HKeyBio Industry Commentary

CD47 and CD20 Bispecific Therapies from SLE to Broader Autoimmune Indications

Autoimmune Disease Targets and Models | Series 50

Originally published in Chinese on January 29, 2026. This commentary reflects information available as of January 29, 2026.

Overview

As the molecular basis of systemic lupus erythematosus (SLE) becomes better defined, therapies targeting interactions between B cells and innate immune effector cells have attracted interest. CD47 × CD20 bispecific antibodies combine CD20-mediated localization to B cells with inhibition of the CD47–SIRPα “do not eat me” checkpoint. Where the antibody architecture and Fc function permit, this may facilitate macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Their potential extends beyond SLE to other disorders involving pathogenic B cells, but disease-specific benefit must be demonstrated.

01 Molecular Characteristics and Mechanism of Action

CD47, CD20 and bispecific design

CD47 (integrin-associated protein) is a widely expressed immunoglobulin-superfamily membrane glycoprotein. Binding to signal regulatory protein α (SIRPα) on myeloid cells transmits an inhibitory signal that helps protect healthy cells from phagocytosis. Because CD47 is also expressed on erythrocytes and many other tissues, systemic CD47 blockade raises important on-target safety considerations.

Figure 1. Overview of CD47-directed antibody activity and potential on-target, off-tumor effects.

CD20 is a nonglycosylated, four-pass transmembrane protein expressed from later stages of B-cell development through mature B cells, but generally absent on terminally differentiated plasma cells. Its stable surface expression has made it an established therapeutic target. Rituximab and ofatumumab demonstrate the clinical value of targeting this compartment. CD47 × CD20 constructs can use different antibody and fusion-protein architectures. IMM0306 specifically combines an anti-CD20 monoclonal antibody with engineered SIRPα domains on its heavy chains, rather than two conventional antibody-binding arms. Geometry, affinity and Fc engineering shape target selectivity and effector activity. [1]

Macrophage engagement and downstream effects

A CD20-binding component anchors the molecule to the B cell. CD47 binding interrupts the inhibitory interaction with macrophage SIRPα, while an effector-competent Fc engages activating Fcγ receptors, including FcγRIIA and FcγRIIIA. Together, checkpoint blockade and Fc-receptor activation support antibody-dependent cellular phagocytosis (ADCP). IMM0306 also has preclinical evidence of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity. These effects depend on the construct and experimental setting. [1]

B-cell clearance. Enhanced removal of autoreactive, activated and memory B cells is a principal pharmacodynamic objective.

Autoantibody production. Changes in antinuclear antibodies (ANA) and anti-dsDNA can help assess downstream effects, interpreted alongside CD20-negative plasma-cell persistence.

Clearance of apoptotic material and immune complexes. These outcomes would test whether the intervention also affects sustained autoantigen exposure; they require direct assessment.

Immune environment and tolerance. IL-6, BAFF, regulatory T-cell and regulatory B-cell populations are relevant exploratory readouts for assessing inflammatory and regulatory changes.

Figure 2. General illustration of CD47-directed bispecific immune-effector mechanisms in an oncology setting. The tumor-associated antigen (TAA), tumor cells and T-cell interactions shown are illustrative; this is not a CD47 × CD20-specific autoimmune mechanism diagram.

02 SLE Pathogenesis: From Genetic Susceptibility to Immune Dysregulation

SLE is a chronic multisystem autoimmune disease characterized by impaired self-tolerance, autoantibodies, immune-complex deposition and tissue inflammation. Its heterogeneous presentation results from interactions among susceptibility loci, environmental exposures, hormonal influences and immune-cell networks.

Genetic susceptibility includes more than 150 reported susceptibility loci, with HLA-DR2/DR3, IRF5, STAT4, BLK and BANK1 among the examples linked to immune signaling, type I interferon biology and B-cell activation. Environmental exposures include ultraviolet light, Epstein–Barr virus (EBV), smoking and certain drugs. UV-induced skin-cell death increases autoantigen availability; EBV-associated molecular mimicry is one proposed route to cross-reactive immune responses.

Figure 3. Genetic, immune and organ-level contributors to lupus and clinical management.

