Gazyva: New Drug Gets Breakthrough Status
Background
Membranous nephropathy (MN) is a leading cause of kidney damage in nondiabetic adults and is highly associated with malignancy, characterization of cancer7. Left untreated, two-thirds of patients with MN can develop nonprogressive chronic kidney disease or progress to end-stage renal disease in 10 years. The recognition of MN as an autoimmune disease has paved the way for the use of anti–B-cell therapy in its eradication. B-cells are a type of white blood cell responsible for creating antibodies that trap specific invading viruses and bacteria2. The major goal of B-cell depletion therapy is to destroy any malignant B lineage cells or autoimmune disease-producing B-cells in patients with cancers or autoimmune diseases while retaining protective B-cell immunity. Over the last decade, Rituximab has been used to treat MN. However, 40% of patients with MN do not respond to Rituximab9. Potential reasons for non-responsiveness include different ligand concentrations in patients suffering from proteinuria and protein polymorphisms that cause an imbalance of activation signals to the B-cells. Therefore, there is an urgent need for additional treatment options for patients with MN1.
Figure 1: Membranous glomerulopathy and membranous nephropathy (MN) are used interchangeably. This diagram demonstrates how immune complexes deposit in the kidney. Antibodies (Y-shaped, black in the picture) in the bloodstream attach to antigens (triangles, black in the picture) and form immune complexes that build up between the layers of the filter (glomerulus). These immune complexes activate the immune system, causing inflammation. Immune complex buildup and inflammation cause the filter to stop working properly and can lead to MN
Genetics/Pathophysiology:
Studies have described an unusual genetic architecture of MN, with four loci and their genetic interactions accounting for nearly one-third of the disease risk. Research demonstrates dysregulation of NFKB1 and IRF4 genes in the disease pathogenesis, providing genetic support for individuals suffering from primary MN3. These genes produce proteins that play a key role in regulating the immunological responses to infections. The dysregulation of NFKB1 increases the severity of injuries within the glomerulus, the microscopic filters located within the nephrons of our kidney, and is associated with increased levels of proteins in the urine and persistent pro-inflammatory gene expression5. Increased IRF4 gene activation can have a dual role in driving MN by altering immune cell biological responses and modulating the response of resident renal cells to injury. It does so by provoking chronic intrarenal inflammation, and epithelial cell loss2.
Previous research:
Rituximab is an antibody targeting glomerular subepithelial IgG deposits of B-cells. (CD19+/CD20+ cells) are proteins found on immature malignant B-cells, and are primarily responsible for the onset of MN. Rituximab therapeutic properties allow it to get rid of these deposits by disintegrating these cells. Rituximab is now used in many auto-immune diseases including MN, with a viable track record of tolerability in comparison to more conventional treatment regimens such as cyclosporin9. Rituximab induced clinical remission in 60–80% of patients with primary MN in several non-randomized studies and its efficacy was established in a past controlled study after an extended follow-up. Rituximab efficacy increases with regimens using high doses (1-2 g) with 67% of remission at month-6 vs. low doses (375 mg-1 g) with 33% of remission at month-68. While Rituximab efficacy seems to be well-established in MN, many factors could modify Rituximab response. Rituximab efficiency is largely variable among patients, related to genetic factors or disease, which could impact B-cell disintegration and clinical response. Rituximab may be lost in the urine of nephrotic patients and close monitoring of Rituximab residual level could help to retreat patients underexposed to Rituximab after a first line2. Some cases of resistance have been reported by noticing an uptick of CD20+ expression after repeated Rituximab therapies. Moreover, monoclonal antibodies released as a result of Rituximab adherence to cell membranes can elicit antidrug antibodies, which may interfere with the overall therapeutic response. Avoiding unnecessary re-exposure to Rituximab is cost-saving and may limit the production of antibodies that may increase the risk for adverse reactions and prevent re-treatment of disease recurrences5.
Current research and New Findings:
Obinutuzumab (Gazyva) is a type II anti-CD20+ antibody that has superior in vitro B-cell cytotoxicity compared with Rituximab. Obinutuzumab can evoke a greater B-cell apoptotic response. Obinutuzumab leads to an increased affinity to FcgRIII proteins due to a more exposed binding site and, thereby, causes antibody-dependent cellular cytotoxicity at a higher rate compared to Rituximab4. These FcgRIII, found on the surface of white blood cells, are immune receptors that have a primary role in controlling inflammation. The binding is critical for down-regulating kidney inflammation and fibrosis. Particularly, the mechanism involves Obinutuzumab binding to the IgG segment of FcgRIII proteins, activating a downstream mechanism for the effective control of inflammation and responses to infection. The use of Rituximab induces the redistribution, rather than depletion, of CD20+ into lipid rafts (assemblies of proteins and lipids that float within cellular membranes), which is not noted with Obinutuzumab6. Therefore, Obinutuzumab is more effective at inducing B-cell death via FcgRIII-dependent programmed cell death. However, it is important to note some of the limitations of the study1. These include having a small sample size, retrospective non-protocoled nature, and the lack of a control arm. The researchers also did not confirm peripheral CD19+ or CD20+ B-cell concentration that could potentially influence the final count. Therefore, Obinutuzumab was concluded to be efficacious in reducing proteinuria (elevated levels of proteins in urine) in patients with mild tissue damage from MN8.
