B-Cell Targeting Landscape | B-Engaged

The role of B cells varies across autoimmune diseases¹

The immune system contains different types of white blood cells, including and , that help fight infections. Normally, B cells support immune responses by recognizing , presenting them to T cells, producing antibodies, and releasing that help regulate immune activity.^2-4

When B cells become dysregulated, they drive through multiple mechanisms. These include production, T-cell activation, and cytokine production.^4,5

With growing understanding of B cell biology, researchers have found that B cells can contribute to disease in different ways across autoimmune diseases.³

Roles of B cells across select autoimmune diseases¹

Autoimmune disease	Key role(s) of B cells	Key clinical manifestation(s)
ANCA-associated vasculitis (AAV)	Autoantibody production⁶ Neutrophil activation⁶ Downstream endothelial damage⁶	Small-vessel inflammation and damage⁶
Idiopathic inflammatory myopathies (IIM)	Autoantibody production⁷ T-cell activation⁷ Proinflammatory cytokine production⁷	Muscle inflammation and weakness⁷
Rheumatoid arthritis (RA)	Autoantibody production^8,9 T-cell activation^8,9 Proinflammatory cytokine production^8,9	Joint inflammation and damage⁸
Sjögren's disease (SjD)	Autoantibody production⁸ B-cell hyperactivity and glandular infiltration⁸ Proinflammatory cytokine production⁸ Lymphomagenesis¹⁰	Glandular dysfunction and systemic inflammation⁸
Systemic lupus erythematosus (SLE)	Autoantibody production and immune complex formation^8,9 T-cell activation^8,9 Proinflammatory cytokine production^8,9	Multi-organ inflammation and dysfunction⁸
Systemic sclerosis (SSc)	Autoantibody production¹¹ Profibrotic cytokine production¹¹ B-cell vascular and tissue infiltration¹¹	Fibrosis, vascular and organ dysfunction¹¹

ANCA-associated  vasculitis (AAV)

Key role(s) of B cells

Autoantibody production⁶
Neutrophil activation⁶
Downstream endothelial damage⁶

Key clinical manifestation(s)

Small-vessel inflammation and damage⁶

Idiopathic inflammatory  myopathies (IIM)

Key role(s) of B cells

Autoantibody production⁷
T-cell activation⁷
Proinflammatory cytokine production⁷

Key clinical manifestation(s)

Muscle inflammation and weakness⁷

Rheumatoid arthritis (RA)

Key role(s) of B cells

Autoantibody production^8,9
T-cell activation^8,9
Proinflammatory cytokine production^8,9

Key clinical manifestation(s)

Joint inflammation and damage⁸

Sjögren's disease (SjD)

Key role(s) of B cells

Autoantibody production⁸
B-cell hyperactivity and glandular infiltration⁸
Proinflammatory cytokine production^8,9
Lymphomagenesis¹⁰

Key clinical manifestation(s)

Glandular dysfunction and systemic inflammation⁸

Systemic lupus  erythematosus (SLE)

Key role(s) of B cells

Autoantibody production and immune complex formation^8,9
T-cell activation^8,9
Proinflammatory cytokine production^8,9

Key clinical manifestation(s)

Multi-organ inflammation and dysfunction⁸

Systemic sclerosis (SSc)

Key role(s) of B cells

Autoantibody production and immune complex formation¹¹
Proinflammatory cytokine production⁸
B-cell vascular and tissue infiltration¹¹

Key clinical manifestation(s)

Fibrosis, vascular and organ dysfunction¹¹

B cells have diverse roles and contribute to unique clinical manifestations across autoimmune diseases, and remain an important therapeutic target. Targeting B cells can help to control disease activity over time.^1,3,12

FOR PATIENTS

B cells can play different roles in different autoimmune diseases, contributing to inflammation and symptoms in the body^3,12

B cell target and therapeutic modality together influence B-cell depletion¹³

Expression of surface proteins across the

B cells express different proteins on their surface at different stages of their maturation and development, or B-cell lineage. The figure below shows the expression of select proteins, CD19, CD20, and BCMA, across stages of B-cell development. Targeting specific proteins with can engage distinct , which may play different roles in driving autoimmune disease.^3,12,13

Diagram of CD19, CD20, and BCMA expression across B-cell development stages

Diagram of CD19, CD20, and BCMA expression across B-cell development stages

Several B-cell targets have been studied and continue to be explored in autoimmune disease³

Target (B cell surface protein)	B cell populations targeted	Scientific considerations
CD19	Across the B cell lineage³	Validated target with clinical experience¹⁴ Researchers are continuing to explore how engagement across the B-cell lineage can impact depth of B-cell depletion and clinical outcomes¹⁰
CD20	Primarily mature B cells³	Validated target with extensive clinical experience³ Researchers are continuing to explore how engagement of mature B cells can impact depth of B-cell depletion and clinical outcomes⁴
BCMA	Primarily antibody-producing cells, such as plasmablasts and plasma cells³	Emerging target with early clinical validation¹⁴ Researchers are continuing to understand the role of plasmablasts and plasma cells in driving disease across autoimmune conditions¹⁴

Target (B cell surface protein) CD19

B-cell populations targeted

Across the B cell lineage³

Scientific considerations

Validated target with clinical experience¹⁴
Researchers are continuing to explore how engagement across the B-cell lineage can impact depth of and clinical outcomes¹⁰

