Systematic Review of Safety and Efficacy of Second- and Third-Generation CD20-Targeting Biologics in Treating Immune-Mediated Disorders

Abstract

BackgroundB cells can contribute to immune-mediated disorders. Targeting CD20 has proved to be efficacious in several B cell-mediated immunopathologies, as illustrated by the use of rituximab, the first anti-CD20 monoclonal antibody (mAb). Following rituximab, second- and third-generation anti-CD20 mAbs have been developed and tried in immune-mediated diseases, including obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab. However, their safety and efficacy has not been systematically reviewed.ObjectiveTo evaluate safety and efficacy of obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics.MethodsThe PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 22 July 2021 concentrating on immune-mediated disorders.ResultsThe literature search identified 2220 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 27 articles were finally included in a narrative synthesis.ConclusionsObinutuzumab has shown promising results in a case series of patients with phospholipase A2 receptor-associated membranous nephropathy and mixed results in systemic lupus erythematosus. Ocrelizumab has been approved for the use in patients with relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. Ocrelizumab was also tested in patients with rheumatoid arthritis, demonstrating promising results, and in systemic lupus erythematosus, revealing mixed results; however, in these conditions, its use was associated with increased risk of serious infections. Ofatumumab received approval for treating patients with relapsing-remitting multiple sclerosis. Moreover, ofatumumab showed promising results in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis, and systemic lupus erythematosus, as well as mixed results in phospholipase A2 receptor-associated membranous nephropathy. Ublituximab was assessed in relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorder, with promising results, however, the included number of patients was too small to conclude. Veltuzumab was tested in patients with immune thrombocytopenia resulting in improved platelet counts.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD4201913421.

Autoantibodies as Biomarker and Therapeutic Target in Systemic Sclerosis

“…Therefore, second-generation anti-CD20 antibodies (e.g., ocrelizumab, obinutuzumab, veltuzumab and ofatumumab) have been developed. These second-generation anti-CD20 antibodies are humanized or even fully human and have a higher therapeutic potential compared to rituximab in vitro [ 166 ]. Currently, none of these second-generation anti-CD20 antibodies have been evaluated in SSc.…”

Pediatric membranous nephropathy: In the novel antigens era

“…The treatment of pediatric patients with MN should be more individualized and targeted, especially considering the side effects of immunotherapy. The use of second- and third-generation CD20 antibodies [e.g., ofatumumab, Obinutuzumab, and ocrelizumab ( 73 – 76 )] could be tried, especially in certain refractory membranous nephropathies or in pediatric patients who develop serum sickness after the use of rituximab.…”

Inducible costimulator ligand (ICOSL) on CD19+ B cells is involved in immunopathological damage of rheumatoid arthritis (RA)

“…However, the mechanism involved in activation of autoreactive B cells and regulation of autoantibody production is unclear. Although increasing evidence shows that rituximab (a B cell lysosomal chimeric IgG1 CD20 specific monoclonal antibody) is effective in clinic, it is not able to inhibit the production of autoantibodies completely ( 27 , 28 ). Accordingly, to elucidate the process of B cell activation and autoantibody production can help to prevent activated B cells in synovium from differentiating into plasma blasts, and thus, result in effective inhibition of the production of autoantibodies at the source.…”