LONDON — Complete eradication of pathogenic B cells and plasma cells within deep tissue niches could offer an “immune reset” for patients with highly refractory, severe autoimmune diseases, according to clinical data presented at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting.

For more than two decades, standard B-cell targeting in rheumatology has centered heavily on conventional anti-CD20 monoclonal antibodies such as rituximab. B cells are an attractive therapeutic target because they drive autoantibody production, act as highly efficient antigen-presenting cells that activate T cells, and secrete a cascade of proinflammatory cytokines. However, conventional therapies face significant biological hurdles. Because they rely on the host’s innate immune system, such as complement activation or natural killer cells via antibody-dependent cellular cytotoxicity, to destroy target cells, they frequently leave tissue niches untouched.

“Rituximab has a very established treatment, but it has several shortcomings,” Wolfgang Merkt, MD, Division of Rheumatology, Department of Hematology, Oncology and Rheumatology, Internal Medicine V, Medical Faculty, Heidelberg University, Heidelberg, Germany, said at the meeting. These limitations include incomplete depletion within deep tissue (such as the bone marrow and lymph nodes), target antigen internalization, antidrug antibody formation, and an inherent failure to reach CD20-negative, long-lived plasma cells. These plasma cells act as autonomous autoantibody factories, entirely unbothered by anti-CD20 therapy.

“B cells play a key role in autoimmune diseases via producing autoantibodies but also presenting autoantigens and releasing proinflammatory cytokines,” said Ricardo Grieshaber-Bouyer, MD, a professor of clinical systems immunology and head of the Clinical Trial Unit at Friedrich-Alexander University Erlangen-Nürnberg in Erlangen, Germany. “However, as we’ve also learned, depleting B cells, in particular in tissue niches, can be rather challenging with conventional approaches, and therefore, approaches for deeper depletion of B cells in tissue are required.”

To eradicate the aberrant immune memory and allow a healthy, non-autoreactive immune system to grow back, scientists are turning to synthetic retargeting using bispecific T-cell engagers (BiTEs). Unlike traditional antibodies that simply bind to a target and wait for the rest of the immune system to notice, a BiTE is an engineered molecule designed to actively force two different cells together. It features two distinct arms: One arm locks onto a specific marker on B cells such as CD19 or CD20 or on plasma cells using the B-cell maturation antigen (BCMA) as an antigen, whereas the other arm grabs onto the CD3, CD4, or CD8 cell-surface molecules on T cells. By physically bringing these two cells close, the BiTE bypasses the strict rules of normal T-cell activation. It tricks the T cell into recognizing the target cell as a hostile threat, triggering the formation of a synthetic cytotoxic synapse. The T cell then unleashes a wave of perforins and granzymes, systematically dissolving the pathogenic B cell or plasma cell directly within its tissue niche.

“BiTEs are certainly more scalable and accessible compared to ex vivo manufactured chimeric antigen receptor (CAR) T cells. But at the current stage, it is unclear whether BiTEs can induce a full immune reset,” Hans Ulrich Scherer, MD, PhD, a professor of translational rheumatology at the Department of Rheumatology at Leiden University Medical Center in Leiden, Netherlands, told Medscape Medical News. “It seems that most patients eventually relapse, suggesting that full immune reset may be more challenging to achieve. However, not every BiTE is the same.”

T-Cell Engagers: A Comparison of Three Distinct Modalities

Teclistamab is an immunoglobulin G (IgG)-based bispecific molecule targeting BCMA and CD3 that features a full fragment crystallizable (Fc) domain, giving it a longer circulatory half-life and allowing for periodic subcutaneous administration rather than continuous infusion. By targeting BCMA — a surface receptor highly and selectively expressed on late-stage B cells — its cytotoxic payload is explicitly aimed at mature plasma cells and plasmablasts.

Grieshaber-Bouyer presented updated data from Universitätsklinikum Erlangen on a cohort of 18 patients with severe, progressive multidrug refractory autoimmune diseases who had exhausted all standard options. Teclistamab is a targeted cancer immunotherapy used to treat adults with relapsed or refractory multiple myeloma. For the past 2 years, it has also been used in patients with refractory autoimmune diseases, he explained.

The cohort included nine patients with systemic sclerosis (SSc), three with IgG4-related disease (IgG4-RD), two with inflammatory myositis, two with rheumatoid arthritis, one with Sjögren disease, and one with Graves disease.

The team utilized the standard oncologic step-up dosing protocol (0.06, 0.3, and 1.5 mg/kg). Initially, patients received the target dose twice (at baseline and at 1 month), but based on pharmacokinetic modeling, the protocol was optimized to four total target doses to ensure maximum depletion.

