Application of B Cell Depletion Therapy in Autoimmune Diseases: Part II

October 29, 2025 /

Autoimmune diseases represent a category of disorders characterized by aberrant immune responses against self-tissues, including conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). B cells play pivotal roles in the pathogenesis and progression of these diseases. In recent years, B-cell depletion therapy (BCDT) has emerged as critical therapeutic strategies for autoimmune disorders. This article will describe the developmental stages of B cells and their surface antigen expression, discuss established and emerging therapeutic targets, analyze the advantages and limitations of various targeted therapies, and focus particularly on the clinical applications and prospects of monoclonal antibody therapy and CAR-T cell therapy.

 

1. B Cell Developmental Stages and Surface Antigen Expression

B cells develop in the bone marrow and peripheral lymphoid organs. Their key developmental stages and corresponding surface antigen expression are outlined below:

 

  • Pro-B cells: Derived from hematopoietic stem cells, these cells form in the bone marrow, initiate immunoglobulin heavy chain gene rearrangement, andexpress CD19 and CD22.
  • Pre-B cells: After completing immunoglobulin heavy chain gene rearrangement, they begin light chain gene rearrangement and express CD19 and the pre-B cell receptor (Pre-BCR).
  • Immature B cells: Following successful light chain gene rearrangement, they express the IgM-type B cell receptor (BCR), migrate from the bone marrow to peripheral tissues, and start expressing CD20.
  • Mature B cells: Residing in peripheral lymphoid organs, they express both IgM- and IgD-type BCRs, possess full antigen recognition capacity, and expressCD19, CD20, and CD22.
  • Germinal center B cells: Upon activation, they migrate to germinal centers, undergo somatic hypermutation andimmunoglublin class switching, enhance antibody affinity and functional diversity, and express CD19, CD20, CD38, and BCMA.
  • Plasmablasts and plasma cells: These differentiate into antibody-secreting plasma cells, express CD38 and CD138, exhibit low CD19 expression, and no longer express CD20.
  • Memory B cells: Long-lived in the body, they rapidly respond to re-exposure to antigens and express CD27.

As summarized above,Key surface antigens on B cells, which serve as effective targets for B cell depletion strategies, include:

  • CD19: Expressed across all B cell developmental stages (including plasma cells), a vitalB cell marker.
  • CD20: Expressed from immature B cells to memory B cells, but not on plasma cells.
  • CD38: Highly expressed on activated B cells and plasma cells, a plasma cell marker.
  • BCMA: Primarily expressed on subsets of mature B cells and plasma cells, involved in plasma cell survival and maintenance.
  • BAFF-R: Expressed on transitional, mature, and memory B cells, essential for maintaining peripheral B cell numbers and function.

 

2. The Role of B Cells in Autoimmune Diseases

B cells contribute to autoimmune diseases through multiple mechanisms:

  • Autoantibody production: B cells differentiate into plasma cells, producing autoantibodies against self-antigens. These antibodies directly attack self-tissues or form immune complexes with self-antigens, activating the complement system, triggering inflammation, and causing tissue damage. Examples include anti-collagen inRA and anti-dsDNA in SLE.
  • Antigen presentation and co-stimulation: As antigen-presenting cells (APCs), B cells uptake self-antigens, present antigen fragments to CD4+ T cells via MHC II molecules, and activate autoreactive T cells. They also express co-stimulatory molecules (e.g., CD40, CD80, CD86) to amplify T cell activation and immune responses.
  • Cytokine secretion: Activated B cells and plasma cells secrete pro-inflammatory cytokines and chemokines (e.g., IL-6, TNF-α, IL-8), promoting the recruitment and activation of inflammatory cells and exacerbating tissue damage.
  • Ectopic lymphoid structure (ELS) formation: In chronic inflammatory environments, B cells and other immune cells form ELS in damaged tissues, continuously promotelocal autoimmune responses.
  • Innate immune involvement: B cells directly participate in innate immunity via Toll-like receptors (TLRs), promoting the initiation and maintenance of autoimmune responses.

Through these mechanisms, B cells play a pivotal role in the pathogenesis of autoimmune diseases. Dysregulated B cell function disrupts immune homeostasis, potentially triggering or worsening disease. Thus, B cell-targeted therapies are of profound clinical importance for managing autoimmune conditions.

 

3. Existing B Cell Depletion Therapies and Their Targets

For over 20 years, B cell depletion therapy (BCDT) has shown significant efficacy in treating autoimmune diseases. Initially relying on CD20-targeted monoclonal antibodies like Rituximab, recent advancements in B cell biology have led to the development of BCDT methods targeting diverse B cell surface antigens, particularly in haematological malignancies. These include ADCC-enhanced monoclonal antibodies, CAR-T cell therapy, and multispecific T cell engagers (TCE) or NK cell engagers (NKCE). Given their success in haematological malignancies, these emerging approaches hold promise for refractory B cell-mediated autoimmune diseases.

