The potential of CD38 protein as a target for autoimmune diseases

Ye, Xiaochun; Zhao, Yongxia; Ma, Wanqing; Arés, Irma; Martínez, Marta; López-Torres, Bernardo; Martínez-Larrañaga, María-Rosa; Wang, Xu; Anadón, Arturo; Martínez, María-Aránzazu

doi:10.1016/j.autrev.2023.103289

Cited by 5 publications

(5 citation statements)

References 12 publications

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“…It was first identified as a lymphocyte specific antigen, but current studies revealed that it is ubiquitously expressed ( 238 , 239 ). Plasma cells and memory B cells express high levels of CD38, while it is expressed at low levels in normal lymph and bone marrow cells ( 240 ). CD38 is also expressed in B cell precursors, germinal center B cells, and plasma cells and in other immune cells like NK cells, neutrophils and myeloid cells ( 239 ).…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

“…The role of CD38 in immune cells ranges from immunomodulation to effector functions during inflammation, where it could regulate cell recruitment, cytokine release and NAD availability. This expression profile of CD38, together with its role in inflammatory processes, make CD38 an interesting target in the context of autoimmune diseases ( 239 , 240 ). Antibodies targeting CD38 have been proposed as a potential therapeutic approach to eliminate plasma cells that produce autoantibodies.…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

“…Isatuximab binds to an epitope that partially covers the catalytic site of CD38, without changing its configuration, while Daratumumab is binding outside the catalytic site ( 242 ). In SLE patients, Daratumumab was found to restore NK cytotoxic function which promoted the elimination of circulating plasma cells ( 240 ). Thus, anti-CD38 might be a potent drug to reduce the levels of ASCs.…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

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Exploring the depths of IgG4: insights into autoimmunity and novel treatments

Ünlü,

Sánchez Navarro,

Cakan

et al. 2024

Front. Immunol.

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IgG4 subclass antibodies represent the rarest subclass of IgG antibodies, comprising only 3-5% of antibodies circulating in the bloodstream. These antibodies possess unique structural features, notably their ability to undergo a process known as fragment-antigen binding (Fab)-arm exchange, wherein they exchange half-molecules with other IgG4 antibodies. Functionally, IgG4 antibodies primarily block and exert immunomodulatory effects, particularly in the context of IgE isotype-mediated hypersensitivity reactions. In the context of disease, IgG4 antibodies are prominently observed in various autoimmune diseases combined under the term IgG4 autoimmune diseases (IgG4-AID). These diseases include myasthenia gravis (MG) with autoantibodies against muscle-specific tyrosine kinase (MuSK), nodo-paranodopathies with autoantibodies against paranodal and nodal proteins, pemphigus vulgaris and foliaceus with antibodies against desmoglein and encephalitis with antibodies against LGI1/CASPR2. Additionally, IgG4 antibodies are a prominent feature in the rare entity of IgG4 related disease (IgG4-RD). Intriguingly, both IgG4-AID and IgG4-RD demonstrate a remarkable responsiveness to anti-CD20-mediated B cell depletion therapy (BCDT), suggesting shared underlying immunopathologies. This review aims to provide a comprehensive exploration of B cells, antibody subclasses, and their general properties before examining the distinctive characteristics of IgG4 subclass antibodies in the context of health, IgG4-AID and IgG4-RD. Furthermore, we will examine potential therapeutic strategies for these conditions, with a special focus on leveraging insights gained from anti-CD20-mediated BCDT. Through this analysis, we aim to enhance our understanding of the pathogenesis of IgG4-mediated diseases and identify promising possibilities for targeted therapeutic intervention.

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Section: Therapeutic Interventionsmentioning

confidence: 99%

Section: Therapeutic Interventionsmentioning

confidence: 99%

Section: Therapeutic Interventionsmentioning

confidence: 99%

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Exploring the depths of IgG4: insights into autoimmunity and novel treatments

Ünlü,

Sánchez Navarro,

Cakan

et al. 2024

Front. Immunol.

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“…34 Originally developed for the treatment of multiple myeloma, anti-CD38 monoclonal antibodies are now under investigation for the treatment of autoimmune disorders, including ITP. 35 Depletion of long-lived platelet autoantibody-producing plasma cells may allow for treatment responses in patients with otherwise refractory ITP.…”

Section: Principles and Rationalementioning

confidence: 99%

“…CD38 (cyclic ADP ribose hydrolase), an enzymatic glycoprotein found on the surface of many immune cells including T cells, B cells and NK cells, is highly expressed on plasma cells 34 . Originally developed for the treatment of multiple myeloma, anti‐CD38 monoclonal antibodies are now under investigation for the treatment of autoimmune disorders, including ITP 35 . Depletion of long‐lived platelet autoantibody‐producing plasma cells may allow for treatment responses in patients with otherwise refractory ITP.…”

Section: Plasma Cell Depletion Via Targeting Cd38mentioning

confidence: 99%

Novel therapeutics and future directions for refractory immune thrombocytopenia

Al‐Samkari,

Neufeld

2023

Br J Haematol

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SummaryImmune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti‐CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in‐depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health‐related quality of life as an indispensable clinical trial end‐point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life‐threatening bleeding.

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2025 update on clinical trials in immune thrombocytopenia

Al‐Samkari

2024

American J Hematol

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Although the development and regulatory approval of the thrombopoietin receptor agonists revolutionized aspects of the immune thrombocytopenia (ITP) treatment landscape over the past two decades, there remain many areas of high unmet need. Therefore, a number of investigational and repurposed agents are currently undergoing clinical development in ITP. In a departure from historical trials, which largely focused on the indefinite treatment of persistent or chronic ITP, ongoing trials run the gamut of disease phases, and include novel agents being evaluated in early phases of the disease to attempt to modify the disease course. Many agents in development target disease pathophysiologic mechanisms not previously targeted by agents in current use, including platelet autoantibody recycling, B‐cell maturation and differentiation, long‐lived plasma cells, and the complement system, among others. These agents represent promising treatment options for patients with otherwise refractory disease or who are intolerant of currently available therapies. Additionally, with our increasing understanding of the diverse immune mechanisms at play in ITP, the expansion of the therapeutic armamentarium to include agents targeting diverse pathophysiologic mechanisms may allow a more personalized therapeutic selection in the future. This manuscript provides an up‐to‐date, in‐depth overview of recently completed and ongoing clinical trials in ITP.

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The potential of CD38 protein as a target for autoimmune diseases

Cited by 5 publications

References 12 publications

Exploring the depths of IgG4: insights into autoimmunity and novel treatments

Exploring the depths of IgG4: insights into autoimmunity and novel treatments

Novel therapeutics and future directions for refractory immune thrombocytopenia

2025 update on clinical trials in immune thrombocytopenia

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