Low affinity FcγRIIIa allotypes the reason Rituximab doesn't work well in some ME/CFS patients?

[leokitten]

Low-affinity (F/F and F/V) polymorphisms of FcγRIIIa (CD16) are thought to predict lower response rates and shorter duration of responses to rituximab.

The Relationship of Fc’RIIIa Genotype to Degree of B Cell Depletion by Rituximab in the Treatment of Systemic Lupus Erythematosus

From the article:

For example, if Fc’RIIIa on effector cells plays an important
role in the depletion of B cells by rituximab, then patients who are homozygous or heterozygous for the high-affinity V allele (which has a 10-fold higher affinity for IgG1, the isotype of the humanized Fc portion of rituximab) should deplete B cells to a greater extent than those who are homozygous for the low-affinity F allele, at any given rituximab level. This is depicted in Figure 2, where the percentage of B cells is plotted as a function of the rituximab level for the low-affinity (FF; n 5) versus the high-affinity (VV or VF; n 7) cohorts.

As predicted, patients with the low-affinity FF genotype required about a 10-fold increase in rituximab levels to achieve the same degree of B cell depletion as that in patients with the high-affinity genotypes (VV or VF) (Figure 2).

 

[alex3619]

This link is blocked for me right now.

 

[leokitten]

@alex3619 try again now I f**ed up the link

 

[leokitten]

If still doesn't work here is PDF attached

 

[leokitten]

Also just finished reading this, inhibitory receptor FcγRIIb also plays a role:

Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy.

 

[Sasha]

@Jonathan Edwards?

 

[Jonathan Edwards]

Low-affinity (F/F and F/V) polymorphisms of FcγRIIIa (CD16) are thought to predict lower response rates and shorter duration of responses to rituximab.

The Relationship of Fc’RIIIa Genotype to Degree of B Cell Depletion by Rituximab in the Treatment of Systemic Lupus Erythematosus

From the article:

This is from John Looney, Jennifer Anolik and Robert Eisenberg's first study of lupus back in about 2001. It was a very small study of a few patients and pretty difficult to interpret. We did a much bigger study of FcRIIIa polymorphism in RA and it made no difference to the result at standard dosage. (Anolik had used sub-depleting doses that nobody would now use in practice.) FcRIIIa polymorphism does seem to have some effect in lymhoma but to be honest that can probably be overcome by giving a bit more drug. In RA and lupus we concluded that there was no reason to change dose based on allotype.

But the FcRIIb story is much much more interesting. It comes from Martin Glennie who is the canniest of antibody biologists I know. I don't think this is a polymorphism story - just that different monoclonals may engage IIb differentaly, particularly if they are engineered to do so. So people are playing about engineering the Fc part of their antibodies. As indicated on another thread, we do not yet know if these will actually get at the cells that rituximab misses but it is likely that doses can be reduced and it may be that longer remissions obtained.

 

[Jonathan Edwards]

My apologies. Although Robert Eisenberg was collaborating with Jennifer and John at that time he was not part of this study.

 

[leokitten]

But the FcRIIb story is much much more interesting. It comes from Martin Glennie who is the canniest of antibody biologists I know. I don't think this is a polymorphism story - just that different monoclonals may engage IIb differentaly, particularly if they are engineered to do so. So people are playing about engineering the Fc part of their antibodies. As indicated on another thread, we do not yet know if these will actually get at the cells that rituximab misses but it is likely that doses can be reduced and it may be that longer remissions obtained.

Sorry yes I understood that, the FcRIIb story has nothing to do with genotypes, should have added to the end of my post "...also plays a role in rituximab efficacy".

I found both these papers while doing some research as to why possibility rituximab doesn't work so well in some PWME. Not only reading Fluge/Mella's numbers but also testimonials of people here on PR where they went to OMI and paid a good deal of money and their remissions we're short or it just didn't work. I was wondering if there is something that could be missing.

