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19-12-2022 | Lymphoma | Research

CD20/TNFR1 dual-targeting antibody enhances lysosome rupture-mediated cell death in B cell lymphoma

Authors: Jeong Ryeol Kim, Donghyuk Lee, Yerim Kim, Joo Young Kim

Published in: Cancer Immunology, Immunotherapy | Issue 6/2023

Abstract

Obinutuzumab is a therapeutic antibody for B cell non-Hodgkin’s Lymphoma (BNHL), which is a glyco-engineered anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and causes binding-induced direct cell death (DCD) through lysosome membrane permeabilization (LMP). Tumour necrosis factor receptor 1 (TNFR1), a pro-inflammatory death receptor, also evokes cell death, partly through lysosomal rupture. As both obinutuzumab- and TNFR1-induced cell deaths are mediated by LMP and combining TNFR1 and obinutuzumab can amplify LMP-mediated cell death, we made dual-targeting antibody for CD20 and TNFR1 to enhance DCD of obinutuzumab.

Obinutuzumab treatment-induced CD20 and TNFR1 colocalisation, and TNFR1-overexpressing cells showed increased obinutuzumab-induced DCD. Two targeting modes, anti-CD20/TNFR1 bispecific antibodies (bsAbs), and obinutuzumab-TNFα fusion proteins (OBI-TNFα^WT and OBI-TNFα^MUT), were designed to cluster CD20 and TNFR1 on the plasma membrane. OBI-TNFα^WT and OBI-TNFα^MUT showed significantly enhanced LMP, DCD, and ADCC compared with that induced by obinutuzumab. TNFR1 expression is upregulated in many BNHL subtypes compared to that in normal B cells; OBI-TNFα^MUT specifically increased DCD and ADCC in a B cell lymphoma cell line overexpressing TNFR1. Further, OBI-TNFα^MUT blocked NF-κB activation in the presence of TNF-α, implying that it can antagonise the proliferative role of TNF-α in cancers.

Our study suggests that dual targeting of CD20 and TNFR1 can be a new therapeutic strategy for improving BNHL treatment. The OBI-TNFα^MUT fusion protein enhances DCD and ADCC and prevents the proliferating effect of TNFα signalling; therefore, it may provide precision treatment for patients with BNHL, especially those with upregulated TNFR1 expression.

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Title: CD20/TNFR1 dual-targeting antibody enhances lysosome rupture-mediated cell death in B cell lymphoma
Authors: Jeong Ryeol Kim
Donghyuk Lee
Yerim Kim
Joo Young Kim
Publication date: 19-12-2022
Publisher: Springer Berlin Heidelberg
Keywords: Lymphoma
Obinutuzumab
Obinutuzumab
Published in: Cancer Immunology, Immunotherapy / Issue 6/2023
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-022-03344-9

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