Primary membranous nephropathy (PMN) is an autoimmune disease that is one of the most common causes of nephrotic syndrome among adults (1). In China, the prevalence of PMN is increasing annually, accounting for 23.4% of cases of nephrotic syndrome, second only to immunoglobulin A (IgA) nephropathy at 28.1% (2, 3). PMN can manifest at any age but is more prevalent among individuals aged 50 to 60 (1), with a male-to-female ratio of 2:1 (4). Although approximately one‐third of PMN patients may achieve spontaneous complete remission (CR) or partial remission (PR) after receiving conservative treatment, the remaining one-third of patients have an elevated risk of disease progression, potentially leading to end‐stage renal disease (ESRD) within 10 years (5).

Currently, the treatment approach for patients with PMN is highly individualized, with experts recommending tailored regimens based on each patient's risk evaluation. The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases recommends that all PMN patients receive optimal supportive care, along with the administration of rituximab (RTX) or cyclophosphamide (CTX) as well as glucocorticoids (GC) every other month for 6 months for patients with at least one risk factor for disease progression (6). In recent years, targeted therapy has emerged as a promising and precise treatment modality, complementing or replacing traditional immunosuppressive therapies and providing a novel avenue for personalized treatment. RTX is a monoclonal antibody that targets the CD20 antigen and specifically binds to the CD20 antigen on the surface of B lymphocytes (7). The vast majority of PMN patients who are treated with RTX achieve either CR or PR, with an overall remission rate of 60% to 80% (8, 9). Despite its favorable efficacy and safety profile, the high cost of RTX has resulted in limited accessibility in China.

Ripertamab (SCT400) is a recombinant human-mouse chimeric anti-CD20 immunoglobulin G1 (IgG1) monoclonal antibody that shares the same amino acid sequence of antigen binding sites and a variable region as RTX, with a single amino acid difference at position 219 of the heavy chain constant region 1 (10). It was approved by the National Medical Products Administration in 2022 for treating B-cell non-Hodgkin lymphoma (NHL). Previous studies have shown that ripertamab has similar pharmacokinetics, pharmacodynamics, immunogenicity, and safety profiles to RTX in Chinese patients with CD20-positive B-cell NHL (10, 11). In a real-world setting, ripertamab has also been utilized in patients with PMN; however, its efficacy and safety for treating PMN has not yet been reported.

Given the potential benefits of ripertamab, we designed this multicenter, retrospective study to evaluate the efficacy and safety of ripertamab for treating PMN among Chinese patients. This study aimed to elucidate the role of ripertamab in managing PMN, and to provide a scientific foundation for its clinical application.

Ripertamab has been used in an off-label manner to manage PMN within clinical settings despite the absence of robust evidence to substantiate its use. This multicenter, retrospective study is the first to examine the effectiveness and safety of ripertamab as a treatment for PMN in the context of Chinese real-world practice. We enrolled a total of 52 PMN patients whose demographic characteristics closely aligned with those reported in previous studies (12–14), thereby providing a certain level of representativeness despite the modest sample size.

Our results indicated that ripertamab was effective in the initial therapy group, with remission rates of 67.9% at 6 months and 86.7% at 12 months. These outcomes are superior to those reported in earlier randomized controlled trials (RCTs). For example, in the MENTOR trial (15), the remission rates of RTX were 35% at 6 months and 60% at 12 months, whereas the RI-CYCLO trial (16) reported remission rates of 51% at 6 months and 62% at 12 months. Our findings are more consistent with those from Chinese retrospective studies, such as those by Wang et al. (67.5% remission at 6 months and 87.5% at 12 months of RTX) (12) and Zhang et al. (48.1% at 6 months and 80.2% at 12 months of RTX) (14). Several factors may explain why our results are superior to those of the RCTs but align with those of the Chinese retrospective studies. First, the RCTs had stricter inclusion criteria, often requiring that 24-h UP levels be measured multiple times before enrollment. Second, patients in RCTs tended to have higher baseline 24-h UP levels, which could make it more challenging to achieve remission. Third, differences in body surface area exist, as Chinese patients generally had lower body mass index and smaller body surface areas than Western patients. Consequently, patients with smaller body surface areas may receive relatively greater drug exposure, potentially leading to superior outcomes.

