Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis
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 ha...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.871802/full |
| _version_ | 1828344760104910848 |
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| author | Cayman Williams Alan Kennedy Maximillian A. Robinson Christopher Lloyd Simon J. Dovedi David M. Sansom |
| author_facet | Cayman Williams Alan Kennedy Maximillian A. Robinson Christopher Lloyd Simon J. Dovedi David M. Sansom |
| author_sort | Cayman Williams |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T00:01:59Z |
| format | Article |
| id | doaj.art-50e5c69156f645a59e40cf30cc612fe5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T00:01:59Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-50e5c69156f645a59e40cf30cc612fe52022-12-22T02:23:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.871802871802Impact of CTLA-4 checkpoint antibodies on ligand binding and TransendocytosisCayman Williams0Alan Kennedy1Maximillian A. Robinson2Christopher Lloyd3Simon J. Dovedi4David M. Sansom5University College London (UCL) Institute of Immunity and Transplantation, London, United KingdomUniversity College London (UCL) Institute of Immunity and Transplantation, London, United KingdomUniversity College London (UCL) Institute of Immunity and Transplantation, London, United KingdomBiologics Engineering, R&D, AstraZeneca, Cambridge, United KingdomEarly Oncology R&D, AstraZeneca, Cambridge, United KingdomUniversity College London (UCL) Institute of Immunity and Transplantation, London, United KingdomAnti-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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.871802/fullCTLA4checkpoint blockadeanti-CTLA4transendocytosisipilimumabtremelimumab |
| spellingShingle | Cayman Williams Alan Kennedy Maximillian A. Robinson Christopher Lloyd Simon J. Dovedi David M. Sansom Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis Frontiers in Immunology CTLA4 checkpoint blockade anti-CTLA4 transendocytosis ipilimumab tremelimumab |
| title | Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis |
| title_full | Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis |
| title_fullStr | Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis |
| title_full_unstemmed | Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis |
| title_short | Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis |
| title_sort | impact of ctla 4 checkpoint antibodies on ligand binding and transendocytosis |
| topic | CTLA4 checkpoint blockade anti-CTLA4 transendocytosis ipilimumab tremelimumab |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.871802/full |
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