Anti-PLA2R monoclonal antibody, clone CL0474

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Since the moment of animal model creation and the recognition of podocytes damage as a key mechanism of MN development, the identification of antigens, first of all the phospholipase A2 receptor (PLA2R), and the development of methods of PLA2R autoantibodies detection and its monitoring opened a new era in the idiopathic MN (iMN) diagnosis, treatment and prognosis evaluation. MN continues to be actively studied in the new millennium, since a number of aspects of its pathogenesis still need to be clarified, and there is still no clear opinion on the iMN treatment optimal approach. Comprehensive clinical and serological assessment of patients with iMN can be the key to individual choice of treatment protocols. In patients with aPLA2R-positive iMN, the predictor of disease remission is the aPLA2R titer decrease or aPLA2R disappearance in the blood serum, and disease relapse is associated with the aPLA2R appearance ore increase of aPLA2R titer in the circulation. Studies which were conducted by today (GEMRITUX, MENTOR, STARMEN, NICE, etc.) confirmed the acceptable safety profile and effectiveness of iMN therapy by anti-CD20 monoclonal antibodies (rituximab): more than half of of iMN patients had remission of nephrotic syndrome or proteinuria decrease, remissions in anti-CD20 monoclonal antibodies treated patients were longer compared to traditional therapy. The obtained data allows us to consider rituximab and anti-CD20 antibody therapy of a new generation not only as an alternative to the more toxic treatment with cyclophosphane and calcineurin inhibitors, but as an independent promising direction of therapy for patients with IMN, which completely changes the paradigm of treatment of this glomerulopathy.

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.