Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab.
The efficacy of PD-1 monoclonals such as pembrolizumab can be modulated by the signals delivered via their Fc region. Tumour/inflammation associated proteases can generate F(ab')2 fragments of therapeutic monoclonals, and subsequent recognition of F(ab')2 epitopes by circulating anti-hinge...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0290793 |
| _version_ | 1797679356848373760 |
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| author | Barry D Hock Liping Goddard Sean A MacPherson Matthew Strother David Gibbs John F Pearson Judith L McKenzie |
| author_facet | Barry D Hock Liping Goddard Sean A MacPherson Matthew Strother David Gibbs John F Pearson Judith L McKenzie |
| author_sort | Barry D Hock |
| collection | DOAJ |
| description | The efficacy of PD-1 monoclonals such as pembrolizumab can be modulated by the signals delivered via their Fc region. Tumour/inflammation associated proteases can generate F(ab')2 fragments of therapeutic monoclonals, and subsequent recognition of F(ab')2 epitopes by circulating anti-hinge antibodies (AHA) can then, potentially, link F(ab')2 binding to the target antigen with novel Fc signalling. Although elevated in inflammatory diseases, AHA levels in cancer patients have not been investigated and functional studies utilising the full repertoire of AHA present in sera have been limited. AHA levels in pembrolizumab treated melanoma patients (n = 23) were therefore compared to those of normal donors and adalimumab treated patients. A subset of melanoma patients and the majority of adalimumab patients had elevated levels of AHA reactive with F(ab')2 fragments of IgG4 anti-PD-1 monoclonals (nivolumab, pembrolizumab) and IgG1 therapeutic monoclonals (rituximab, adalimumab). Survival analysis was restricted by the small patient numbers but those melanoma patients with the highest levels (>75% percentile, n = 5) of pembrolizumab-F(ab')2 reactive AHA had significantly better overall survival post pembrolizumab treatment (p = 0.039). In vitro functional studies demonstrated that the presence of AHA+ sera restored the neutrophil activating capacity of pembrolizumab to its F(ab')2 fragment. Neither pembrolizumab nor its F(ab')2 fragments can induce NK cell or complement dependent cytotoxicity (CDC). However, AHA+ sera in combination with pembrolizumab-F(ab')2 provided Fc regions that could activate NK cells. The ability of AHA+ sera to restore CDC activity was more restricted and observed using only one pembrolizumab and one adalimumab patient serum in combination with rituximab- F(ab')2. This study reports the presence of elevated AHA levels in pembrolizumab treated melanoma patients and highlight the potential for AHA to provide additional Fc signaling. The issue of whether tumour associated proteolysis of PD-1 mAbs and subsequent AHA recognition impacts on treatment efficacy requires further study. |
| first_indexed | 2024-03-11T23:13:26Z |
| format | Article |
| id | doaj.art-5c5343f1c5614282a9d7c4d55c3316c4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-11T23:13:26Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5c5343f1c5614282a9d7c4d55c3316c42023-09-21T05:32:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01189e029079310.1371/journal.pone.0290793Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab.Barry D HockLiping GoddardSean A MacPhersonMatthew StrotherDavid GibbsJohn F PearsonJudith L McKenzieThe efficacy of PD-1 monoclonals such as pembrolizumab can be modulated by the signals delivered via their Fc region. Tumour/inflammation associated proteases can generate F(ab')2 fragments of therapeutic monoclonals, and subsequent recognition of F(ab')2 epitopes by circulating anti-hinge antibodies (AHA) can then, potentially, link F(ab')2 binding to the target antigen with novel Fc signalling. Although elevated in inflammatory diseases, AHA levels in cancer patients have not been investigated and functional studies utilising the full repertoire of AHA present in sera have been limited. AHA levels in pembrolizumab treated melanoma patients (n = 23) were therefore compared to those of normal donors and adalimumab treated patients. A subset of melanoma patients and the majority of adalimumab patients had elevated levels of AHA reactive with F(ab')2 fragments of IgG4 anti-PD-1 monoclonals (nivolumab, pembrolizumab) and IgG1 therapeutic monoclonals (rituximab, adalimumab). Survival analysis was restricted by the small patient numbers but those melanoma patients with the highest levels (>75% percentile, n = 5) of pembrolizumab-F(ab')2 reactive AHA had significantly better overall survival post pembrolizumab treatment (p = 0.039). In vitro functional studies demonstrated that the presence of AHA+ sera restored the neutrophil activating capacity of pembrolizumab to its F(ab')2 fragment. Neither pembrolizumab nor its F(ab')2 fragments can induce NK cell or complement dependent cytotoxicity (CDC). However, AHA+ sera in combination with pembrolizumab-F(ab')2 provided Fc regions that could activate NK cells. The ability of AHA+ sera to restore CDC activity was more restricted and observed using only one pembrolizumab and one adalimumab patient serum in combination with rituximab- F(ab')2. This study reports the presence of elevated AHA levels in pembrolizumab treated melanoma patients and highlight the potential for AHA to provide additional Fc signaling. The issue of whether tumour associated proteolysis of PD-1 mAbs and subsequent AHA recognition impacts on treatment efficacy requires further study.https://doi.org/10.1371/journal.pone.0290793 |
| spellingShingle | Barry D Hock Liping Goddard Sean A MacPherson Matthew Strother David Gibbs John F Pearson Judith L McKenzie Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab. PLoS ONE |
| title | Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab. |
| title_full | Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab. |
| title_fullStr | Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab. |
| title_full_unstemmed | Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab. |
| title_short | Levels and in vitro functional effects of circulating anti-hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab. |
| title_sort | levels and in vitro functional effects of circulating anti hinge antibodies in melanoma patients receiving the immune checkpoint inhibitor pembrolizumab |
| url | https://doi.org/10.1371/journal.pone.0290793 |
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