Key immune components include autoreactive B cells that escape tolerance, differentiate into antibody-producing cells, present antigen to T cells and release mediators such as IL-6 and lymphotoxin-α. Autoantibodies include anti-dsDNA, anti-Sm and anti-RNP. Dysregulated Th1, Th2 and Th17 responses, together with impaired regulatory T-cell function, contribute to immune imbalance. Immune complexes activate plasmacytoid dendritic cells through TLR7/9-linked pathways, driving type I interferon production. Impaired clearance of apoptotic material prolongs autoantigen exposure. The contribution of CD47 expression in individual cell populations is a further research question.

Figure 4. Selected innate and adaptive pathways involved in SLE.

These reinforcing pathways can sustain a cycle of autoantigen exposure, immune activation, tissue injury and further antigen release. A CD47 × CD20 approach aims to combine targeted B-cell depletion with modulation of the phagocytic checkpoint; it should not be assumed to remove every source of pathogenic autoantibodies, particularly long-lived CD20-negative plasma cells.

03 Development Landscape: CD47 × CD20 in Autoimmune Disease

As of January 29, 2026, no CD47 × CD20 bispecific therapy had been approved for an autoimmune indication. ImmuneOnco’s amulirafusp alfa (IMM0306; IMC-002), a clinical-stage bispecific fusion protein, offers an early example of this approach. At ACR Convergence 2025, the company presented an open-label phase Ib/II SLE study. Its subsequent October 31 update reported results through September 10, 2025: week-24 SRI-4 responses were observed in 5/7 evaluable patients at 0.8 mg/kg and 4/5 at 1.2 mg/kg. B-cell depletion and improvements in disease activity and biomarkers supported further development; the 1.6 mg/kg cohort was being studied. [2]

Among 19 participants in the company update, 14 reported treatment-related adverse events. Two experienced grade 3 or higher transient thrombocytopenia, resolving within 4–5 days without intervention. No serious treatment-related adverse events, dose-limiting toxicity, CRS or significant infectious events were reported in that update. These early observations support continued evaluation of activity, response durability and safety in larger cohorts. [2]

Development status differs by indication. SLE was being evaluated in a phase Ib/II program; company materials described NMOSD development as phase Ib. In oncology, a phase III protocol for relapsed/refractory follicular lymphoma had received CDE clearance in November 2025. Clearance of a protocol and initiation of a trial are distinct milestones. [2,3]

04 Potential Indications and Translational Model Selection

Rheumatoid arthritis (RA)

B cells contribute to rheumatoid factor and anti-citrullinated protein antibody production, antigen presentation and ectopic lymphoid structures in inflamed synovium. Rituximab has established value in selected RA populations, while variable response and relapse create opportunities for further improvement. Combining CD20 targeting with CD47 checkpoint blockade provides a rationale for studying whether macrophage-mediated tissue B-cell clearance can improve joint inflammation and structural outcomes. Relevant studies should compare tissue B-cell depletion, joint pathology and bone erosion with an appropriate anti-CD20 control.

Sjögren’s disease (SjS)

B-cell infiltration of salivary and lacrimal glands and the formation of lymphoid-like structures contribute to Sjögren’s disease (SjS), with gland dysfunction, hypergammaglobulinemia, cryoglobulinemia and elevated lymphoma risk in some patients. Responses to anti-CD20 therapy vary; incomplete tissue B-cell depletion is one proposed explanation. CD47 × CD20 approaches therefore provide a rationale for investigating tissue-resident macrophage activity, B-cell clearance, gland injury and preservation of function. Effects on lymphoma risk require separate evidence.

Autoimmune hemolytic anemia (AIHA)

In autoimmune hemolytic anemia (AIHA), autoantibodies and/or complement promote red-cell destruction, including macrophage clearance of sensitized erythrocytes in the spleen and liver. Anti-CD20 therapy is used in warm AIHA to target B-cell contributions. Mature erythrocytes lack CD20, whereas long-lived antibody-producing plasma cells are also generally CD20-negative. A dual-target strategy aims to enhance B-cell clearance while limiting erythrocyte engagement. IMM0306 showed very low human red-cell binding and no hemagglutination in reported preclinical assays, providing a constructive basis for further evaluation. Anemia, hemolysis and other hematological effects remain essential safety endpoints. [1,4]

Multiple sclerosis (MS)

B cells contribute to multiple sclerosis (MS) through antigen presentation, cytokine signaling, antibody responses and compartmentalized CNS inflammation, including meningeal lymphoid-like structures. Ofatumumab and ocrelizumab demonstrate the clinical value of anti-CD20 treatment in relapsing MS. Tissue access and persistence of CNS-associated B-cell populations motivate investigation of additional approaches. CD47 × CD20 development in this setting should establish relevant CNS exposure, effects on B cells and microglia, and neurological safety before drawing conclusions about disease progression.

