Beyond rituximab: Next generation of B-cell depletion in lupus ‘moving on the right track’

Learning from 2 decades of off-label rituximab use in systemic lupus erythematosus may point the way toward developing “new and improved” B-cell depleting agents for patients with the disease, according to researchers.

In a review paper, Marit Stockfelt, MD, PhD, of the department of rheumatology and inflammation research at the University of Gothenburg, in Sweden, and colleagues aimed to determine what is working and what is not, and why, with rituximab (Rituxan, Genentech) in SLE.

Their findings, published in Nature Reviews Rheumatology, suggest that although rituximab has established the utility of targeting B cells, it only induces remission in a subset of set of patients. The paper notes potential limitations of rituximab, such as immunological factors, the presence of residual B cells and increases in B-cell activating factor (BAFF) after treatment. A discussion of genetic factors is also included, as well as an assessment of how T cells may aid in future B-cell depleting therapies.

Healio sat down with Stockfelt to discuss the limitations of rituximab, the optimal SLE populations for B-cell depletion and the future of personalized medicine in the disease.

Healio: Why did you decide to study the limits of B-cell depletion in lupus? What was the rationale behind the study?

Stockfelt: B-cell depletion with rituximab has been used off-label in lupus for more than 2 decades. There are both case series, registries and two systematic reviews that indicate its efficacy in lupus, and this is in line with our clinical experience.

However, several factors limit the efficacy of rituximab. Knowledge about these limitations can help us use rituximab more effectively and could guide the development of new and improved B-cell depletion therapies in SLE.

Healio: What are some of those limitations?

Stockfelt: One important factor is that the B-cell depletion is probably insufficient in a proportion of our patients. In particular, tissue-resident B cells may persist even if peripheral blood B cells are depleted. Then there is the repopulation of B cells that occurs after B cell depletion. In many patients, a surge in BAFF levels occur after rituximab treatment. This could promote the survival of more autoreactive B-cell subsets.

Then there are safety issues. Rituximab is a chimeric molecule with mouse parts. Therefore, some patients experience immunogenic reactions to rituximab. In addition, hypogammaglobulinemia affects some of our patients. If we find ways to circumvent these limitations, we could treat more effectively with less adverse effects.

Healio: What are some of the SLE patient populations in which B-cell depletion is not effective?

Stockfelt: Although B-cell depletion is used for several different lupus manifestations, patients with mucocutaneous disease have a lower clinical response rate. In particular, this is true for chronic cutaneous lupus (CCLE). Even when there is biological response with depleted B cells, this does not translate to clinical response.

For these patients, inflammation is probably B-cell independent, and they might benefit from therapy targeting other biological mechanisms.

Then some patients have good initial response but develop resistance to rituximab over time. For them, clinical response can be restored by switching to alternative B-cell depletion therapies with improved depletion mechanisms.

Healio: What have we learned from trials of rituximab in SLE that can be applied to current and future investigations of other agents?

Stockfelt: There was much surprise when rituximab did not reach its endpoints in the LUNAR and EXPLORER trial. On the flip side, this led to much thought about improving the design of clinical trials in lupus.

Some factors that may have influenced the results are high doses of background corticosteroids, as well as other simultaneous immunosuppressive therapies.

In addition, lupus patients are a heterogenous group, which may need to be factored in the trial design.

Healio: Specifically, what have we learned about the following (from your article): “Monoclonal antibodies, modalities that redirect the specificity of patient T cells using chimeric antigen receptor T cells or bispecific T-cell engagers, and combination treatment that simultaneously inhibits the BAFF pathway”?

Stockfelt: So, these are all potential novel treatment options that aim for B-cell depletion in different ways. For example, there are new anti-CD20 antibodies that are less immunogenic than rituximab and that deplete B cells more efficiently.

Then the CAR T-cell development cannot have been missed by anyone, where patient T cells are modified to target B cells. A somewhat similar approach is offered by the bispecific T-cell engagers (BiTEs) that, in a different manner, redirect the patient’s own T cells. We have only data from very few patients with SLE or other rheumatic diseases, and many questions still need to be answered, but the development will be interesting to follow.

There is also the combination treatment that you mention, that combines B-cell depletion with inhibition of the BAFF pathway. This could potentially reduce the repopulation of B cells after depletion.

And finally, monoclonal antibodies that target distinctly expressed surface markers on B cells, for example those expressed mostly on plasma cells, to direct B-cell depletion towards certain subsets of B cells.

Healio: Given all of the above, how can B-cell depletion be further optimized in SLE?

Stockfelt: I think we are moving on the right track. We have several and very different modalities in the pipeline. In the future, we may have several treatment options to choose from. More knowledge about clinical factors and biomarkers that could inform our choices is important.

Ideally, we should be able to identify the option with the highest likelihood of improvement for the disease pattern of the individual patient. We will also need to balance short- and long-term costs and effects, as well as toxicity, and patient effort.

Head-to-head studies comparing the new treatment options to each other would of course be very helpful. However, having several options to choose from is a luxury problem that we should not complain about!

Healio: How can other factors like genetics be leveraged with B-cell depletion?

Stockfelt: After rituximab binds to a B cell, a phagocyte can bind the Fc part of the rituximab molecule to target the B cell. How effective this process is depends upon the affinity of its Fc gamma receptors (FcR).

Patients have different allotypes of FcRIII, which influences the efficiency of rituximab. It is likely that patients with lower affinity allotypes may need higher doses of rituximab or alternative agents to achieve equal biological and clinical response as patients with higher affinity allotypes.

Healio: Will personalized medicine eventually be a reality for patients with SLE? If so, could you offer a timeline of when that could be expected?

Stockfelt: We are already considering some patient factors when choosing the right therapy for the individual lupus patient. However, the more options we have, and the more we understand about why some patients respond better than others to certain treatments, the more flexibility we will have to offer the individual patient an option that suits both her biological disease pattern and her life situation.

References:

Stockfelt, M, et al. Nat Rev Rheumatol. 2025;doi:10.1038/s41584-024-01210-9.