Ultra Low Dose efficacy Rituximab in autoimmunity, any efficacy?

[siobhanfirestone]

Hi all
Ive just been reading about Rituximab within the context of autoimmune disease. Im aware of the CD20 and plasma (antibody generating) split within cells, but that for a lot of autoimmune diseases there is clinical response and patient symptom relief.

We all know about the failed Ritux phase 3, ive gone for a different Long COVID treatment on this basis, but regardless. There is a theory that the "low dose" could have hampered efficacy, im not so sure about this.
This made me explore some questions in autoimmunity, as i think ME/LC is a variant of a type of disease like this.
I explored some stuff about low dose ritux and some people have responce at a very low dose, i even found a paper on peoples b cells dropping loads with 1mg per kg ritux!

https://www.researchgate.net/public...ications_for_dosing_and_biosimilarity_testing

Can anyone explain why this isnt in trial or isnt feasible for me in terms of classic autoimmune diseases? Is it that ritux isnt hitting the target which is really the plasma, but it hits the pre-target so it takes like three months at a high dose to work?

 

[Jonathan Edwards]

This is all pretty well understood. Rituximab will produce profound B lymphocytopenia at quite small doses. We went down to a single dose of 500mg and still got total blood depletion. I am sure you can go lower.

But the point of killing B cells is not to kill B cells themselves, since they don't secrete significant amounts of free antibody, but to starve the system of a supply of new cells to become plasma cell - either short or long lived.

The simplest model is that if you starve the system of new plasma cells autoantibodies will go down and you will see improvement. The problem with that is that you can expect all your protective antibodies to go down and to be at risk of infection. The key observation that we made with the very first trial of rite in RA (1998-9) is that some autoantibodies go down much more than protective antibodies. This seems to be because autoantibodies are often made by short lived plasma cells and protective antibodies by long lived.

Before we knew that, Martin Glennie, who made the first anti-B cell monoclonal, years back, said quite reasonably that the whole idea made no sense, just to keep people without B cells.

But as I explained in my answer to his question from the podium, that was never the original idea of using rituximab in autoimmunity for us. Antibody production is a chain reaction. In order to produce antibody to antigen X in bulk the immune system has to already have some antibody to X to even pick it up and show it to B cells. Which is why we generate every day a basic level of antibodies to almost everything that isn't self - mostly IgM, which is very good at picking stuff up and engaging complement, which is needed to prime the system, but not that good at mediating killing etc.

So our idea was that if we got levels of autoantibody to drop enough with a short sharp shock of rituximab that killed off all current clones recognising the antigen, then the autoimmune response might collapse because there was no starter antibody (it should be deleted in bone marrow). It turns out that this actually works for a decent proportion of people with immune thrombocytopenia and maybe some other autoimmune diseases like Wegener's vasculitis but for most autoimmune diseases there are some long lived plasma cells that go on producing background autoantibody so that the problem can re-start. The good news is that even in our first cohort we have one patient who went into complete remission for 5 years - so it seems that you can very nearly break the vicious cycle. Remissions in RA have been reported for 8 years for more after a single course of ritux.. But it looks as if you need to go deeper to break the cycle for good.

So low dose ritux has no advantages, because you just have to have it more often and you will have no 'free-wheeling' periods of remission unless you drive Ig levels low enough to be at risk. The real problem is that very few physicians using rituximab for autoimmunity understand the dynamics of B cells well enough to know what it is they are wanting to do and so suggest regimens that are never going to be of use. Doctors tend to be rather simple souls I am afraid, and rheumatologists perhaps the simplest!!

 

[siobhanfirestone]

This is all pretty well understood. Rituximab will produce profound B lymphocytopenia at quite small doses. We went down to a single dose of 500mg and still got total blood depletion. I am sure you can go lower.

But the point of killing B cells is not to kill B cells themselves, since they don't secrete significant amounts of free antibody, but to starve the system of a supply of new cells to become plasma cell - either short or long lived.

The simplest model is that if you starve the system of new plasma cells autoantibodies will go down and you will see improvement. The problem with that is that you can expect all your protective antibodies to go down and to be at risk of infection. The key observation that we made with the very first trial of rite in RA (1998-9) is that some autoantibodies go down much more than protective antibodies. This seems to be because autoantibodies are often made by short lived plasma cells and protective antibodies by long lived.

Before we knew that, Martin Glennie, who made the first anti-B cell monoclonal, years back, said quite reasonably that the whole idea made no sense, just to keep people without B cells.