Target (B cell surface protein) CD20

B-cell populations targeted

Primarily mature B cells³

Scientific considerations

Validated target with extensive clinical experience³
Researchers are continuing to explore how engagement of mature B cells can impact depth of B-cell depletion and clinical outcomes⁴

Target (B cell surface protein) BCMA

B-cell populations targeted

Primarily antibody-producing cells, such as plasmablasts and plasma cells³

Scientific considerations

Emerging target with early clinical validation¹⁴
Researchers are continuing to understand the role of plasmablasts and plasma cells in driving disease across autoimmune conditions¹⁴

While different B cell targets engage different B cell populations, researchers are also studying how different therapeutic modalities may influence B-cell depletion.

Multiple B-cell–targeting modalities continue to be explored for autoimmune disease³

each have a unique mechanism of action and set of considerations. They can be broadly categorized as:¹³

Non-cellular therapies³

TCEs are readily available and do not require cell engineering¹⁴

Can be designed as:¹⁵

- Bispecific TCE, which binds on T cells and a single target on B cells

- Trispecific TCE, which binds CD3 on T cells and multiple additional targets

How they work³

Diagram showing how a T-cell engager binds CD3 and a B-cell target to deplete B cells

Diagram showing how a T-cell engager binds CD3 and a B-cell target to deplete B cells

*Example bispecific TCE format shown.

mAbs are readily available and do not require cell engineering³

How they work³

Diagram showing how a monoclonal antibody binds and depletes a target B cell

Diagram showing how a monoclonal antibody binds and depletes a target B cell

Cellular therapies

Approaches being explored include , , and CAR T-cell therapies¹⁶

Manufacturing and delivery can vary across these approaches:

- Autologous: patient’s T cells are retrieved, engineered and re-infused¹⁰

- Allogeneic: T cells are engineered and infused into the patient¹⁰

- In vivo: patient’s T cells are engineered within the body¹⁶

How they work³

Diagram showing how CAR T-cell therapy binds and depletes target B cells

Diagram showing how CAR T-cell therapy binds and depletes target B cells

Together, these therapeutic modalities provide multiple approaches to targeting B cells and achieving B-cell depletion. Ongoing research will help to improve understanding of how differences between these approaches may influence B-cell depletion, disease activity, and clinical outcomes.³

FOR PATIENTS

There are several ways to target B cells. Researchers are studying how these different approaches can be used to treat patients with autoimmune disease³

Research continues to explore how different B cell targets and therapeutic modalities influence the depth, breadth, and location of B-cell depletion,  as well as whether these differences can improve disease control and clinical outcomes^14,16

ANCA, anti-neutrophil cytoplasmic antibodies; CAR, chimeric antigen receptor; CD, cluster of differentiation.

References: 1. Merino-Vico A, Frazzei G, van Hamburg JP, et al. Targeting B cells and plasma cells in autoimmune diseases: From established treatments to novel therapeutic approaches. Eur J Immunol. 2023;53:2149675. 2. Chi H, Pepper M, Thomas PG. Principles and therapeutic applications of adaptive immunity. Cell. 2024;187:2052-2078. 3. Robinson WH, Fiorentino D, Chung L, et al. Cutting-edge approaches to B-cell depletion in autoimmune diseases. Front Immunol. 2024;15:1454747. 4. Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20:179-199. 5. Getahun A. Role of inhibitory signaling in peripheral B cell tolerance. Immunol Rev. 2022;307:27-42. 6. Nakazawa D, Masuda S, Tomaru U, et al. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol. 2019;15:91-101. 7. Liu T, Chen B, Yin G, et al. Targeting B Cells for the Treatment of Idiopathic Inflammatory Myopathy. Clin Rev Allergy Immunol. 2025;68:40. 8. Song Y, Li J, Wu Y. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct Target Ther. 2024;9:263. 9. Jung SM, Kim W-U. Targeted Immunotherapy for Autoimmune Disease. Immune Netw. 2022;22:e9. 10. Schett G, Müller F, Taubmann J, et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat Rev Rheumatol. 2024;20:531-544. 11. Beesley CF, Goldman NR, Taher TE, et al. Dysregulated B cell function and disease pathogenesis in systemic sclerosis. Front Immunol. 2023;13:999008. 12. Pisetsky DS. Pathogenesis of autoimmune disease. Nat Rev Nephrol. 2023;19:509-524. 13. Ramírez-Valle F, Maranville JC, Roy S, et al. Sequential immunotherapy: towards cures for autoimmunity. Nat Rev Drug Discov. 2024;23:501-524. 14. Junt T, Calzascia T, Traggiai E, et al. Defining immune reset: achieving sustained remission in autoimmune diseases. Nat Rev Immunol. 2025;25:528-541. 15. Grieshaber-Bouyer R, Wu L, Schett G, et al. T cell engagers in autoimmune diseases. Nat Rev Immunol. Published online ahead of print: 2026. doi:10.1038/s41577-026-01318-x. 16. Li Y-R, Yang L. Autologous, allogeneic, in vivo CAR for autoimmune diseases. Trends Pharmacol Sci. 2026;47:11-14.