Key targets for monoclonal antibodies, multispecific antibodies, or cell engagers:

  1. CD20: Expressed on nearly all B cells except pro-B cells, plasmablasts, and plasma cells, CD20 is the most widely used BCDT target.
  • First-generation anti-CD20 mAbs: Represented by Rituximab, effective in pemphigus, RA, granulomatosis with polyangiitis, and microscopic polyangiitis, but failed to meet primary endpoints in SLE.
  • Second-generation anti-CD20 mAbs: Approved for MS(e.g., Ocrelizumab, Ofatumumab), demonstrating favorable
  • Third-generation anti-CD20 mAbs:ADCC-enhanced antibodies like Obinutuzumab, more effective at depleting tissue-resident B cells.
  1. CD22: Expressed on B cells excluding plasmablasts and plasma cells. However, Epratuzumab underperformed in clinical trials, possibly due to low CD22 expression on CD27+ memory B cells.
  1. BAFF (B cell activating factor): Overexpression of BAFF drives B cell expansion and impairs germinal center negative selection, contributing to autoimmunity diseases. Belimumab, a BAFF-targeted mAb approved for SLE, reduces B cell survival by blocking BAFF-receptor binding, with minimal impact on plasma cells and memory B cells.
  1. CD19: Expressed across all B cell stages and subsets of plasma cells. Theoretically, CD19-targeted therapy could deplete B cells more effectively than CD20-targeted approaches. Inebilizumab (anti-CD19 mAb) is approved for neuromyelitis optica spectrum disorder (NMOSD), but other anti-CD19 mAbs have yet to meet expectations in autoimmunity diseases.
  1. CD38: Highly expressed on plasmablasts and short-/long-lived plasma cells. Daratumumab (anti-CD38 mAb), used for multiple myeloma, shows potential in refractory SLE but may increase infection risk and affect other immune cells.

 

Key CAR-T targets:

  1. CD19: Initially for B cell malignancies, CD19 CAR-T has shown promising results in refractory SLE, significantly improving disease activity indexwith good tolerability.
  2. CD20: A classic B cell depletion target, CD20 CAR-T (originally for CD19 CAR-T-resistant or CD19-negative malignancies) reduces inflammation and joint damage in RA models.
  3. BCMA (B cell maturation antigen): Whilecurrently approved for relapsed/refractory multiple myeloma, BCMA CAR-T also demonstrates significant redcutions in autoantibody levels and improves lesions in SLE and pemphigus models.
  4. CD7:primarily expressed on T cells and NK cells, CD7 targeted CAR-T therapy is primarily utilized for T cell malignancies. It also holds significant potential for depleting pathogenic T cells in T cell-mediated autoimmune diseases (e.g., dermatomyositis, MS).
  5. MuSK CAART: Targeting muscle-specific tyrosine kinase (MuSK), a key neuromuscular junction protein, MuSK CAART depletes autoreactive B cells/plasma cells in myasthenia gravis, improving muscle weakness in disease models.
  6. DSG3 CAART: Targeting desmoglein 3 (DSG3), a skin/mucosal cell adhesion molecule, DSG3 CAART clears DSG3-specific autoreactive B cells/plasma cells, promoting skin/mucosal healing in pemphigus animal models.

 

4. Data Highlights

PharmaLegacy has accumulated extensive experience in BCDT research, mataining a diverse portfolio of specialized experimental platforms, including non-human primate models, humanized immune system micemodels, and gene-humanized mice models. Equipped with advanced tools (e.g., 21-color flow cytometers, MSD/Luminex multi-factor analyzers, digital PCR), PharmaLegacy supports comprehensive analyses of pharmacodynamic (PD) parameters, biomarkers, cell therapy persistence, and biodistribution studies. Leveraging its advanced experimental platform, PharmaLegacy has established comprehensive efficacy evaluation capabilities for diverse BCDT modalities, including cell therapies, monoclonal antibodies (mAbs), multispecific antibodies, and cell engagers.

PharmaLegacy Case studies:

  • B cell depletion by Rituximab in cynomolgus monkeys.

  • B cell depletion by CD19 CAR-T in cynomolgus monkeys.

  • CAR-T-mediated B cell depletion in CD34 humanized immune system mice.

  • T cell engager-induced B cell depletion in CD34 humanized immune system mice.

 

 

B cell depletion therapy(BCDT) holds significant clinical value in treating autoimmune diseases, particularly refractory cases. By deepening our understanding of B cell biology and disease mechanisms, we can develop more precise and effective therapeutic strategies. Currently, while monoclonal antibody therapies are widely used clinically, emerging technologies like CAR-T and CAAR-T cell therapies demonstrate immense potential. PharmaLegacy, with its robust experimental platforms and dedicated scientific team, is committed to driving innovation and advancement in the field of BCDT research. We warmly welcome collaborations with partners across the field, ultimately delivering superior treatment options for patients.

 

 

Reference:

1.”Cutting-edge approaches to B-cell depletion in autoimmune diseases”
2.”B cell depletion therapies in autoimmune diseases: Monoclonal antibodies or chimeric antigen receptor-based therapy?”