But as I explained in my answer to his question from the podium, that was never the original idea of using rituximab in autoimmunity for us. Antibody production is a chain reaction. In order to produce antibody to antigen X in bulk the immune system has to already have some antibody to X to even pick it up and show it to B cells. Which is why we generate every day a basic level of antibodies to almost everything that isn't self - mostly IgM, which is very good at picking stuff up and engaging complement, which is needed to prime the system, but not that good at mediating killing etc.

So our idea was that if we got levels of autoantibody to drop enough with a short sharp shock of rituximab that killed off all current clones recognising the antigen, then the autoimmune response might collapse because there was no starter antibody (it should be deleted in bone marrow). It turns out that this actually works for a decent proportion of people with immune thrombocytopenia and maybe some other autoimmune diseases like Wegener's vasculitis but for most autoimmune diseases there are some long lived plasma cells that go on producing background autoantibody so that the problem can re-start. The good news is that even in our first cohort we have one patient who went into complete remission for 5 years - so it seems that you can very nearly break the vicious cycle. Remissions in RA have been reported for 8 years for more after a single course of ritux.. But it looks as if you need to go deeper to break the cycle for good.

So low dose ritux has no advantages, because you just have to have it more often and you will have no 'free-wheeling' periods of remission unless you drive Ig levels low enough to be at risk. The real problem is that very few physicians using rituximab for autoimmunity understand the dynamics of B cells well enough to know what it is they are wanting to do and so suggest regimens that are never going to be of use. Doctors tend to be rather simple souls I am afraid, and rheumatologists perhaps the simplest!!

right that makes sense thanks for this comprehensive write up

hypothetically could someone combine ritux with dara in a short, intense snap of memory and plasma to try and reduce down that "starter antibody" and then background stuff? or even the future for antibody driven disease would be that but via targeted CAR-T?
cheers

 

[siobhanfirestone]

out of interest what was it that made you target the b cells and not t cells, are there publications of this area of research i can look into?

 

[Jonathan Edwards]

hypothetically could someone combine ritux with dara in a short, intense snap of memory and plasma to try and reduce down that "starter antibody" and then background stuff? or even the future for antibody driven disease would be that but via targeted CAR-T?
cheers

That was what we tried to do with combinations early on but soon realised that we did not have the tools to break through. I have been trying to persuade people to take this approach for twenty years now but almost nobody seems to get the rationale - they just think of killing B cells without deeper thought. I resigned myself to hoping that if people try enough things they may one day achieve what is needed.

Combination treatment is always tricky because you need to involve more than one drug company in the patent situation.

 

[Jonathan Edwards]

out of interest what was it that made you target the b cells and not t cells, are there publications of this area of research i can look into?

We targeted the B cells in RA because we have worked out all the steps in the mechanism, including why B cells are specifically suited to colonise joint synovium in a chronic inflammatory situation, why joint synovial is susceptible to small immune complex mediated inflammation, why rheumatoid factor production is at risk of a positive feedback cycle, and a load of other things, all based on lab work from 1990-1996. The key point was that all the steps needed could be fitted together without any need for autoreactive T cells - which nobody had ever found anyway.

In 1998 we published a review (Edwards, JC, Cambridge G, Brit J Rheumatol.) in which we proposed that rituximab might have a major beneficial effect on RA. By the end of 1998 we had managed to scrape together the funds for a pilot study, the drug company having refused to get involved because it did not suit their financial strategy. In 1999 we published a more general model for autoimmune disease (Edwards, Cambridge and Abrahams, Immunology.) and the role of B cell loops. The proof of concept study in RA funded by Roche was reported 2001 and published 2004 in New England Journal of Medicine.

 

[siobhanfirestone]

We targeted the B cells in RA because we have worked out all the steps in the mechanism, including why B cells are specifically suited to colonise joint synovium in a chronic inflammatory situation, why joint synovial is susceptible to small immune complex mediated inflammation, why rheumatoid factor production is at risk of a positive feedback cycle, and a load of other things, all based on lab work from 1990-1996. The key point was that all the steps needed could be fitted together without any need for autoreactive T cells - which nobody had ever found anyway.

In 1998 we published a review (Edwards, JC, Cambridge G, Brit J Rheumatol.) in which we proposed that rituximab might have a major beneficial effect on RA. By the end of 1998 we had managed to scrape together the funds for a pilot study, the drug company having refused to get involved because it did not suit their financial strategy. In 1999 we published a more general model for autoimmune disease (Edwards, Cambridge and Abrahams, Immunology.) and the role of B cell loops. The proof of concept study in RA funded by Roche was reported 2001 and published 2004 in New England Journal of Medicine.

thank you for this