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Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis

Williams, Cayman; Kennedy, Alan; Robinson, Maximillian AA; Lloyd, Christopher; Dovedi, Simon JJ; Sansom, David MM; (2022) Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis. Frontiers in Immunology , 13 , Article 871802. 10.3389/fimmu.2022.871802. Green open access

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Abstract

Anti-CTLA-4 antibodies have pioneered the field of tumour immunotherapy. However, despite impressive clinical response data, the mechanism by which anti-CTLA-4 antibodies work is still controversial. Two major checkpoint antibodies (ipilimumab and tremelimumab) have been trialled clinically. Both have high affinity binding to CTLA-4 and occupy the ligand binding site, however recently it has been suggested that in some settings such antibodies may not block ligand-CTLA-4 interactions. Here we evaluated blocking capabilities of these antibodies in a variety of settings using both soluble and cell bound target proteins. We found that when ligands (CD80 or CD86) were expressed on cells, soluble CTLA-4-Ig bound in line with affinity expectations and that this interaction was effectively disrupted by both ipilimumab and tremelimumab antibodies. Similarly, cellular CTLA-4 binding to soluble ligands was comparably prevented. We further tested the ability of these antibodies to block transendocytosis, whereby CTLA-4 captures ligands from target cells during a cognate cell-cell interaction. Once again ipilimumab and tremelimumab were similar in preventing removal of ligand by transendocytosis. Furthermore, even once transendocytosis was ongoing and cell contact was fully established, the addition of these antibodies could prevent further ligand transfer. Together these data indicate that the above checkpoint inhibitors performed in-line with predictions based on affinity and binding site data and are capable of blocking CTLA-4-ligand interactions in a wide range of settings tested.

Type: Article
Title: Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2022.871802
Publisher version: https://doi.org/10.3389/fimmu.2022.871802
Language: English
Additional information: © 2022 Williams, Kennedy, Robinson, Lloyd, Dovedi and Sansom. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: CTLA4, checkpoint blockade, anti-CTLA4, transendocytosis, ipilimumab, tremelimumab
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10162372
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