The Type II Anti-CD20 Antibody Obinutuzumab (GA101) Is More Effective Than Rituximab at Depleting B Cells and Treating Disease in a Murine Lupus Model

Arthritis Rheumatol. 2021 May;73(5):826-836. doi: 10.1002/art.41608. Epub 2021 Mar 24.

Abstract

Objective: Depleting pathogenic B cells could treat systemic lupus erythematosus (SLE). However, depleting B cells in an inflammatory setting such as lupus is difficult. This study was undertaken to investigate whether a type II anti-CD20 monoclonal antibody (mAb) with a different mechanism of action, obinutuzumab (GA101), is more effective than a type I anti-CD20 mAb, rituximab (RTX), in B cell depletion in lupus, and whether efficient B cell depletion results in amelioration of disease.

Methods: We treated lupus-prone MRL/lpr mice expressing human CD20 on B cells (hCD20 MRL/lpr mice) with either RTX or GA101 and measured B cell depletion under various conditions, as well as multiple clinical end points.

Results: A single dose of GA101 was markedly more effective than RTX in depleting B cells in diseased MRL/lpr mice (P < 0.05). RTX overcame resistance to B cell depletion in diseased MRL/lpr mice with continuous treatments. GA101 was more effective in treating hCD20 MRL/lpr mice with early disease, as GA101-treated mice had reduced glomerulonephritis (P < 0.05), lower anti-RNA autoantibody titers (P < 0.05), and fewer activated CD4+ T cells (P < 0.0001) compared to RTX-treated mice. GA101 also treated advanced disease, and continual treatment prolonged survival. Using variants of GA101, we also elucidated B cell depletion mechanisms in vivo in mice with lupus.

Conclusion: Albeit both anti-CD20 antibodies ameliorated early disease, GA101 was more effective than RTX in important parameters, such as glomerulonephritis score. GA101 proved beneficial in an advanced disease model, where it prolonged survival. These data support clinical testing of GA101 in SLE and lupus nephritis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology
  • Flow Cytometry
  • Immunologic Factors / pharmacology*
  • Kidney / drug effects*
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred MRL lpr
  • Rituximab / pharmacology*
  • Skin / drug effects*
  • Skin / pathology

Substances

  • Antibodies, Monoclonal, Humanized
  • Immunologic Factors
  • Rituximab
  • obinutuzumab