Daratumumab, isatuximab (CD38 drugs)

[Jaybee00]

But IGG did go down in Fluge et al.

 

[Jaybee00]

Someone who took the time to look at the paper (unlike me) has pointed out the baseline IGG was low due to pretreatment.

 

[Jonathan Edwards]

But IGG did go down in Fluge et al.

Someone who took the time to look at the paper (unlike me) has pointed out the baseline IGG was low due to pretreatment.

I wondered that. So things do not necessarily go as pear-shaped as it seemed.
But resistant plasma cells are perhaps most likely to be the long lived bone marrow ones. So Fluge and Mella may just have killed the easy short lived ones that rituximab depletes. Ritux does tend to produce falls in IgM and IgA but not much in IgG.

 

[Pibee]

I wondered that. So things do not necessarily go as pear-shaped as it seemed.
But resistant plasma cells are perhaps most likely to be the long lived bone marrow ones. So Fluge and Mella may just have killed the easy short lived ones that rituximab depletes. Ritux does tend to produce falls in IgM and IgA but not much in IgG.

I mean, the drop with daratumumab was much higher than it ever happens from ritux so no, he didn't kill off only those, his IgG fell 54% in responders.
I think LLPC in the tissues like in Sjogrens in salivary glands are even more resistant than those in BM, at least based on the data from teclistamab, where IgG falls to < 4g/L for all autoimmune patients (n=4), regardless of the baseline which is interesting to me, but SSA, SSB were falling much less sharply, I think it was 80% for IgG vs 20% for SSA, or so, ... that might be concerning for autoimmune, I don't know if Sjogrens is exception there.

btw. I remember we were discussing this for SLE dual BCMA-CD19 CAR-T data, where Ro60 and Ro52 were very slow to fall, unlike other antibodies, you said it's a lab artifact, but it seems to be a pattern with other drugs as well, so I guess it is about the nature of LLPC produced in salivary gland, more protected in the niches, harder to access by drugs. It still went to 0 with CAR-T but I don't know is it really possible to clear all...

 

[Jonathan Edwards]

I mean, the drop with daratumumab was much higher than it ever happens from ritux so no, he didn't kill off only those, his IgG fell 54% in responders.

It isn't that simple. Dara kills the plasma cells. Ritux just prevents replacement. Some people on rituximab, although a small minority, do get deep IgG depletion on a single dose. I know because I was the first to do this in large numbers for autoimmunity. Moreover, if you repeat rituximab four or five times a substantial number get significant IgG depletion. The effect from dara is clearly more direct and a bit more powerful but I think we have to assume that there is a potential reservoir of dara resistant cells.

 

[Jonathan Edwards]

where Ro60 and Ro52 were very slow to fall, unlike other antibodies, you said it's a lab artifact,

I don't remember saying that. We were the first (Leandro et al) to show that Ro antibodies are particularly slow to fall with B cell depletion.

 

[Pibee]

It isn't that simple. Dara kills the plasma cells. Ritux just prevents replacement. Some people on rituximab, although a small minority, do get deep IgG depletion on a single dose. I know because I was the first to do this in large numbers for autoimmunity. Moreover, if you repeat rituximab four or five times a substantial number get significant IgG depletion. The effect from dara is clearly more direct and a bit more powerful but I think we have to assume that there is a potential reservoir of dara resistant cells.

I thought it was well known that there is a reservoir of daratumumab-resistant cells. And the average IgG drop with rituximab isnt 54%


You said it here: CAR-T thread

Johnathan Edwards: That looks like a calibration artefact to me. You have to be ever so careful about cross-calibrating these assays.

 

[Jonathan Edwards]

You said it here: CAR-T thread

I don't know what i was referring to there (I cannot see a link back) but it sounds like something else.

 

[Pibee]

You were referring to the SSA dropping slower than other antibodies and calling it an lab artefact. The link i posted leads to your post.

 

[Jonathan Edwards]

You were referring to the SSA dropping slower than other antibodies and calling it an lab artefact. The link i posted leads to your post.

I was referring to a more detailed and hard to explain shape of a curve, not the persistence of Ro antibodies in the first place.

 

[Pibee]

But you said it's unlikely they persist in such a way as the shape of the curve suggests, calling it a lab artefact?

Anyway, seems we can agree it wasn't. So seems those SSA antibodies whether they are from salivary glands or from BM, are harder to get rid of than even total IgG?! As they're last ones to go :-/
Do you think it's from glands? I'm afraid it is.

The interesting part is the study said none of the patients had Sjogrens but if their SSA is so high and so hard to knock down which would mean that it is coming from glands most likely, then by definition they do have SjD with positive gland focus score, probably, right? As dr Donald Thomas said 40% of SLE have SjD, but they tend to exclude it in SLE just by asking "are your mouth dry?" .

 

[Jonathan Edwards]

So seems those SSA antibodies whether they are from salivary glands or from BM, are harder to get rid of than even total IgG?! As they're last ones to go :-/
Do you think it's from glands? I'm afraid it is.

No, I think that is implausible. I have written papers on Sjogren's gland immunohistology and although there can be follicular structures with lots of B cells the number of plasma cells present in most cases is small.

 

[Pibee]

No, I think that is implausible. I have written papers on Sjogren's gland immunohistology and although there can be follicular structures with lots of B cells the number of plasma cells present in most cases is small.

So they have no role in the disease or only locally? I know its only 1-24% LLPC on biopsies but if protected environment in salivary glands niches is not the reason that SSA persists even more than total IgG, even with teclistamab it is a huge difference, why it persists so much then? So disproportionately to the total IgG.