Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways

Jennifer Edelmann; Arran D Dokal; Emma Vilventhraraja; Karlheinz Holzmann; David Britton; Tetyana Klymenko; Hartmut Döhner; Mark Cragg; Andrejs Braun; Pedro Cutillas; John G Gribben

doi:10.1016/j.isci.2021.102089

Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways

iScience. 2021 Jan 22;24(2):102089. doi: 10.1016/j.isci.2021.102089. eCollection 2021 Feb 19.

Authors

Jennifer Edelmann^{1

2}, Arran D Dokal^{1

3}, Emma Vilventhraraja¹, Karlheinz Holzmann⁴, David Britton^{1

3}, Tetyana Klymenko^{1

5}, Hartmut Döhner², Mark Cragg⁶, Andrejs Braun¹, Pedro Cutillas^{1

3}, John G Gribben¹

Affiliations

¹ Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
² Department of Internal Medicine III, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
³ Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UK.
⁴ Center for Clinical Research, Genomics Core Facility, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany.
⁵ Sheffield Hallam University, City Campus, Howard Street, Sheffield, S1 1WB, UK.
⁶ Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK.

Abstract

The anti-CD20 monoclonal antibodies rituximab and obinutuzumab differ in their mechanisms of action, with obinutuzumab evoking greater direct B cell death. To characterize the signaling processes responsible for improved B cell killing by obinutuzumab, we undertook a phosphoproteomics approach and demonstrate that rituximab and obinutuzumab differentially activate pathways downstream of the B cell receptor. Although both antibodies induce strong ERK and MYC activation sufficient to promote cell-cycle arrest and B cell death, obinutuzumab exceeds rituximab in supporting apoptosis induction by means of aberrant SYK phosphorylation. In contrast, rituximab elicits stronger anti-apoptotic signals by activating AKT, by impairing pro-apoptotic BAD, and by releasing membrane-bound NOTCH1 to up-regulate pro-survival target genes. As a consequence, rituximab appears to reinforce BCL2-mediated apoptosis resistance. The unexpected complexity and differences by which rituximab and obinutuzumab interfere with signaling pathways essential for lymphoma pathogenesis and treatment provide important impetus to optimize and personalize the application of different anti-CD20 treatments.

Keywords: cancer; immunology; systems biology: proteomics.

Abstract

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