Membranous nephropathy (MN) - the leading cause of nephrotic syndrome (NS) in adults - is an immune-mediated disease that results from the deposition of immunoglobulins and complement components onto the sub-epithelial layer of the glomerular capillary wall. The availability for clinical use of rituximab, a monoclonal antibody against the B-cell surface antigen CD20, offered the opportunity to test the effects of specific CD20-targeted intervention aimed to prevent B-cell dependent mechanisms resulting in the production of nephritogenic autoantibodies. Rituximab-induced B-cell depletion reduced proteinuria in eight patients with MN while avoiding the adverse effects of steroids and other immunosuppressants. Subsequent studies confirmed that rituximab is remarkably safer than non-specific immunosuppressive agents, including cyclosporine, and achieves remission in approximately two-thirds of patients with MN-associated nephrotic syndrome. After rituximab-induced remission, however, NS may relapse in approximately one third of patients. Thus, novel therapeutic options are needed for a substantial proportion of patients with MN who may fail rituximab therapy. Conceivably, in patients with MN refractory to CD20-targeted therapy, the production of nephritogenic autoantibodies is sustained by mechanisms that do not depend on autoreactive CD20+ B cells. Recently, it was shown that CD19-negative bone marrow plasma cells, which express CD38, are enriched in chronically inflamed tissue and secrete autoantibodies. Treatment of patients with MN with CD38-targeting antibodies may represent a new therapeutic approach. MOR202 is a fully human recombinant monoclonal antibody against CD38 that has demonstrated in-vitro and in-vivo efficacy in experimental models of multiple myeloma. Antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis are the principal mechanisms of action for MOR202-induced lysis of myeloma cells. The working hypothesis is that CD38-targeted therapy with MOR202 may abrogate autoantibody-dependent mechanisms in patients with plasma-cell mediated forms of MN who failed previous treatment with rituximab and second-generation anti-CD20 monoclonal antibodies such as ofatumumab. With this background, MOR202 therapy may have an indication for patients with MN and NS resistant to CD20 targeted therapy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
Each patient will be treated for 24 weeks and received a total of 9 doses. During the first treatment cycle, MOR202 will be administered weekly. For the following 5 months, patients will receive one dose every 4 weeks.
ASST HPG23 - Unità di Nefrologia
Bergamo, BG, Italy
Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò"
Ranica, BG, Italy
Change in 24-hour urinary protein excretion
Time frame: Changes from screening and baseline, 1, 5,6,9,12,18 and 24 months after the first MOR202 administration.
Complete remission or partial remission of nephrotic syndrome.
Complete remission is intended as : 24-hour urinary protein excretion \<0.3 g or urinary protein to creatinine ratio \< 300 mg/g, with serum albumin \> 3.5 g/dL. Partial remission is intended as: 24-hour urinary protein excretion \<3.5 g or urinary protein to creatinine ratio \< 3500 mg/g, with at least 50% reduction compared to baseline.
Time frame: Changes from screening and baseline, 1, 5,6,9,12,18 and 24 months after the first MOR202 administration.
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