Daratumumab in systemic lupus erythematosus: a single-arm phase 2 trial, 2026, Ostendorf et al

OrganicChilli

OrganicChilli

Senior Member (Voting Rights)
Abstract

Antibody-secreting cells (ASCs) play a central role in the pathophysiology of systemic lupus erythematosus (SLE). This single-arm, open-label, phase 2 clinical trial aims to evaluate the safety and efficacy of the ASC-depleting anti-CD38 monoclonal antibody daratumumab in patients with SLE (NCT04810754).

The primary endpoint is the reduction in serum anti-double-stranded DNA (anti-dsDNA) antibody levels at week 12. Key secondary end points include safety, clinical efficacy, and immunologic changes. Ten female patients with active disease and inadequate responses to at least two immunosuppressive drugs have received eight subcutaneous injections of 1800 mg daratumumab weekly, with dexamethasone as premedication (20 mg for first two injections, then 10 mg).

By week 12, anti-dsDNA antibody levels have been reduced by a median of 109.6 IU/ml (95% CI 38.1 – 274.5). The treatment resulted in rapid and sustained clinical improvements across all patients and organ domains, reflected by a 100% SRI-4 (Systemic Lupus Erythematosus Responder Index-4) response rate at week 12. Hypogammaglobulinemia occurred in 5/10 patients, requiring immunoglobulin substitution.

Daratumumab treatment has depleted circulating ASCs, reduced type I interferon activity, and profoundly modulated the T-cell responses. These findings highlight the pivotal role of ASCs in SLE pathogenesis and support daratumumab as therapeutic option for SLE.

www.nature.com

Daratumumab in systemic lupus erythematosus: a single-arm phase 2 trial - Nature Communications

CD38 is highly expressed by antibody-secreting cells (ASC) and depleting antibodies targeting CD38 have the potential to treat autoimmune diseases with ASC involvement. Here authors treat systemic lupus erythematosus patients with the ASC-depleting anti-CD38 monoclonal antibody daratumumab in...
www.nature.com www.nature.com

---
Median NK cell levels at baseline were 80 cells/µL as opposed to 153 cells/µL in the ME/CFS pilot study and they didn't seem to impact the outcome.
 
Last edited:
V.R.T. said:
would reducing type I interferon resolve the kind of mechinism/signalling loop you have proposed in ME/CFS?
Click to expand...
Potentially. It's interesting here, this supplemental plot tells us that dara does also bind to CD38 on myeloid cells that typically produce type I interferon in lupus:
1770313483699.png

The question is whether the reduced type I interferon response here is a secondary effect of fewer antibodies from plasma cell killing, or whether blocking CD38 on type I IFN-producing cells is enough to inhibit their interferon output directly.

This paper would suggest that the latter is true, though both options may be true simultaneously in lupus:
(It's showing that IFN-I response to RSV induces CD38 expression in DCs, but blocking CD38 also lowered IFN production, meaning that CD38 seems to be necessary for maintaining IFN-I production)

So yeah, technically plausible that dara could work for an illness mediated by type I interferon independent from any plasma cell killing. And it might work on a different level than JAK inhibitors. But more work would need to be done to prove it
 


Do Americans not eat marmalade?​

FOOD & DRINK

I was buying marmalade at my local Safeway yesterday, and the cashier said, "Ooh, marmalade! No one buys that. I like it, myself, but I've never seen anyone else buy it".

My husband and I are imports, we grew up British so we brought our weird British breakfast ways with us to California. Marmalade on toast is a morning staple for us.

Is it un-American? An old people thing? Something you only eat in hotels, but never at home? Or just, you know, gross?
 
Last edited:
jnmaciuch said:
The question is whether the reduced type I interferon response here is a secondary effect of fewer antibodies from plasma cell killing, or whether blocking CD38 on type I IFN-producing cells is enough to inhibit their interferon output directly.

This paper would suggest that the latter is true,
Click to expand...

I agree, but since we are pretty sure that the pathology in lupus is mediated by antibody it is stretching things a bit to suggest that blocking interferon, which might have reduced the production of antibody from the cells you have already killed (if you hadn't killed them) matters much. It is a bit like the people who said that rituximab worked in RA by stopping the B cells presenting antigen to T cells that would have helped the B cells you killed a while back from producing pro-inflammatory Igs.

Interferons are fun but I don't think the drop in interferons here reflects anything more than the fashion for interferons (and indeed still T cell responses) in lupus.
 
leokitten said:
Surprising to me that it’s taken this long to run clinical trials using plasma cell depleting treatments in antibody-mediated disorders
Click to expand...

I was asking people if we could do it for RA and lupus in 2000 but everyone said that anti-CD38 would be too dangerous. As with the other agents, it took oncologists faced with people with no chance of survival otherwise, to try these things out. And in fact it isn't a particularly clever thing to use dara in lupus, even if it works a bit for a while. They will relapse just like ritux.

And of course rituximab depletes plasma cells if you keep giving it, and by 2010 we had done that and found out, but you are right that people seem to be rather slow doing these things even when they have been shown why it should work and that it does work. I gave up in 2010 because nobody was really interested in providing the necessary resources, just inflating their wallets or egos.
 
Jonathan Edwards said:
I agree, but since we are pretty sure that the pathology in lupus is mediated by antibody it is stretching things a bit to suggest that blocking interferon, which might have reduced the production of antibody from the cells you have already killed (if you hadn't killed them) matters much. It is a bit like the people who said that rituximab worked in RA by stopping the B cells presenting antigen to T cells that would have helped the B cells you killed a while back from producing pro-inflammatory Igs.

Interferons are fun but I don't think the drop in interferons here reflects anything more than the fashion for interferons (and indeed still T cell responses) in lupus.
Click to expand...
I don't disagree, interferons are probably secondary to the thing actually giving clinical benefit in this case. What I find interesting is just the possibility that a CD38 mAb could regulate type I interferon production directly by blocking CD38 activity on IFN-I producing cells (and doing so at a different point of intervention than other medications targeting IFN production). Whether that's the case here isn't clear but if dara ends up proven to work for ME/CFS it would be another explanation to consider besides autoantibody
 
You must log in or register to reply here.
Back
Top Bottom