Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1
Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) rem...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/4/636 |
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| author | Perrine Jacquot Javier Muñoz-Garcia Maurine Fleury Denis Cochonneau Rémi Gaussin Elise Enouf Caroline Roze Emilie Ollivier Mathieu Cinier Dominique Heymann |
| author_facet | Perrine Jacquot Javier Muñoz-Garcia Maurine Fleury Denis Cochonneau Rémi Gaussin Elise Enouf Caroline Roze Emilie Ollivier Mathieu Cinier Dominique Heymann |
| author_sort | Perrine Jacquot |
| collection | DOAJ |
| description | Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell’s selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition. |
| first_indexed | 2024-03-11T05:12:03Z |
| format | Article |
| id | doaj.art-7ae2e14e7a294c4092b3471af5a93db7 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T05:12:03Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-7ae2e14e7a294c4092b3471af5a93db72023-11-17T18:29:14ZengMDPI AGBiomolecules2218-273X2023-03-0113463610.3390/biom13040636Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1Perrine Jacquot0Javier Muñoz-Garcia1Maurine Fleury2Denis Cochonneau3Rémi Gaussin4Elise Enouf5Caroline Roze6Emilie Ollivier7Mathieu Cinier8Dominique Heymann9Affilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceTumor Heterogeneity and Precision Medicine Laboratory, Institut de Cancérologie de l’Ouest, Université de Nantes, 44805 Saint-Herblain, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceTumor Heterogeneity and Precision Medicine Laboratory, Institut de Cancérologie de l’Ouest, Université de Nantes, 44805 Saint-Herblain, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceTumor Heterogeneity and Precision Medicine Laboratory, Institut de Cancérologie de l’Ouest, Université de Nantes, 44805 Saint-Herblain, FranceAffilogic SAS, 24 rue de la Rainière, 44300 Nantes, FranceTumor Heterogeneity and Precision Medicine Laboratory, Institut de Cancérologie de l’Ouest, Université de Nantes, 44805 Saint-Herblain, FranceRe-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell’s selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition.https://www.mdpi.com/2218-273X/13/4/636epidermal growth factor receptor (EGFR)programmed cell death ligand 1 (PDL1)bispecific Nanofitintumor specificimmune checkpoint inhibitor (ICI) |
| spellingShingle | Perrine Jacquot Javier Muñoz-Garcia Maurine Fleury Denis Cochonneau Rémi Gaussin Elise Enouf Caroline Roze Emilie Ollivier Mathieu Cinier Dominique Heymann Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 Biomolecules epidermal growth factor receptor (EGFR) programmed cell death ligand 1 (PDL1) bispecific Nanofitin tumor specific immune checkpoint inhibitor (ICI) |
| title | Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 |
| title_full | Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 |
| title_fullStr | Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 |
| title_full_unstemmed | Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 |
| title_short | Engineering of a Bispecific Nanofitin with Immune Checkpoint Inhibitory Activity Conditioned by the Cross-Arm Binding to EGFR and PDL1 |
| title_sort | engineering of a bispecific nanofitin with immune checkpoint inhibitory activity conditioned by the cross arm binding to egfr and pdl1 |
| topic | epidermal growth factor receptor (EGFR) programmed cell death ligand 1 (PDL1) bispecific Nanofitin tumor specific immune checkpoint inhibitor (ICI) |
| url | https://www.mdpi.com/2218-273X/13/4/636 |
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