Future Directions:
CD20+ B-cells is an appropriate strategy in treating patients with MN, and lack of response to Rituximab may be due to incomplete B-cell depletion because peripheral CD19+ cell count may not be the best marker to ensure that B-cells are depleted. Notably, the effect of Obinutuzumab was long-lasting, particularly in patients 1 and 3 (in the case study), both of whom have remained in clinical remission 18 to 24 months after 1 course. The true impact of the drug’s efficacy as a first-line treatment in patients with MN or patients with a limited response or frequent relapses after initial immunosuppressive therapy should be evaluated through randomized and well-powered clinical trials7. Whether patients with high antibody counts associated with MN should be treated initially with Obinutuzumab needs to be further investigated in a prospective randomized trial. For now, it is proposed that patients with MN who do not achieve appropriate immunologic remission with Rituximab may be considered as candidates for Obinutuzumab treatment down the line, especially patients whose PLA2R antibody (circulating antibody detected in over 85% of patients with MN, induced by B-cell immune responses) counts fail to decline adequately with Rituximab treatment6.
Ayush Suri
Works Cited
1. Said, R., & Tsimberidou, A. (2017). Obinutuzumab for the treatment of chronic lymphocytic leukemia and other B-cell lymphoproliferative disorders. Expert Opinion On Biological Therapy, 1-8. doi: 10.1080/14712598.2017.1377178
2. Boyer-Suavet, S., Andreani, M., Lateb, M., Savenkoff, B., Brglez, V., & Benzaken, S. et al. (2020). Neutralizing Anti-Rituximab Antibodies and Relapse in Membranous Nephropathy Treated With Rituximab. Frontiers In Immunology, 10. doi: 10.3389/fimmu.2019.03069
3. Sethi, S., Kumar, S., Lim, K., & Jordan, S. (2020). Obinutuzumab is Effective for the Treatment of Refractory Membranous Nephropathy. Kidney International Reports, 5(9), 1515-1518. doi: 10.1016/j.ekir.2020.06.030
4. Lionaki, S., Marinaki, S., Nakopoulou, L., Skalioti, C., Iniotaki, A., & Sfikakis, P. et al. (2013). Depletion of B Lymphocytes in Idiopathic Membranous Glomerulopathy: Results from Patients with Extended Follow-Up. Nephron Extra, 3(1), 1-11. doi: 10.1159/000345487
5. Remuzzi, G., Chiurchiu, C., Abbate, M., Brusegan, V., Bontempelli, M., & Ruggenenti, P. (2002). Rituximab for idiopathic membranous nephropathy. The Lancet, 360(9337), 923-924. doi: 10.1016/s0140-6736(02)11042-7
6. Klomjit, N., Fervenza, F., & Zand, L. (2020). Successful Treatment of Patients With Refractory PLA2R-Associated Membranous Nephropathy With Obinutuzumab: A Report of 3 Cases. American Journal Of Kidney Diseases, 76(6), 883-888. doi: 10.1053/j.ajkd.2020.02.444
7. Weiner, G. (2003). Rituximab: complementary mechanisms of action. Blood, 101(3), 788-788. doi: 10.1182/blood-2002-12-3676
8. Bomback, A., Derebail, V., McGregor, J., Kshirsagar, A., Falk, R., & Nachman, P. (2009). Rituximab Therapy for Membranous Nephropathy: A Systematic Review. Clinical Journal Of The American Society Of Nephrology, 4(4), 734-744. doi: 10.2215/cjn.05231008
9. Cravedi, P., Ruggenenti, P., Sghirlanzoni, M., & Remuzzi, G. (2007). Titrating Rituximab to Circulating B Cells to Optimize Lymphocytolytic Therapy in Idiopathic Membranous Nephropathy. Clinical Journal Of The American Society Of Nephrology, 2(5), 932-937. doi: 10.2215/cjn.01180307
Cite This Article:
Suri A., Bhans M., & Patel M. Gazyva: New Drug Gets Breakthrough Status. Illustrated by Z Hasan. Rare Disease Review November 2021 DOI: 10.13140/RG.2.2.19871.28325