Compared with the initial therapy group, the non-initial therapy group had a lower remission rate after ripertamab treatment: 41.7% at 6 months and 57.1% at 12 months. In the non-initial therapy group, most patients had previously responded to immunosuppressive therapies (Supplementary material). Therefore, it can be inferred that the low response rate to ripertamab is not attributable to prior treatment failures. Our results are consistent with previous findings related to RTX, such as those reported by Zhang et al. (40% remission at 6 months) (14). A cohort study from Peking University First Hospital also revealed that 41.7% of patients achieved remission with RTX after a median follow-up of 12 months (17). Additionally, a long-term cohort study revealed that 56.3% of patients achieved remission after receiving RTX as second-line therapy, with a median follow-up of 29 months (18). In general, our 12-month remission rate is consistent with those reported in other studies, which supports the efficacy of ripertamab in this context.

With respect to CR, our study revealed that 5.0% of patients achieved CR at 6 months, and 9.1% achieved CR at 12 months. These rates are lower than those reported in the RI-CYCLO trial (8% at 6 months, 16% at 12 months) (16), the study by Zhang et al. (6.2% at 6 months, 25.9% at 12 months) (14) and the study by Wang et al. (5.0% at 6 months, 22.5% at 12 months) (12). The lower CR rate at 12 months in our cohort could be attributed to several factors. First, loss to follow-up: In real-world settings, patients who achieve CR may be less motivated to return for follow-up visits, leading to underreporting of CR rates. Only one of the six patients who achieved CR continued attending follow-up visits, which may explain the observed lower CR rate at 12 months. Second, short follow-up duration: A shorter follow-up period may also limit the detection of CR (19). For example, Dahan et al. suggested that the likelihood of achieving CR increases with longer follow-up (20). In the MENTOR trial (15), although the CR rate was 35% at 6 months, after an extended follow-up period of 17 months, 64.9% of patients treated with RTX were in remission. In our study, 57.7% (30/52) of patients did not complete the 12-month follow-up, further complicating the assessment of remission. Third, differences in treatment modality: In RCTs, patients are typically retreated with RTX at the 6-month mark, regardless of their clinical status (7, 15). In contrast, Chinese clinical practices often rely on additional RTX infusions only when B-cell counts exceed 5 cells/mL or when anti-PLA2R antibody levels remain elevated (12, 21). However, owing to constraints in testing and associated costs, monitoring of B-cell counts and anti-PLA2R antibodies is not routinely conducted in real-world settings, which may contribute to less frequent retreatment and lower CR rates than those reported in RCTs.

A previous meta-analysis demonstrated a statistically significant reduction in 24-h UP and an increase in serum albumin levels post-RTX treatment, with changes recorded at −4.90 g/d and 10.4 g/L, respectively (22). Severe proteinuria is a risk factor for the progression of PMN to ESRD, and urine protein levels are valuable for informing treatment-related decisions (23). While the changes in the serum creatinine level and eGFR were not significant, our findings align with these results, revealing a significant decrease in 24-h UP by 4.16 g/d and an increase in the serum albumin level by 16.3 g/L at 12 months. Similarly, Fiorentino et al. reported significant increases in albumin levels following RTX therapy throughout follow-up (24), a phenomenon correlated with stable renal function, which is consistent with outcomes from other studies (18, 25).

In terms of safety, ripertamab was generally well tolerated, with no major safety concerns reported. The incidence of AEs in our study was lower than that reported in previous RTX-related studies, which reported rates ranging from 22% to 80% (12–15). This discrepancy may stem from the nature of real-world studies, where some minor or nonurgent AEs might not be documented. Notably, infusion reactions, which are the most common type of AEs reported in previous studies, were relatively infrequent in our cohort. This may be attributed to the prophylactic use of antiallergic medications prior to infusion and a carefully controlled infusion rate aimed at mitigating infusion-related events. However, we cannot entirely rule out the possibility that some AEs were undetected due to the limited sample size and short duration of follow-up. Overall, the favorable safety profile of ripertamab supports its use as a viable therapeutic option for this patient population.

