How to modulate IgG4 and much more

The Galectin connection

This substack will feel a little “disconnected” but this is an example of how my brain works and how when you actively do research things, you often find answers literally elsewhere, where you would never look. I recently tweeted a pool with the following message.

Should I write some peculiar aspects of IgG4 and a cheap way to treat it (the other 2 ways are hella hard/expensive), or not ? The rats in alt-covid really annoy me, so I will let the public decide. Even though I do hate democracy.

The overwhelming response was Yes so here we are. Let us first build to that. In my eternal quest to understand why, mechanistically, Azvudine works so well to the point it has the reverse biological response of SARS-CoV-2 I was reminded to once again, do some research outside my common parameters because of the following paper.

Real-world effectiveness of Azvudine in hospitalized patients with COVID-19: a retrospective cohort study

Notably, male Azvudine recipients had a stronger effectiveness than female recipients with respect to both composite outcome and all-cause death. These findings suggest that Azvudine treatment showed substantial clinical benefits in hospitalized COVID-19 patients, and should be considered for use in this population of patients.

This is not the focus here, so I see no point covering the paper further, even so, because I already wrote about Azvudine months ago. Alas by looking into new literature on Azvudine, I stumbled upon quite a remarkable paper.

Research and development of Chinese anti-COVID-19 drugs

Besides the mention of Colchicine tablets (something a doctor who follows me swears by and indeed the evidence is there, besides his clinical experience), there is also the mention of Berberine, the following excerpt from the paper.

Berberine is a quaternary ammonium alkaloid isolated from Rhizoma Coptidis, which can inhibit AP-1 and NF-κB, the key factors in cell signal transduction, thereby reducing the inflammatory response. Berberine can be used to treat COVID-19 by blocking “cytokine storms” and maintaining intestinal microenvironment balance^83,84. A phase IV clinical trial of berberine in severe patients with COVID-19 has been completed in China.

But what incidentally caught my eye and the search query was the following.

LY-CovMab is a monoclonal antibody against COVID-19, which belongs to the IgG4 subtype. The cryo-electron microscopy revealed that LY-CovMab had multiple advantages of high affinity and high activity. LY-CovMab occupies 13 amino acid epitopes on the SARS-CoV-2 spike protein, where nine coincide with the epitope of ACE2. Under cryo-electron microscopy, LY-CovMab can bind and block all three RBD on the spike protein. One LY-CovMab IgG molecule can simultaneously bind two RBD on the spike protein simultaneously. Furthermore, LY-CovMab can avoid the antibody-dependent enhancement (ADE) effect by designing and modifying the FC end of McAb. The preclinical study indicated that LY-CovMab could significantly reduce the viral titers in the lungs and tracheas of the BALB/c mice that received MAScp6 challenge compared with a vehicle control group. Phase I clinical study of LY-CovMab in China has been completed, revealing good safety and pharmacokinetic characteristics. At present, phase II clinical trials of LY-CovMab have been approved to be carried out in China³⁸.

Did you catch it ? A potent monoclonal antibody against SARS-CoV-2 that binds to the Receptor-Binding Domain, basically stopping the virus from invading cells, the trick here is the class of such antibody. An IgG4 monoclonal led me into a light rabbit hole.

To my surprise, there are quite a few novel treatments for inflammatory and autoimmune diseases using monoclonal antibodies derived from the IgG4 subtype. Such as IC 100, which directly interferes with processes inside cells and disrupts the release of IL-1B (beta), impacting the regulation of inflammasomes. In simple terms, it stops a specific and powerful inflammatory cascade inside the cell, before it even starts. With this evidence and a lot more, it is self-evident for some, and clear for even the layperson why there was a shift in antibody class in many of the mRNA vaccinated.

This was a compensatory response, such as the cytokine storm in severe cases of certain viral infections. Now you have a decent idea why the shift happened, and has very little to do with “allergy”, a little bit to do with “tolerance”, and much more to do as compensation to continuous inflammatory cascades starting inside and outside cells for a myriad of reasons.

In relation to IgG4-Related Diseases, effectively, there are few treatments “scientifically proven”, one of them is monoclonal antibodies aimed at depleting B Cells (basically getting rid of certain antibodies inside your body) with the most cited in the literature, even on SARS-CoV-2 literature being Rituximab.

The other is called Immunoadsorption, an old method used to filter certain molecules or proteins from the body, depending on where you get the treatment it can get pretty expensive, especially when you need to treat specific, targeted autoantibodies (something very common in IgG4 Related pathologies), but this one has a very decent rate of success, bringing varied levels of relief to patients that undergo this intervention.

Rituximab is incredibly expensive, Immunoadsorption is expensive (1.500 to 5.000 USD), and neither scalable if we are talking about a few million people within the next decade. Do you know what is easily scalable, accessible, and generic ? This.

Should be of no surprise to any of my readers.

NAC, Metformin positively impacts Long Covid

Perhaps Berberine may achieve the same effect, but mostly in relation to IgG4, berberine will downregulate (lower the levels of) IgGE, this one linked to many types of allergic reactions and long-lasting allergies. This is the reason I wrote last time that any vaccinated person should just add Metformin or Berberine for now. Diminishing the development of any IgG4-related adverse effect.

I know must briefly cover another paper, because it is incredibly important in the subject discussed here.

Galectin-3 as an important prognostic marker for COVID-19 severity

In case you missed it, the Galectin-3 is one of, if not the biggest and most important aspect of this whole pandemic, and the Spike Protein and virus itself. I rarely state something I wrote is an obligatory reading, but this is one such exception.

The NTD (N-Terminal Domain, a part of the Spike) is a literal mimic of human Galectin, specifically, Galectin-3, and Galectin-3 not only plays a major role in human health and pathology but also is directly linked to IgG4-Related Diseases.

Chimeric nature of Galectin-3 and SARS-CoV-2

Here is a short guide on how to modulate Galectin-3, and you will see there is a sizable crosstalk between many of the molecular pathways we have been discussing, and how to treat them. And yes, Metformin and Berberine do in fact modulate Galectin-3. Dietary intervention (a ketogenic diet) and fasting are the best, and cheapest tools for one to avoid much of what is discussed here.

Hopefully, this is helpful, next one ain’t much of good news, alas I write about the real world.

I am really grateful for the ones who choose to support me here or on Kofi when they feel like it, and the ones who share, which is also really helpful.