Tissue biopsies confirmed complete ablation of plasma cells directly within bone marrow and lymph nodes. In a standout case of a young patient with severe, progressive endocrine orbitopathy from Graves disease, who had already failed orbital decompression surgery, high-dose steroids, and mycophenolate mofetil, teclistamab induced complete seroconversion of thyroid-stimulating hormone receptor autoantibodies to zero, fully normalized endogenous thyroid function, and entirely averted a scheduled thyroidectomy. In patients with IgG4-RD, the therapy prompted rapid resolution of severe retroperitoneal fibrosis and inflammatory aortitis.

However, safety requires vigilance. Cytokine release syndrome (CRS) occurred in 83% of the cohort, though all cases were low grade (grade 1 or 2) and successfully managed with the interleukin-6 receptor antagonist tocilizumab. No cases of immune effector cell-associated neurotoxicity syndrome were observed. Because BCMA targeting eliminates long-lived plasma cell memory, hypogammaglobulinemia developed in 100% of treated patients, which required proactive management via substitution with intravenous Ig, Grieshaber-Bouyer said.

In contrast to full IgG structures, blinatumomab is a small fragment-based molecule consisting of only variable antigen-binding domains that target CD19 and CD3. Because it lacks an Fc region, it has an exceptionally short half-life of approximately 2 hours, requiring a continuous 24-hour intravenous infusion via a portable pump over a multiday course.

While highly effective at clearing CD19-positive peripheral B cells, Merkt said that the kinetics of a brief, single-course infusion frequently allows rapid peripheral B-cell repopulation from hidden bone marrow precursors, occasionally leading to early clinical relapses. To address this issue, his team pioneered an induction-maintenance protocol in a patient with severe myositis, using blinatumomab as an aggressive induction tool, followed by quarterly rituximab to lock in the tissue depletion and prevent premature repopulation.

Mosunetuzumab is a full-length IgG bispecific molecule engineered to engage CD20 and CD3. Unlike plasma cell-directed therapies, mosunetuzumab targets mature B cells while sparing the untargeted plasma cell niche, significantly reducing the downstream risk for profound hypogammaglobulinemia.

Merkt detailed the first successful crossover use of this agent outside of oncology to treat a highly refractory retro-orbital granuloma in a patient with granulomatosis with polyangiitis. The drug achieved significant tissue reduction as a monotherapy in an outpatient-compatible setting due to its very favorable, low-grade CRS profile.

Evaluating the Evidence 

Merkt told Medscape Medical News that the low-grade nature of adverse events is a crucial differentiator for autoimmune patients compared with oncologic cohorts. “In some cases, it’s really a historical finding,” he said. “[But] it depends on the selection of the patients.” So far, BiTEs have been trialed in highly refractory patients. “[It’s] great to see that we have something at hand that can be effective.”

A particularly intriguing aspect of the findings was the concept of sequential therapeutic sequencing, Merkt said. The shared data demonstrated that these advanced modalities can rescue one another when an individual pathway fails. For instance, within the collaborative German registry, two patients with SSc who relapsed after CD19 CAR T-cell therapy were successfully rescued using the plasma cell-targeting mechanisms of teclistamab. Conversely, a patient with severe myositis who failed to respond adequately to teclistamab subsequently achieved major clinical improvements when switched to a CAR T-cell protocol.

However, Merkt delivered a vital clinical warning regarding disease timing and the limits of structural reversal. While an aggressive B-cell or plasma cell reset can decisively quench active, self-perpetuating autoimmune inflammation, it possesses no intrinsic capability to heal advanced, established tissue destruction or scarring.

In conditions such as late-stage SSc, where autonomous fibroblast activation and secondary tissue fibrosis have already taken structural hold, the window for a purely immune-directed intervention has closed. For these advanced populations, Merkt concluded that the future will require multiphase combination concepts: utilizing deep cellular depletion as an early induction tool to completely switch off the autoimmune driver, followed immediately by novel anti-fibrotic or stroma-directed treatments to target the remaining tissue damage.

Looking ahead to the next decade, Merkt is confident that these oncology-born therapies will establish a permanent foothold in rheumatology clinic pipelines, driven by upcoming biopsy data and robust trial infrastructure. “I’m pretty sure that we will see these drugs in the clinics because there are already many companies starting clinical trials, and this is the decisive factor that we actually need,” he said. “In the future, we will have a whole array of different therapies and also different targets, so we will determine which patient subset will profit from which BiTE. One important question on the research agenda is to find biomarkers or phenotypes in tissue biopsies that could guide speculations toward the one or the other BiTE.”

Merkt reported having financial relationships with multiple pharmaceutical companies but none of the manufacturers of the BiTEs mentioned in this article. Grieshaber-Bouyer reported having financial relationships with multiple pharmaceutical companies, including Johnson & Johnson, which manufactures teclistamab. Scherer reported having no relevant financial relationships. 

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.