Signal Transduction and Targeted Therapy | Anti-CD38 monoclonal antibody CM313 for the treatment of systemic lupus erythematosus

This study evaluated the safety, pharmacokinetics, and preliminary efficacy of the anti-CD38 monoclonal antibody CM313 in patients with systemic lupus erythematosus (SLE), finding that CM313 demonstrated good tolerability and significant immunomodulatory effects at doses of 8mg/kg and 16mg/kg, offering a new targeted therapeutic strategy for SLE treatment.

 

Literature Overview

The article, 'Anti-CD38 monoclonal antibody CM313 for systemic lupus erythematosus: a randomized, double-blind, placebo-controlled phase Ib/IIa trial', published in the journal Signal Transduction and Targeted Therapy, reviews and summarizes the results of a phase Ib/IIa clinical trial of the anti-CD38 monoclonal antibody CM313 in patients with systemic lupus erythematosus. The study assessed the safety, pharmacokinetics, pharmacodynamic profile, and preliminary efficacy of CM313 at different doses and provided evidence for its potential therapeutic role in targeting the CD38 pathway.

Background Knowledge

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by multi-organ involvement and the production of autoantibodies, particularly anti-dsDNA antibodies, which are closely associated with disease activity. CD38 is a glycoprotein widely expressed on the surface of various immune cells, such as plasma cells, NK cells, B cells, and T cells, and has multiple immunomodulatory functions. Anti-CD38 monoclonal antibodies, such as daratumumab, have been used in the treatment of multiple myeloma and demonstrate strong plasma cell depletion in vitro. CM313 is a novel anti-CD38 monoclonal antibody with CDC, ADCC, and ADCP activity, having shown favorable safety and efficacy profiles in multiple myeloma and immune thrombocytopenia (ITP). This study aimed to evaluate the safety, pharmacokinetics, and preliminary efficacy of CM313 in SLE patients, providing a foundation for the development of therapies targeting plasma cell-related autoimmune diseases.

 

 

Research Methods and Experiments

This was a multi-center, randomized, double-blind, placebo-controlled phase Ib/IIa clinical trial, which enrolled 40 SLE patients. Patients were divided into four dose groups (2, 4, 8, and 16mg/kg), with 8 patients in each group randomized in a 4:1 ratio to receive either CM313 or placebo via intravenous infusion. Treatment occurred on days 1, 29, 36, 43, and 50. The primary endpoint was safety, while secondary endpoints included pharmacokinetics, pharmacodynamics, and preliminary efficacy. Safety assessments covered adverse events, laboratory tests, vital signs, and electrocardiograms. Efficacy assessments included SELENA-SLEDAI scores, PGA scores, anti-dsDNA antibody levels, immunoglobulin levels, and complement C3/C4 concentrations.

Key Conclusions and Perspectives

• In terms of safety, the incidence of adverse events was 90.6% in the CM313 group and 62.5% in the placebo group, with all events being mild or moderate in severity, and no serious adverse events or treatment discontinuations observed.
• CM313 significantly reduced anti-dsDNA antibody levels and decreased IgG, IgA, IgM, and IgE concentrations at doses of 8mg/kg and 16mg/kg, while increasing complement C3 and C4 levels.
• On day 57 of treatment, the SRI-4 response rates for CM313 were 33.3% (2mg/kg), 40.0% (4mg/kg), 62.5% (8mg/kg), and 71.4% (16mg/kg), all significantly higher than the placebo group (37.5%).
• CM313 exhibited dose-dependent pharmacokinetics in SLE patients, with an extended half-life and increased drug exposure following multiple doses, supporting a once-weekly dosing regimen.
• CD38+ NK cells and plasma cell counts rapidly declined after the first dose and remained suppressed after subsequent doses, indicating that CM313 exerts a sustained impact on immune cells.
• Although the CM313 group had a higher incidence of infections (upper respiratory tract infections, urinary tract infections, and herpes zoster), all events were mild to moderate and manageable.

Research Significance and Prospects

This study represents the first systematic evaluation of the safety and preliminary efficacy of a CD38-targeting monoclonal antibody in SLE patients, laying the groundwork for the application of anti-CD38 therapies in autoimmune diseases. CM313 demonstrated significant immunomodulatory effects at 8mg/kg and 16mg/kg, supporting its potential as a novel therapeutic approach. Further phase II clinical trials (NCT06791772) with larger cohorts and longer follow-up are required to confirm its efficacy and safety in SLE patients, while also exploring the relationship between immune cell reconstitution and disease activity during long-term treatment.

 

 

Conclusion

In summary, the anti-CD38 monoclonal antibody CM313 demonstrated favorable safety and dose-dependent pharmacodynamic characteristics in patients with systemic lupus erythematosus. At doses of 8mg/kg and 16mg/kg, CM313 significantly reduced anti-dsDNA antibody levels and immunoglobulin concentrations while increasing complement C3 and C4 levels, indicating its potential in eliminating pathogenic plasma cells and modulating humoral immunity. Although the incidence of infections was slightly higher in the higher-dose groups, all events were manageable and did not compromise efficacy. This study supports CM313 as a promising new targeted therapy for SLE, with future phase II trials aimed at confirming its efficacy and long-term safety, providing new treatment options for patients with systemic lupus erythematosus.

 

Jiuliang Zhao, Changsong Lin, Qibing Xie, Bo Chen, and Xiaofeng Zeng. Anti-CD38 monoclonal antibody CM313 for systemic lupus erythematosus: a randomized, double-blind, placebo-controlled phase Ib/IIa trial. Signal Transduction and Targeted Therapy.