Targeting B cells and plasma cells is a key strategy for treating a variety of autoimmune diseases. In recent years, chimeric antigen receptor T cell (CAR-T) therapy has made some progress in autoimmune diseases, and many patients who received CD19-targeted CAR-T therapy have achieved long-term drug-free remission. However, the long production process of this type of therapy, the need for patients to undergo pretreatment in advance, and the inability to flexibly adjust the dose of CAR-T cells after the start of treatment have limited its widespread application. In addition, for some patients, their disease may be caused by long-lived plasma cells that express B cell maturation antigen (BCMA) but not CD19. Therefore, even after receiving CD19-targeted CAR-T therapy, autoimmune antibodies such as antinuclear antibodies and polymyositis-scleroderma-associated antibodies (PM-Scl) still exist in patients.
In view of the limitations of CAR-T therapy in the application of autoimmune diseases, researchers have set their sights on the off-the-shelf T cell engager teclistamab. This is a fully humanized bispecific antibody that targets both BCMA and CD3 receptors on the surface of T cells. It is the first bispecific therapy approved for the treatment of multiple myeloma and the first bispecific antibody approved to target BCMA. The therapy can bind to both T cells and B cells at the same time, thereby activating T cells to attack pathogenic B cells. Coupled with the high efficacy of the therapy in patients with multiple myeloma, researchers think that teclistamab's ability to deplete BCMA-expressing B cells and plasma cells may make it effective in patients with severe autoimmune diseases who have failed conventional B cell depletion therapy.

Researchers at Berlin Charité Hospital reported a case of a patient with SLE with a 6-year history. Before receiving teclistamab treatment, she had active lupus nephritis, accompanied by autoimmune hemolytic anemia, blistering skin lesions, and polyarthritis symptoms. Previously, she had tried 6 different conventional drugs and two biologics commonly used for SLE, but none of them achieved significant relief. The patient had stopped using the immunosuppressant mycophenolate mofetil (MMF) before receiving subcutaneous teclistamab treatment, and stopped taking oral prednisolone at week 6 of the trial.
Analysis showed that the patient's double-stranded DNA antibody level dropped rapidly, from 2440 IU/ml at the beginning of treatment to the normal range at week 5, and continued to maintain until week 16; the patient's complement level and type I interferon activity returned to normal. Teclistamab treatment caused the patient's peripheral B cells to be rapidly depleted in week 1, and her bone marrow plasma cells and B cells were massively eliminated at week 8.

In addition, the patient's urine protein to creatinine ratio dropped from 2352 before treatment to less than 500 at week 6; the patient's hemoglobin level and antiglobulin test results also returned to normal, and her mucocutaneous and musculoskeletal symptoms also achieved complete remission after completing teclistamab treatment, and her quality of life also showed gradual improvement. Clinically, the patient's Systemic Lupus Erythematosus Disease Activity Index 2K (SLEDAI-2K) score dropped from 20 points at baseline to 0 points at week 6 and remained at 0 points at the end of the 16-week follow-up.
However, the patient also experienced some adverse reactions. The patient experienced grade 2 cytokine release syndrome (CRS), pneumonia, sinusitis, and hypogammaglobulinemia. The researchers pointed out that these adverse reactions have also been reported in patients with multiple myeloma. Other adverse reactions, such as neutropenia, anemia, and neurotoxicity, were not observed in this patient.

On the other hand, scientists from FAU examined the efficacy of teclistamab in four patients with autoimmune diseases who were resistant to more than five immunosuppressants. These patients suffered from systemic sclerosis, primary Sjögren's syndrome, idiopathic inflammatory myopathy, and rheumatoid arthritis.
The analysis showed that after treatment, the patient's circulating B cells were depleted, and the reduction of antibody light chains in the blood circulation in the body confirmed the plasma cell targeting effect of teclistamab. The levels of autoimmune antibodies such as antinuclear antibodies, MDA5, SS-A/Ro, SS-B/La and PL-7 in the patients also decreased.

It is worth mentioning that teclistamab improved disease activity in all four patients. Patient 1's dermatopathy index measured by the modified Rodnan skin score improved from 39 points to 24 points. Patient 2's European Sjögren's Syndrome Disease Activity Index score improved from 34 points to 15 points. Patient 3's skin dermatomyositis disease area and severity index improved from 22 points to 6 points, and rheumatoid arthritis disease activity score 28 (DAS28-CRP) improved from 3.6 points to 1.6 points. Patient 4's arthritis score improved from 5.9 points to 1.9 points on DAS28-CRP. In patient 2, positron emission tomography-computed tomography (FAPI-PET-CT) using gallium-68-labeled fibroblast activation protein inhibitor showed that arthritis in the hands and knees disappeared. Patient 3 also had a significant reduction in skin inflammation and ulcers.
In this study, teclistamab showed good safety, no neurotoxicity or bone marrow toxicity was observed in patients, only low-grade cytokine release syndrome.
These data show that the strategy of using BCMA-targeted T cell engagers to fight plasma cells in patients with autoimmune diseases is feasible. However, longer follow-up is still needed in the future, especially until the patient's B cells regenerate, and trials in a larger patient population are conducted to verify the response rate and sustainability of the treatment. In any case, these two studies published in the New England Journal of Medicine have undoubtedly brought new hope to the majority of patients with autoimmune diseases. It is expected that in the near future, this type of therapy will be further clinically verified so that more patients can benefit from it.

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