Have we no clue how Ublituximab works, if we think it is all CD20 T cells?


The makers of Ublituximab and related neuros have, in my opinion, little clue how it works:-). Of course they will say it is depleting CD20 cells and we will say NSS…..what do you expect it is a CD20 depleting antibody that has been engineered to kill more effectively than rituximab by having a mechanism of killing that has natural killer cells/neutrohils etc binding to the end of the antibody to release a toxic pay load on the target cells.

The authors seem to be keen on the the anti-CD20 works by the killing T cells chestnut. It seems funny to me that people are willing to want to accept the implausible and ignore the obvious….that it has a B cell-dependent mechanism. This is why anti-CD19 works too. p.s. CD19 is not really expressed by T cells although you can find a FACS-plots to show otherwise. T cells can still be the centre of the immunological universe but I doubt it is in this way.

Yes B cells do down and so do CD20+ T cells. But what an opportunity missed and without looking at B cell subsets has the company done this?

Hey! Don't shoot yourself in the foot | by Grace Adewumi | Medium

I suppose we know what happens to B cell subsets and they all stay down if you treat every 6 months. Is there a difference between small and larger BMI people like ocrelizumab?

The key is to know what happens when you stop dosing and watch the cells return. Has this been done? I don’t know if the B cells were measured, but it would be nice to know as this is going to impinge on your COVID-19 booster responses. The could do it as they measured CD27.

It seems the idea that B memory cells are important to look at as are the other B cell subsets has yet to catch-on. People ( T cell immunologists) are happy to focus on the implausible that it is this small T cell subset accounting for a few percent of T cells that are important.

I suppose to be fair the study was probably planned before the authors/advisory board didn’t read our paper.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis.EBioMedicine. 2017;16:41-50. 

They also do mention memoy B cells and EBV infected cells in the discussion

Maybe there was no plan to look in case it showed that six monthly dosing was overdoing it:-). If it turns out to be this way (CD20 T cells are the issue) I will hold up my hands and say I was wrong, but until they show this, we need alternative opinions

But here is the plan for the paper…No B cell subsets

Unlabelled Image

Hopefully for the manufacturers…..They have avoided the COVID-19 mud sling that has stuck to ocrelizumab and rituximab as probelms for those infected and those vaccinated agains SARS-CoV-2, but one thing that has not been reported is the level of anti-drug antibodies, because that is a difference between chimeric rituximab and humanised/human ofatumumab and ublituximab is chimeric

Remember when you work in percentages if something goes up something else must go down…What’s the important bit. What goes up or what goes down?

B cell depletion changes the immune cell profile in multiple sclerosis patients: One-year report.Lovett-Racke AE, Yang Y, Liu Y, Gormley M, Kraus E, Graham C, Wray S, Racke MK, Alvarez E, Bass A, Fox E.J Neuroimmunol. 2021 ;359:577676. doi: 10.1016/j.jneuroim.2021.577676. PMID: 34364105

B cell depletion therapy has been shown to be beneficial in multiple sclerosis (MS). However, the mechanism by which B cell depletion mediates its beneficial effects in MS is still unclear (really?). To better understand how B cell depletion may benefit patients with a disease previously thought to be primarily mediated by CD4 T cells, immune profiles were monitored in 48 patients in a phase II trial of ublituximab, a glycoengineered CD20 monoclonal antibody, at 18 time points over a year. As we previously described there was a significant shift in the percentages of T cells, NK cells, and myeloid cells following the initial dose of ublituximab, but this shift normalized within a week and these populations remained stable for the duration of the study. However, T cell subsets changed with an increase in the percentage of naïve CD4 and CD8 T cells and a decline in memory T cells. Importantly, the percentage of Th1 and CD4+GM-CSF+ T cells decreased, while the percentage of Tregs continued to increase over the year. Ublituximab not only depleted CD20+ B cells, but also CD20+ T cells. The favorable changes in the T cell subsets may contribute to the beneficial effects of B cell depletion therapy.

Why bother commenting on this paper?

Well it is the new kid on the block and the semi-star of ECTRIMS2021 as the phase III trial data is released and as we have been supporting the B cell hypothesis we need to report things that support and refute the idea, or should I say try and fail to refute the idea:-).

P.S. It also adds to the altmetric in a weird way

So now you will have ofatumumab, ocrelizumab, ublituximab and off-label others like rituximab. Which will you choose? Will we have competition or a cartel?. Maybe that is the way….we have four sphingosine-1-phosphate 1 receptor modulators maybe four Brutons tyrosine kinase inhibitors, we have four beta interferons…….Spare a thought trying to teach this stuff the lecture on drugs now takes ages…Good for you but how do you choose which one.

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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