A novel anti-CD38 monoclonal antibody, CM313, has demonstrated a manageable safety profile and encouraging early clinical efficacy in patients with systemic lupus erythematosus (SLE), according to results from a phase Ib/IIa study published recently in Signal Transduction and Targeted Therapy.
SLE is a chronic autoimmune disease characterized by the production of pathogenic autoantibodies that drive inflammation and multi-organ damage. Because autoantibody levels often correlate closely with disease activity, antibody-secreting plasma cells have long been considered an attractive therapeutic target. However, these cells, particularly long-lived plasma cells, are difficult to eliminate with existing treatments. CD38 is a transmembrane glycoprotein expressed at high levels on plasmablasts and plasma cells, as well as on other activated immune cells, and has therefore emerged as a promising target.
CM313 is a next-generation anti-CD38 monoclonal antibody engineered to eliminate CD38-expressing cells through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. Preclinical studies demonstrated potent activity against pathogenic CD38-positive cells comparable to the established anti-CD38 antibody daratumumab. Earlier clinical studies showed that CM313 had a tolerable safety profile and sustained efficacy in patients with relapsed or refractory multiple myeloma and immune thrombocytopenia, supporting its further evaluation in autoimmune diseases.
The phase Ib/IIa trial enrolled 40 patients with SLE between October 2022 and March 2024. Participants were sequentially assigned to one of four ascending dose cohorts of 2, 4, 8, or 16 mg/kg and randomized in a 4:1 ratio to receive intravenous CM313 or placebo on days 1, 29, 36, 43, and 50.
Adverse events were reported in 90.6% of patients receiving CM313 and in 62.5% of those receiving placebo, with all events classified as mild or moderate. Upper respiratory tract infections occurred more frequently in the higher-dose CM313 groups. Urinary tract infections were observed only in the 8 mg/kg and 16 mg/kg cohorts. A single case of Herpes zoster was reported in the 8 mg/kg group.
Biological markers of disease activity improved more substantially in patients treated with CM313 than in those receiving placebo. These included greater reductions in anti–double-stranded DNA antibodies and immunoglobulin levels, along with increases in complement components C3 and C4. Clinical response rates assessed using the SLE Responder Index-4 at day 57 increased in a dose-dependent manner, reaching 62.5% and 71.4% in the 8 mg/kg and 16 mg/kg groups, respectively, compared with 37.5 percent in the placebo group.
Unlike most existing SLE therapies, which act upstream by broadly suppressing immune activation or modulating B-cell survival and interferon signaling, CM313 directly targets CD38-expressing plasmablasts and plasma cells, the primary source of pathogenic autoantibodies. This downstream mechanism may enable deeper control of autoantibody-driven disease, particularly in patients with refractory lupus, and could reduce reliance on prolonged high-dose corticosteroid therapy.
Although the findings are preliminary, they suggest that CD38-directed plasma cell depletion may represent a promising therapeutic strategy for SLE. Larger and longer-term studies will be required to confirm the durability of response, further characterize safety, and define the role of CM313 in the evolving treatment landscape of lupus.
References
- Zhao J, Lin C, Xie Q, Shu Q, Cui Y, Luo H, Fan W, Huang A, Zhao Y, Fu Z, Xie C, Wu H, Yang N, He L, Feng P, Zhang T, Zhou H, Liu W, Hou Q, Mao X, Sun J, Chen B, Zeng X. Anti-CD38 monoclonal antibody CM313 for systemic lupus erythematosus: a randomized, double-blind, placebo-controlled phase Ib/IIa trial. Signal Transduct Target Ther. 2025 Nov 26;10(1):383.
- Chen Y, Xu Y, Li H, Sun T, Cao X, Wang Y, Xue F, Liu W, Liu X, Dong H, Fu R, Dai X, Wang W, Ma Y, Song Z, Chi Y, Ju M, Gu W, Pei X, Yang R, Zhang L. A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia. N Engl J Med. 2024 Jun 20;390(23):2178-2190.