The treatment of PMN typically involves the combination of GC with an immunosuppressive agent, such as CTX, tacrolimus or RTX. A meta-analysis suggested that the combination of GC and CTX remained one of the most effective treatment regimens, with a remission rate of 77.4% (26). This approach is specifically preferred for patients with renal insufficiency or those with renal vascular lesions (26, 27). Additionally, tacrolimus alone or when in combination with GC, can also lead to remission of PMN. Recent studies showed that tacrolimus combined with a small dose of GC demonstrated a favorable therapeutic effects, with a remission rate of 86.7% at 6 months, but with fewer side effects (28). Our study using ripertamab to treat PMN has also yielded comparable therapeutic outcomes with minimal AEs. As previously mentioned, RTX has been proven to be effective in the treatment of PMN, and recent studies suggested that RTX treatment in patients with HCV infection does not exacerbate its infection, thus safe for such patients (29). Additionally, Zhu et al. reported that RTX combined with traditional Chinese medicine can further aid in the remission of nephropathy (30). Our study’s findings show that ripertamab has a comparable effect to RTX in treating PMN. However, whether it has the same effects in the aspects mentioned above remains to be confirmed by further studies.

Ripertamab specifically binds to B cell surface CD20 antigen, and effectively eliminates CD20-positive B-cell through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and direct growth inhibition (31). The molecular mechanisms underlying the efficacy of ripertamab in PMN may involve multifaceted immunomodulatory pathways targeting B-cell-driven autoimmunity. Through B-cell depletion, anti-CD20 monoclonal antibody could directly reduces the production of pathogenic autoantibodies against podocyte antigens such as PLA2R and thrombospondin type-1 domain-containing 7A (THSD7A) (32, 33). This depletion extends beyond circulating B cells to include tissue-resident B cells and short-lived plasmablasts within the kidney, thereby attenuating immune complex deposition in the glomerular subepithelial space (34, 35). Additionally, anti-CD20 therapy disrupts B-cell-mediated antigen presentation to T cells, impairing the activation of autoreactive T helper cells (like the T helper cell 17) and promoting regulatory T-cell expansion, which collectively restore immune tolerance (36, 37). Complement system modulation is another critical mechanism: B-cell depletion reduces circulating levels of C5b-9 membrane attack complexes, thereby mitigating podocyte injury and preserving nephrin expression (38, 39).

This study had several limitations that should be acknowledged. The retrospective nature of this study introduces selection bias. The primary limitations include the relatively small sample size and short duration of follow-up. Furthermore, the potential for bias inherent in a single-arm study focused on a specific treatment option. Owing to constraints in testing and associated costs, critical indicators such as PLA2R antibody levels and B lymphocyte counts could not be consistently monitored, which hampers statistical analysis and diminishes the study's overall credibility. In addition, Chinese patients with kidney disease are often treated with Chinese medicines, and the inability to access this information makes it impossible to assess the impact of Chinese medicines on the efficacy of ripertamab. Despite these limitations, our study contributes valuable insights into the disease landscape and the application of ripertamab in treating PMN.

The results of this real-world study revealed that ripertamab achieved a high remission rate in patients with PMN, and the initial therapy group had a higher remission rate than did the non-initial therapy group and achieved remission sooner. Ripertamab notably reduced 24-h UP levels and increased serum albumin level. Additionally, ripertamab was generally well tolerated, with a low incidence of AEs. These findings suggest that ripertamab offers significant clinical benefits for patients with PMN, positioning it as a recommended treatment option in this patient cohort. However, as this was a retrospective study, further prospective, large-sample studies should be performed to evaluate the long-term effectiveness and safety of ripertamab for the treatment of PMN. Further research will help solidify the role of this drug in the management of PMN and enhance our understanding of its potential as a therapeutic alternative.