When the immune system erroneously attacks its own cells, it leads to autoimmune diseases. This pathological process is driven by the abnormal activation of autoreactive T cells and the abnormal production of autoantibodies, resulting in chronic inflammation and progressive tissue damage.
Currently, over 100 autoimmune diseases are known, with the top ten diseases alone affecting nearly 15 million patients in the United States (Figure 1). This number highlights the significant public health burden posed by autoimmune diseases.
Figure 1. Comparison of the prevalence of autoimmune diseases and cancer in the United States in 2022
Although disease-modifying therapies are constantly innovating, there are still multiple unmet needs in the clinic: existing treatments are often associated with significant side effects, patients require lifelong medication, efficacy tends to diminish over time, and resistance may occur when rotating between different treatment regimens.
Against this backdrop, B cells, due to their unique immune functions—including antibody secretion, antigen presentation, and cytokine release—have gradually become a core target for immune modulation. Monoclonal antibody therapies targeting CD20 have shown clinical value by mediating transient B cell depletion, but their therapeutic effects vary significantly across indications.
Emerging therapeutic strategies based on T cell-mediated persistent killing (such as CAR-T cell therapy and bispecific antibodies) are rewriting the treatment landscape. These innovative therapies, by achieving deep and lasting B cell elimination, theoretically “reset” the abnormal B cell repertoire, restoring immune tolerance balance and potentially leading to clinical remission or even functional cure without the need for continuous medication.
This scientific hypothesis was clinically validated in 2022: the Schett team used CD19-targeted CAR-T cell therapy to successfully achieve deep B cell depletion and immune marker normalization in five refractory systemic lupus erythematosus (SLE) patients, maintaining long-term drug-free remission (Figure 2). This breakthrough marks the translation of the concept of immune system reset from theory to clinical reality.
Figure 2. Timeline of tumor and autoimmune disease model development
This milestone research quickly triggered a global surge in R&D activities. Currently, 85 candidate therapies are undergoing clinical development, covering over 380 clinical trials.
The following will systematically analyze the competitive landscape and development trends of this innovative field, from treatment models, target selection, indication distribution, and regional development perspectives.
The therapies aimed at achieving continuous B cell depletion are mainly divided into three major technical routes: autologous cell therapy, allogeneic cell therapy, and non-cell therapies (Figure 3).
Figure 3. The evolution of treatment models in this field before and after Schett's team used CAR-T cell therapy trials in 2022
Autologous cell therapy (such as the CD19 CAR-T therapy used by the Schett team) dominates, with nearly 95 clinical trials. It is noteworthy that, in randomized controlled trials, these therapies failed to replicate the 100% initial response rate observed in early investigator-initiated trials (IIT). This efficacy discrepancy could lead to stock price fluctuations of related biotech companies. Moreover, autologous therapies require personalized preparation by isolating T cells from the patient’s body, facing significant challenges in large-scale production, cold-chain logistics, and long-term patient monitoring.
Allogeneic cell therapy uses T cells from healthy donors to prepare “off-the-shelf” treatment products, offering significant advantages in cost control (10-100 times lower) and ease of administration, which can improve treatment accessibility. However, clinical data from the oncology field suggests that allogeneic therapy has relatively limited efficacy compared to autologous therapy. This is mainly because the T cells from the donor have a shorter lifespan in the host body and are easily recognized and eliminated by the host immune system.
This leads to a key scientific question: under the premise of limited cell persistence, can a single allogeneic treatment achieve deep enough B cell elimination to reset the immune system and induce drug-free remission? Although the development of allogeneic therapy started later, it is accelerating, and several key clinical trial results are expected to be revealed in 2025.
In the non-cell therapy domain, bispecific and trispecific antibodies bridge endogenous T cells and target cells for therapeutic effects. These therapies have achieved substantial breakthroughs in cancer treatment (with 9 FDA-approved products) and show potential for translation into autoimmune diseases.
Although clinical trials in oncology show that these therapies have a rapid onset of action, their effects tend to be shorter-lasting compared to autologous CAR-T therapy. The core advantages of multispecific antibodies lie in their highly standardized manufacturing process, superior treatment accessibility, and the absence of complex cell preparation procedures.
In 2024, several clinical case reports showed that CD3 bispecific antibodies (such as blinatumomab and teclistamab), originally developed for cancer treatment, began to show efficacy in treating systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. This discovery has rapidly sparked a new wave of investment.
Regarding target selection, CD20 remains the most popular therapeutic target (about 170 clinical trials), largely due to the rich experience accumulated in treating B cell lymphoma with this target.
Other important targets include CD19, CD22, CD38, and BCMA. Researchers are optimizing the therapeutic safety window by selectively eliminating specific B cell subsets (Figure 4). This diversified target strategy helps develop precision treatment plans for different disease characteristics.
Figure 4. New autoimmune disease candidate drugs and their characteristics
From a disease domain perspective, multiple sclerosis (88 trials) and systemic lupus erythematosus (57 trials) are currently the most research-intensive areas, closely related to their clear B cell pathogenic mechanisms and established clinical evaluation systems.
At the same time, innovative therapies are gradually expanding into subfields such as generalized myasthenia gravis and ANCA-associated vasculitis, showing a trend toward diversified treatment strategies.
In terms of regional distribution, the United States leads with 145 ongoing clinical trials, while China follows closely with nearly 100 trials. With its large patient base and cost advantages in clinical trials, China is rapidly emerging as an important hub for early clinical development.
It is worth noting that some European and American companies have begun to lay out early cell therapy trials in China to take advantage of its rapidly evolving R&D ecosystem. The dynamic evolution of this regional competitive landscape is worth continued attention.
With 380 parallel clinical trials, the products that will eventually pass through rigorous testing and be approved for market will undoubtedly be few and far between. Historical experience shows that even blockbuster drugs like TNF inhibitors have only a few products that end up occupying a major market share.
For autologous cell therapy, its development faces special industrialization challenges: currently, only about 200 medical institutions in the United States are equipped to conduct cell therapies, which presents a significant mismatch with the widespread distribution of autoimmune disease patients. If immune reset therapies can achieve the anticipated breakthroughs, establishing a wider cell therapy network, cultivating professional medical teams, and optimizing patient referral systems will be key tasks to ensure the accessibility of innovative therapies.
[1]. Mayank Bhandari et al. The race to reset autoimmune diseases. Nature Reviews Drug Discovery (2025)
[2]. https://www.nature.com/articles/d41573-025-00085-z
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