IgG4-related disease, ANCA-associated vasculitis and pemphigus are additional B-cell-associated diseases in which indication-specific evaluation could be considered. Their inclusion identifies research opportunities rather than established clinical efficacy of CD47 × CD20 therapy.

HKeyBio model portfolio relevant to the proposed indications

HKeyBio uses a model-development strategy spanning multiple species, strains, mechanisms and disease-course phenotypes. Its disease-model portfolio supports selection of tools aligned with the intended indication and therapeutic question. For IMM0306, published assays reported binding to human and cynomolgus CD47, but not mouse or rat CD47. [1] Rodent models may therefore require a pharmacologically matched surrogate or an appropriate humanized system to evaluate the complete dual-target mechanism. CD20 binding, Fcγ-receptor biology and effector-cell function should also be confirmed.

Selected Model Data

 Figure 5. TLR7 agonist-induced cynomolgus monkey SLE model.

 Figure 6. TLR7 agonist-induced SLE in C57BL/6 mice.

 Figure 7. Collagen-induced arthritis in cynomolgus monkeys.

Figure 8. CIA model in C57BL/6 mice.

Figure 9. MOG1–125-induced B-cell-dependent EAE in C57BL/6 mice.

Figure 10a. Salivary gland protein-induced SjS in mice: functional and tissue endpoints.

Figure 10b. SjS model: serological biomarkers.

Figure 11. DSG3-induced pemphigus model in C57BL/6 mice.

Figures 5–11 illustrate disease-model characteristics and selected treatment responses. Treatment groups shown in these plots should be interpreted according to their respective study protocols; they do not collectively establish efficacy of a CD47 × CD20 therapeutic.

Implications for translational study design

For a CD47 × CD20 program, a mechanism-aligned package should evaluate target binding in relevant species, CD20-dependent selectivity, CD47–SIRPα blockade, Fc-mediated phagocytosis, erythrocyte and platelet safety, tissue B-cell depletion, autoantibodies, cytokines, PK/PD and post-treatment immune reconstitution. Disease-model selection should reflect the target indication and available pharmacologically relevant species.

HKeyBio also offers customized model development for specific program needs and welcomes discussions with partners developing therapies for autoimmune disease.

Author: Muco  |  Scientific review: Ding Ying  |  Editor: Jing Yan

About HKeyBio

HKeyBio is a preclinical contract research organization specializing in in vivo efficacy services for autoimmune disease. Its core technical team has more than 20 years of experience in autoimmune drug development. The company is ISO 9001 certified, with molecular, cellular, pathology, small-animal and analytical testing facilities in Suzhou Industrial Park, and nonhuman primate facilities in Guangxi and Suzhou. HKeyBio has approximately 60 employees, and project leaders hold master’s or doctoral degrees. The team has experience supporting more than 500 investigational new drug (IND) applications and helps partners address complex development and submission questions.

· More than 50 nonhuman primate models of autoimmune disease.

· More than 300 animal models of autoimmune disease.

· Experience supporting more than 500 autoimmune disease IND applications.

References

[1] Yu J, et al. IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα. Leukemia. 2023;37:695–698. Source

[2] ImmuneOnco. Positive progress of amulirafusp alfa in SLE presented at ACR Convergence 2025. October 31, 2025; data cutoff September 10, 2025. Source

[3] ImmuneOnco. Company news: phase III follicular lymphoma protocol clearance, November 27, 2025; autoimmune development presentation, August 2025. Source

[4] Oldenborg PA, et al. CD47–signal regulatory protein α regulates Fcγ and complement receptor-mediated phagocytosis. J Exp Med. 2001;193:855–862. Source

[5] Banchereau R, et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell. 2016;165:551–565. Source

Disclaimer

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