In November 2025, Roche announced that its CD20-targeting monoclonal antibody Gazyva achieved its primary endpoint in a Phase III clinical trial for the treatment of adult systemic lupus erythematosus (SLE). The drug significantly reduced disease activity in patients with SLE. Compared with patients receiving standard therapy alone, a significantly higher proportion of patients treated with Gazyva in combination with standard therapy achieved at least a 4-point improvement on the SLE Responder Index-4 (SRI-4) at Week 52.

Image source: Gazyva official website [1]

Gazyva, also known as Obinutuzumab, was first approved in 2013 for the treatment of chronic lymphocytic leukemia (CLL). Since then, its indications have continued to expand. It is currently approved for five indications in the United States, the European Union, and other regions, including chronic lymphocytic leukemia, follicular lymphoma (as well as relapsed/refractory follicular lymphoma), small lymphocytic lymphoma, and active lupus nephritis. The positive clinical results of Gazyva in autoimmune diseases highlight the successful expansion and validation of CD20 from its traditional lymphoma setting into the field of autoimmune disease treatment [10, 11].

CD20 Expression and Its Relationship with Cancer and Autoimmune Diseases

CD20 is an important B-cell surface marker, also known as MS4A1 (membrane-spanning 4-domains, subfamily A, member 1). It is a four-pass transmembrane protein involved in regulating B-cell responses to external signals and is critical for activating resting B-cells and entering into the cell cycle. CD20 modulates B-cell signaling by regulating calcium flux, thereby influencing B-cell function.

Structure of CD20 [2]

CD20 expression begins at the transition stage from pro-B-cells to pre-B-cells and is maintained on mature B-cells and memory B-cells, while its expression is downregulated or lost at the plasmablast and mature plasma cell stages. CD20 remains an intriguing and exploitable therapeutic target, primarily due to its role in modulating B cell signaling and its consistent expression across most B cell development stages. Its prevalence on pathogenic cells facilitated the historic success of CD20-targeted immunotherapies in high expression malignancies. Its utility extends to diseases with lower CD20 density, where it is exploited in combination with other therapies to achieve standard of care efficacy. The broad functional impact of CD20 in both healthy and diseased immune environments highlights its importance as a versatile focus for advancing treatments in oncology and autoimmunity.

Expression profile of CD20 during B-cell development [3]

In cancer, particularly B-cell lymphomas, disease arises from the uncontrolled expansion of CD20-positive malignant B-cells. CD20 is thought to support tumor cell survival by regulating calcium flux following B-cell receptor (BCR) activation, enabling malignant B-cells to remain in a persistently activated and proliferative state even in the absence of normal antigen stimulation. In addition, the stable membrane localization of CD20 on malignant B-cells facilitates the formation of specific signaling complexes, conferring enhanced anti-apoptotic capacity and greater metabolic adaptability.

In autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS), pathogenic B-cells contribute to disease by boosting production of high-affinity autoantibodies and amplifying immune-driving processes such as antigen presentation and cytokine secretion. Persistent dysregulation of B-cell activation can drive expansion of autoreactive clones, lower the threshold for repeated stimulation, and reinforce self-sustaining inflammatory loops that ultimately result in chronic tissue damage. In addition, a subset of T-cells has been reported to express CD20 and display pro-inflammatory activity, including production of cytokines such as IFN-γ and TNF-α, which may contribute to disease pathology in conditions such as MS and RA.

Functions of B-cells in autoimmune diseases [4]

Landscape of CD20-Targeted Therapies

CD20-Targeted Therapies for Oncology

In regard to B-cell malignancies, CD20-targeted therapies initially took the form of monoclonal antibodies. The first approved CD20 monoclonal antibody was rituximab (trade name MabThera), developed by Roche (Genentech) and IDEC Pharmaceuticals. It was first approved by the U.S. FDA in 1997 for the treatment of follicular lymphoma. Rituximab’s specificity for CD20 and synergistic effects when combined with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone) ushered in the era of targeted immunotherapy for non-Hodgkin lymphoma. However, limitations in cytotoxic potency, immunogenicity, and dosing convenience drove subsequent structural optimization of antibodies to achieve improved efficacy and safety, leading to agents such as ofatumumab and obinutuzumab. Obinutuzumab is a Type II humanized antibody with a glycoengineered Fc region lacking fucose residues, enhancing its binding affinity to FcγRIIIA on immune effector cells and thereby increasing its activity.

