaging went back as feedback to the PID Loop Controller, to what the "set point" asked for, given the current disease state and level of stimulus, the controller was satisfied and since Leronlimab was not around to take away CCR5 communication, the controller went into homeostasis and maintained current setpoint / output.
The next week comes along and the patient received the 2nd Leronlimab injection. Again, Leronlimab has such strong affinity to CCR5, with which it bound 100% to CCR5 and again, the signaling and messaging in the Innate Immune Response became zilch. The body's PID loop controller picked that up as negative feedback and produced a derivative signal for more CCR5 receptors in response. The Innate Immune Response was ramped back up to what was expected and since the CCR5 molecules were produced after the Leronlimab injection, those CCR5 receptors were not bound to Leronlimab, and signaling and messaging communication was re-established.
The 3rd injection of Leronlimab again boosted CCR5 levels. It was given and again all the CCR5 in the body became 100% bound with Leronlimab and again the body became deficient in the Innate Immune Response. The body's PID loop controller ramped up the production of CCR5 until Innate Immune communication came up to par. This cycle happened over and over until the 8th injection which resulted in an overall increased numbers of CCR5.
All of this may have happened because of the stimulus or the call for the Innate Immune Response to ramp up due to the invader which was likely the spike protein from Covid or the spike protein from the vaccination. The invader was the stimulus which caused the Immune Response to call for the Macrophages, Eosinophils, Basophils, Dendrites and Natural Killer Cells to rise, increase in number and attack the invader, all of which are extremely inflammatory. However, with every dosage of Leronlimab, this communication, signaling and messaging capacity of CCR5 was toned down, thereby reducing inflammation, but the Adaptive messaging continued.
However, with the ever increasing number of CCR5, the capacity of CCR5 to message and communicate with the Adaptive Immune Cells including the Lymphocytes, monocytes, the T-Cells and the B-Cells went up with every injection of Leronlimab. Not because Leronlimab augments this communication in any way, but rather because the body produced more CCR5 in response to the binding effects Leronlimab had on CCR5, (the loss of communicative capacity in the Innate system). Since Leronlimab did not impair the messaging and signaling upon the cells of the Adaptive Immune Response, the long term cure for the disease could be made faster and better with more messaging and communication with the increased numbers of CCR5.
Given that Long Haulers is a disease with many varied symptoms (heterogenous), the body is dealing with an attack by a pathogen it hasn't ever dealt with. In addition, these patients have lived with the disease for months. Therefore the disease is chronic. The patient also has not yet developed a means to cure him/herself of the disease, (Adaptive Response is poor). This means the patient is immuno-compromised, at least for this disease, he is. He / She has a disease which they are unable to cure themselves of and that makes them immunocompromised. Leronliimab comes on board and effectively gives them the necessary tools to overcome their problem, an increase in the communication and messaging of the Adaptive Immune System. Therefore, we can claim that Leronlimab ramps up the immune system if it is abnormally suppressed.
What implications could that point to? Immunosuppression is common in many disorders, especially cancer and diabetes. Especially those who require chemotherapy. Chemotherapy acts like a poison. What do you think that does to someone's immune system? Their entire immune system, both Innate and Adaptive are both probably dead from the chemo itself. All white blood cell lines fatigued to the point of exhaustion trying to fight off the chemo. How low do you think the CCR5 count is in chemo patients? Probably zero. Many elderly too are immunosuppressed. Somehow, they are unable to mount the appropriate response when they become infected. Could they have low CCR5 levels as they age? Diabetics who have difficulty with glucose control tend to be immunosuppressed. Could higher sugar levels have an effect on CCR5 surface expression? And what about those who require long stents of and large doses of prednisone and cortisone. Their immune systems are suppressed. Could cortisone itself interact with CCR5 and disable it? Many auto-immune patients see rheumatologists are prescribed cortisone and other anti-inflammatory medications, many of which are called DMARDs which are Disease Modifying Anti-Rheumatic Drugs. These medications suppress select portions of the immune system so the patient no longer suffers from diseases which attack the person him/herself, which are auto-immune disorders.
By this extrapolation, we can see that it is feasible that Leronlimab be added in conjunction with any/all of these disorders to boost patient's immune system capacity so they do not develop life altering diseases such as pneumonia, influenza, cellulitis, hard to treat infections of the body and brain, diseases of the organs, etc, etc... while they are immunocompromised or immunosuppressed either alone or in combination therapy with their treatments.
I tend to think that if Leronlimab is given to a patient, and if the patient is healthy, say there is no underlying disease, then, yes, Leronlimab will bind to 100% of CCR5, but since there is no underlying disease, the body does not subsequently call for an activation of the Innate Immune Response and therefore there is no call for an increase in number of CCR5. If that patient, while on Leronlimab therapy, develops a disease, then the body will call for the Innate Immune Response, but will find that none was issued, because it was blocked by Leronlimab, then the body will immediately call for more CCR5 to be manufactured and expressed on the cells surface. When the body has reached homeostasis, as determined by the PID Loop Controller, then the number of CCR5 will normalize in accordance with the disease level of that stimulus.
Now to answer the question about what is the PID Controller in the body, that is like answering the question as to why do all the trees bloom on the same day after months of cold hibernation. Or how do all the bugs on a bush, flicker all at once, simultaneously in unison, as if there were some invisible communication between them all. Something senses the communication and something upregulates the quantity of CCR5 on the cell surface, but what that something is, it does a good job when the system is healthy, but when the person is old or cancer ridden requiring chemo, diabetic or drugged with DMARDS, then it doesn't work as well as it should.
Adding to what we already have known about this drug, Leronlimab has massive potential. I think we are only on the surface of learning everything it's capable of.
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