Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05845762 |
Other study ID # |
Obinutuzumab-IMN |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
July 2023 |
Est. completion date |
December 2023 |
Study information
Verified date |
May 2023 |
Source |
Qianfoshan Hospital |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical Trial Summary
To observe the efficacy and safety of obinutuzumab in Chinese population with idiopathic
membranous nephropathy and guide clinical management.
Description:
Membranous nephropathy (MN) is currently a common histopathological type of adult nephrotic
syndrome in China. Its typical feature is the thickening of glomerular basement membrane
caused by subepithelial immune complex deposition (mainly IgG and C3). Its prevalence rate in
China is increasing year by year, and it has exceeded IgA nephropathy (34.1%) to become the
primary glomerular disease with the highest incidence rate. 1. MN can occur at any age and is
more common between the ages of 50 and 60. Male to female ratio is 2:1. Primary MN is more
common, accounting for about 70%, and secondary MN accounts for about 30%. 40% to 50% of
untreated patients with persistent nephrotic syndrome eventually progress to end-stage renal
disease (ESRD). The treatment of MN includes symptomatic support therapy without
immunosuppressants [controlling blood pressure, lowering urinary protein levels, using
angiotensin converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs),
etc.] and immunosuppressive therapy. The KDIGO Clinical Practice Guide for Glomerular
Diseases in 2021 points out that risk stratification is carried out according to the
glomerular filtration rate, serum albumin, urinary protein quantification, anti phospholipase
A2 receptor antibody and other indicators of patients, and hormone+cyclophosphamide,
hormone+CNIs, or rituximab (CD20 monoclonal antibody) and other treatments are selected
according to the degree of risk. In clinical application, alkylating agents have significant
toxic side effects, including bone marrow suppression, infection, gonadal suppression, and
tumor risk. After 6 to 12 months of treatment with CNIs, 70% to 85% of MN patients can
achieve CR or PR. However, the high recurrence rate (40%~50%) is a common problem for
patients receiving this regimen, and the risk of chronic nephrotoxicity cannot be
underestimated. In recent years, research has found that autoantibodies against the
phospholipase A2 receptor (PLA2R) on glomerular podocytes can be detected in most MN
patients, while a few patients have antibodies against the platelet reactive protein 7A
domain (THSD7A). The possible mechanism is that the antibodies bind to podocyte surface
antigens PLA2R or THSD7A, forming immune complexes under glomerular epithelial cells,
damaging the glomerular filtration barrier, and subsequently causing proteinuria. These major
breakthroughs indicate that primary MN is an autoimmune disease targeting podocytes. The
pathogenic role of B cells producing autoantibodies in MN is gradually being recognized,
providing strong evidence for the treatment of MN with rituximab (RTX). RTX is a human mouse
chimeric monoclonal antibody that specifically targets the surface antigen CD20 of B cells.
CD20 is a transmembrane phosphoprotein expressed on the membrane surface of most early and
mature B cells. RTX binds to CD20 and consumes CD20+B cells through three ways: antibody
dependent cell mediated cytotoxicity, complement dependent cytotoxicity, and direct induction
of cell apoptosis. In 2021, the first CD20 monoclonal antibody, rituximab, has been included
in the KDIGO guidelines for the clinical treatment of idiopathic membranous nephropathy.
However, after seeking medical evidence and clinical work, it has been found that rituximab
has a clinical remission rate of 60% in the treatment of idiopathic membranous nephropathy,
with about 40% of patients still unresponsive and a high recurrence rate. Researchers are
hoping for more treatment options.
Obinutuzumab is a new generation of humanized CD20 monoclonal antibody, which has been
confirmed to be stronger than rituximab in vitro B-cell toxicity tests. Otuzumab targets an
epitope on CD20 different from that recognized by rituximab, which can cause greater
apoptosis of B cells. Modification of the glycan tree structure of the Fc fragment leads to
an increase in its affinity for FcgRIII, thus enhancing antibody dependent cytotoxicity
through natural killer cell, and enhancing antibody dependent phagocytosis through
macrophages. These B cell depletion mechanisms contrast with the main complement dependent
cytotoxicity of rituximab. During combined chemotherapy, it has been found that rituximab is
more effective in treating certain B-cell malignant tumor patients. Based on these data,
altuzumab has become a powerful choice for the new treatment of MN patients. At present,
there are only two single center reports abroad with limited data on the experience of
treating MN with atozumab, and the results are encouraging. Therefore, the investigators are
preparing to conduct a retrospective study on the efficacy of atozumab in the treatment of
idiopathic membranous nephropathy at our center, with the aim of providing reference for
clinical practice.
3、 Test basis In recent years, the discovery of multiple antibodies has confirmed that
idiopathic membranous nephropathy is an autoimmune disease, and the production of
autoantibodies by B cells has induced the occurrence of idiopathic membranous nephropathy.
The first CD20 monoclonal antibody, rituximab, has been used to treat idiopathic membranous
nephropathy and has been included in the 2021 KDOGI guidelines. Otuzumab and rituximab are
both CD20, which is different from the human mouse chimerism technique of rituximab. Otuzumab
is a fully humanized product, and its mechanism of action is superior to rituximab. Current
clinical studies on B lymphocytes have also confirmed the superior therapeutic effect of
altuzumab over rituximab, and individual case reports from individual centers have also
confirmed the effectiveness of altuzumab in idiopathic membranous nephropathy.