Autoimmune disease is a disease caused by the body’s immune system being mistakenly directed to attack the host itself, and more and more patients with autoimmune diseases need treatment. Researchers have now described more than 80 autoimmune diseases, which can be systemic, such as systemic lupus erythematosus(SLE), which affects the skin, joints, kidneys and central nervous system, or organical, such as type 1 diabetes, which primarily affects the body’s pancreas. Loss of B cell or T cell tolerance is often associated with autoimmunity. In recent decades, the treatment of autoimmune diseases has shifted from the use of hormones and conventional immunosuppressive drugs to the use of biologics. The proliferation and maturation of B lymphocytes play an important role in the pathogenesis of autoimmune diseases. Single B cell screening is becoming increasingly important in the treatment of autoimmune diseases. Monoclonal antibodies that target B cells and plasma cells can effectively treat a wide range of autoimmune diseases, underscoring the importance of B cells in the pathogenesis of such diseases.

In autoimmune diseases, B-cell-associated monoclonal antibodies mainly target CD20, CD19, CD22, CD38 and B-cell activating factor (BAFF). Some drugs have been approved by the US Food and Drug Administration, such as rituximab, Beliuzumab, orfathomumab, etc.

Antibodies targeting CD20 are currently the most widely used monoclonal antibodies, and although these antibodies have the same target, their structures and indications are quite different. The first generation of anti-CD20 drugs, such as rituximab, has good efficacy in pemphigus, rheumatoid arthritis, granulomatous polyvasculitis and microscopic polyvasculitis. Second-generation anti-CD20 drugs, including ocrelizumab, Oftolumab, and veltuzumab (not approved), contain both humanized and fully human monoclonal antibodies to reduce immunogenicity and extend the half-life of the drug. These drugs can bind Fc receptors on B cells more closely. The approved ocrelizumab and oftulizumab are mainly used in the treatment of multiple sclerosis. The third generation of anti-CD20 monoclonal antibodies, represented by Ortuzumab, has a different binding epitope from rituximab and does not induce CD20 aggregation or antibody internalization, so it is more effective and less resistant.

Inellizumab is a humanized anti-CD19 monoclonal antibody that has been approved by the FDA for the treatment of neuromyelitis spectrum disorder (NMOSD). NMOSD is a rare recurrent autoimmune disease of the central nervous system that can lead to paralysis and blindness. Beliuzumab is a fully human anti-BAFF monoclonal antibody that rapidly reduces naive B cells and B cells in early developmental stages, and currently treats SLE and lupus nephritis. In addition, there are several drugs that target other B cell surface antigens, such as epratuzumab, which targets CD22, and daratumumab, which targets CD38, that are being tried for the treatment of SLE. SLE is characterized by the reaction of B cells with autoantigens to produce autoantibodies. These autoantibodies may appear years before the clinical onset of SLE. Overproduction of autoantibodies leads to an inflammatory cascade and a massive immune response that ultimately leads to organ damage in the patient. In addition to secreting autoantibodies, B cells also secrete cytokines that promote inflammation.B cells and plasma cells (effector B cells) play an important role in the pathogenesis of SLE, and their associated antigens are the main therapeutic targets, such as CD19, CD20, CD40, etc. (Figure 1).

Figure 1: The maturation process of B cells

 

References

[1] Davis-Marcisak E F , Deshpande A , Stein-O’Brien G L ,et al.From bench to bedside: single-cell analysis for cancer immunotherapy[J].Cancer Cell, 2021, 39(8).DOI:10.1016/j.ccell.2021.07.004.

[2] Zhang Z, Xu Q, Huang L. B cell depletion therapies in autoimmune diseases: Monoclonal antibodies or chimeric antigen receptor-based therapy? Front Immunol. 2023 Feb 10;14:1126421. doi: 10.3389/fimmu.2023.1126421. PMID: 36855629; PMCID: PMC9968396.

[3] Arbitman L, Furie R, Vashistha H. B cell-targeted therapies in systemic lupus erythematosus[J]. J Autoimmun. 2022 Aug 10:102873. doi: 10.1016/j.jaut.2022.102873. Epub ahead of print. PMID: 35963808.

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