Structure of obinutuzumab and its glycoengineered Fc region [5]

CD20 bispecific antibodies soon followed. Roche developed the world’s first approved bispecific antibody targeting both CD20 and CD3, mosunetuzumab (trade name Lunsumio), which was approved in the EU in June 2022 for adult patients with relapsed or refractory follicular lymphoma who had received at least two prior systemic therapies, and was subsequently approved in the United States, South Korea, and China. Other approved agents include epcoritamab (Epkinly/Tepkinly), jointly developed by Genmab and AbbVie, and Roche’s glofitamab (Columvi). Clinical-stage programs include GB261 from Genor Biopharma and CM355 (ICP-B02) developed by KeyMed Bio in collaboration with InnoCare Pharma. Epcoritamab is administered subcutaneously, significantly improving patient compliance. Glofitamab employs a “2+1” structural design that enhances tumor selectivity and T-cell-directed cytotoxicity; GB261 features lower CD3 affinity and preserved Fc function, reducing the risk of nonspecific T-cell activation while balancing safety and efficacy.

Mechanism of action of the CD20×CD3 T-cell engager bispecific antibody GB261 [6]

Due to the relatively low internalization efficiency of CD20, few antibody–drug conjugates (ADCs) have been disclosed. However, CD20 shows promise in other therapeutic modalities such as trispecific antibodies and CAR-T therapies, attracting broad industry interest. Trispecific programs include CMG1A46 from Chimagen Biosciences (CD20×CD19×CD3; Phase I; licensed to GSK in October 2024 for up to USD 850 million), JNJ-80948543 from Johnson & Johnson (CD20×CD79b×CD3; Phase I), and AZD5492 from AstraZeneca (CD20×CD8×CD3; Phase I/II). CAR-T programs include U16 injection from Unicar-Therapy (Phase I/II) and KJ-C2219 from CARsgen Therapeutics (Allogenic CAR-T; first IIT dosing completed).

Overall, CD20-targeted oncology therapies have evolved from mature monoclonal antibodies exemplified by rituximab to a comprehensive landscape harboring bispecific antibodies, trispecific antibodies, and CAR-T therapies. Future innovation and competition are most likely to focus on further optimization of administration routes, depth of response, safety, specificity, and accessibility.

CD20-Targeted Therapies for Autoimmune Diseases

Interestingly, a number of CD20 monoclonal antibodies originally developed for oncology have been extended to autoimmune indications. Despite obinutuzumab for SLE, other approved mAbs include rituximab (for rheumatoid arthritis, granulomatosis with polyangiitis, and others), ocrelizumab (Ocrevus) for relapsing or primary progressive multiple sclerosis, and ofatumumab for relapsing multiple sclerosis. This demonstrates the broad applicability of CD20 antibodies in regulating aberrant B-cells, making them effective not only in cancer but also in autoimmune disease intervention.

B-cell depletion therapeutic strategies in autoimmune diseases and related therapies [4]

In contrast to oncology, CD20 bispecific antibodies for autoimmune diseases do not aim for potent T-cell–mediated cytotoxicity. Instead, they achieve controllable modulation of abnormal B-cells by engaging inhibitory immune receptors or B-cell survival pathways. As a result, strong activation signals such as CD3 are generally avoided, with greater emphasis on pairing CD20 with targets such as CD19 or BAFF to reduce safety risks and accommodate the long-term treatment needs of chronic diseases. For example, HB2198 developed by Hinge Bio combines Fab fragments derived from rituximab and huFMC63 in a single molecule to achieve bivalent binding to CD20 and CD19. Compared with single antibodies, this approach enables more complete depletion of B-cells, including memory B-cells [7], and is currently being advanced in clinical trials for SLE and other diseases. Take a look at our other blog on BAFF and APRIL in autoimmune diseases to learn more about this therapeutic landscape.