I had already known that in lymphomas rituximab has somewhat similar stats, in some people it just doesn't work well and this led to the discovery of FcgRIIIa and FcgRIIb issues. Correct me if I'm remembering incorrectly but rituximab's b-cell cytotoxicity depends heavily on Fc receptor binding of its Fc portion, so when this isn't as efficient in certain patients then it doesn't work as well.

 

[Jonathan Edwards]

Sorry yes I understood that, the FcRIIb story has nothing to do with genotypes, should have added to the end of my post "...also plays a role in rituximab efficacy".

I found both these papers while doing some research as to why possibility rituximab doesn't work so well in some PWME. Not only reading Fluge/Mella's numbers but also testimonials of people here on PR where they went to OMI and paid a good deal of money and their remissions we're short or it just didn't work. I was wondering if there is something that could be missing.

I had already known that in lymphomas rituximab has somewhat similar stats, in some people it just doesn't work well and this led to the discovery of FcgRIIIa and FcgRIIb issues. Correct me if I'm remembering incorrectly but rituximab's b-cell cytotoxicity depends heavily on Fc receptor binding of its Fc portion, so when this isn't as efficient in certain patients then it doesn't work as well.

All killing mechanisms for rituximab probably require engagement of the Fc with a receptor or complement, although there is an apoptosis mechanism that I do not know much about. In theory polymorphism of FcRIIIa would affect killing efficiency by ADCC (not complement) but it is far from clear that in autoimmunity this is ever a rate limiting factor. If you have enough rituximab to saturate all the CD20 you get killing in everybody, regardless of FcR allotype. If you use a smaller dose the limiting factor is probably that it all gets used up so you do not saturate CD20. In that situation allotype might matter. It may also matter more for lymphoma because the B cells are abnormal in other ways.

 

[BurnA]

From
Relevance of rituximab therapy in pemphigus vulgaris: analysis of current data and the immunologic basis for its observed responses
Ron J Feldmanaa & A Razzaque Ahmed*ab
pages 529-541

Data from studies in rheumatoid arthritis patients treated with rituximab, demonstrated that patients who initially did not respond to rituximab had increased levels of circulating plasmablasts that carry CD19+/-, CD27++, and CD38++ as cell surface markers.[82] During the repopulation process, if these patients were retreated with rituximab prior to these cells reaching baseline levels, clinical improvement occurred. This observation would suggest that monitoring of B-cell subsets during and after rituximab therapy may help in maximizing the clinical response.[82] Importantly, additional cycles of rituximab in these RA patients given prior to total B-cell repopulation were able to enhance B-cell depletion with subsequent clinical improvement, suggesting that retreatment with rituximab may be a viable option for nonresponders with close follow-up of B-cell subsets.[82,83]

Is there anything here ?

 

[Jonathan Edwards]

From
Relevance of rituximab therapy in pemphigus vulgaris: analysis of current data and the immunologic basis for its observed responses
Ron J Feldmanaa & A Razzaque Ahmed*ab
pages 529-541

Data from studies in rheumatoid arthritis patients treated with rituximab, demonstrated that patients who initially did not respond to rituximab had increased levels of circulating plasmablasts that carry CD19+/-, CD27++, and CD38++ as cell surface markers.[82] During the repopulation process, if these patients were retreated with rituximab prior to these cells reaching baseline levels, clinical improvement occurred. This observation would suggest that monitoring of B-cell subsets during and after rituximab therapy may help in maximizing the clinical response.[82] Importantly, additional cycles of rituximab in these RA patients given prior to total B-cell repopulation were able to enhance B-cell depletion with subsequent clinical improvement, suggesting that retreatment with rituximab may be a viable option for nonresponders with close follow-up of B-cell subsets.[82,83]

Is there anything here ?

I doubt it. I am not sure who these people are but they seem not to have been aware of the protocols for using rituximab we developed from the outset at UCL. We have been monitoring B subsets cells and pre-emptively treating patients for nearly fifteen years! We had established that sometimes a second cycle would produce results when the response to a first cycle was poor. I am wondering if the title is the wrong one since this does not seem to be about pemphigus vulgaris?