Structure of the CD20×CD19 bispecific antibody HB2198 [7]

The bispecific field has also seen the emergence of novel modalities such as MCEs (Myeloid Cell Engagers). Compared with T-cell engagers (TCEs), the key advantage of MCEs is that they do not directly activate T-cells but instead gently modulate immune responses or recruit other effector cells such as macrophages and dendritic cells. This allows efficient and targeted B-cell depletion while reducing the risk of systemic cytokine release, resulting in lower toxicity and greater controllability.

A representative example is DR-0201 from Dren Bio, a bispecific antibody that simultaneously binds CD20 and Dectin-1. The CD20 targeted arm is derived from rituximab, while the Dectin-1 targeted arm adopts an scFv format, with Knob-into-Hole technology used to prevent heavy-chain mispairing. DR-0201 is currently in Phase I clinical trials for lupus erythematosus, Sjögren’s syndrome, inflammatory myopathies, and systemic sclerosis. In March 2025, Sanofi acquired DR-0201 with an upfront payment of USD 600 million plus up to USD 1.3 billion in milestone payments. In December 2025, Sanofi further expanded its collaboration with Dren Bio, providing an additional USD 100 million upfront payment, with Dren Bio eligible to receive up to USD 1.7 billion in development, regulatory, and commercial milestones.

Structure of the CD20×Dectin-1 bispecific antibody DR-0201 (MCE) [8]

Other therapeutic modalities are also being actively explored. Representative examples include Mustang Bio’s CAR-T therapy MB-106 (with an indication shift from hematologic malignancies to autoimmune diseases) and ADI-001, an allogeneic CAR-γδ T-cell therapy developed by Adicet Bio (Phase I) [9].

The elegant transition of CD20 from oncology to autoimmunity highlights the tremendous potential of this target and demonstrates that classic targets can create new value through deeper exploration. Autoimmune diseases are typically chronic and highly prevalent, with patient populations far exceeding those of specific B-cell lymphomas. The success of CD20 therapies in autoimmune diseases confirms that B-cells are not merely antibody factories but key disease drivers. This has reshaped our understanding of autoimmune pathogenesis, expanding the focus from T-cells alone to the interplay between T-cells and B-cells, and continues to drive the development of new therapeutic approaches.

KACTUS Recombinant CD20 Proteins

To support CD20-targeted drug development, KACTUS provides high-quality recombinant CD20 protein products, including recombinant CD20 extracellular domain proteins as well as full-length CD20 in VLP and Nanodisc formats. These products are suitable for a wide range of drug development applications. Inquiries are welcome.

Data examples:

Immobilized Human Human CD20 VLP at 5ug/ml (100ul/well) on the plate. Dose response curve for Ofatumumab, hFc Tag with the EC50 of 3.8ng/ml determined by ELISA.

Immobilized Biotinylated Human CD20 Nanodisc, His Tag at 2ug/ml (100ul/well) on the streptavidin precoated plate (5ug/ml). Dose response curve for Ofatumumab, hFc Tag with the EC50 of 30.8ng/ml determined by ELISA.

Product list: 

 

References:

[1] https://www.gazyva.com/first-line-fl/about-gazyva/how-gazyva-works.html 

[2] The Evolution of Anti-CD20 Treatment for Multiple Sclerosis: Optimization of Antibody Characteristics and Function. doi: 10.1007/s40263-025-01187-3.

[3] Anti-CD20–mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives. doi: 10.1016/j.kint.2019.12.025.

[4] B Cell–Directed Therapy in Autoimmunity. doi: 10.1146/annurev-immunol-083122-044829.

[5] Obinutuzumab in hematologic malignancies: lessons learned to date. doi: 10.1016/j.ctrv.2015.07.003.

[6] https://genorbio.com/media/1382/poster-number-1719.pdf

[7] Anti-CD19/CD20 bispecific antibody with dual Fc domains mediates enhanced effector functions and durable depletion of memory B cells in vivo. doi: 10.1038/s41598-025-16461-z.

[8] WO2023196785A1

[9] Allogeneic CD20-targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B-cell lymphoma models. doi: 10.1002/cti2.1373. eCollection 2022.

[10] A Study to Evaluate the Efficacy and Safety of Obinutuzumab in Participants With ISN/RPS 2003 Class III or IV Lupus Nephritis (REGENCY) - Clinical trial summary.

[11] https://www.roche.com/media/releases/med-cor-2025-11-03