Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells
© 2024. The Author(s)..
Over the past decade, US Food and Drug Administration (FDA)-approved immune checkpoint inhibitors that target programmed death-1 (PD-1) have demonstrated significant clinical benefit particularly in patients with PD-L1 expressing tumors. Toripalimab is a humanized anti-PD-1 antibody, approved by FDA for first-line treatment of nasopharyngeal carcinoma in combination with chemotherapy. In a post hoc analysis of phase 3 studies, toripalimab in combination with chemotherapy improved overall survival irrespective of PD-L1 status in nasopharyngeal carcinoma (JUPITER-02), advanced non-small cell lung cancer (CHOICE-01) and advanced esophageal squamous cell carcinoma (JUPITER-06). On further characterization, we determined that toripalimab is molecularly and functionally differentiated from pembrolizumab, an anti-PD-1 mAb approved previously for treating a wide spectrum of tumors. Toripalimab, which binds the FG loop of PD-1, has 12-fold higher binding affinity to PD-1 than pembrolizumab and promotes significantly more Th1- and myeloid-derived inflammatory cytokine responses in healthy human PBMCs in vitro. In an ex vivo system employing dissociated tumor cells from treatment naïve non-small cell lung cancer patients, toripalimab induced several unique genes in IFN-γ and immune cell pathways, showed different kinetics of activation and significantly enhanced IFN-γ signature. Additionally, binding of toripalimab to PD-1 induced lower levels of SHP1 and SHP2 recruitment, the negative regulators of T cell activation, in Jurkat T cells ectopically expressing PD-1. Taken together, these data demonstrate that toripalimab is a potent anti-PD-1 antibody with high affinity PD-1 binding, strong functional attributes and demonstrated clinical activity that encourage its continued clinical investigation in several types of cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
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| Enthalten in: |
Cancer immunology, immunotherapy : CII - 73(2024), 3 vom: 24. Feb., Seite 60 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rajasekaran, Narendiran [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 09.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00262-024-03635-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Rajasekaran, Narendiran |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a Over the past decade, US Food and Drug Administration (FDA)-approved immune checkpoint inhibitors that target programmed death-1 (PD-1) have demonstrated significant clinical benefit particularly in patients with PD-L1 expressing tumors. Toripalimab is a humanized anti-PD-1 antibody, approved by FDA for first-line treatment of nasopharyngeal carcinoma in combination with chemotherapy. In a post hoc analysis of phase 3 studies, toripalimab in combination with chemotherapy improved overall survival irrespective of PD-L1 status in nasopharyngeal carcinoma (JUPITER-02), advanced non-small cell lung cancer (CHOICE-01) and advanced esophageal squamous cell carcinoma (JUPITER-06). On further characterization, we determined that toripalimab is molecularly and functionally differentiated from pembrolizumab, an anti-PD-1 mAb approved previously for treating a wide spectrum of tumors. Toripalimab, which binds the FG loop of PD-1, has 12-fold higher binding affinity to PD-1 than pembrolizumab and promotes significantly more Th1- and myeloid-derived inflammatory cytokine responses in healthy human PBMCs in vitro. In an ex vivo system employing dissociated tumor cells from treatment naïve non-small cell lung cancer patients, toripalimab induced several unique genes in IFN-γ and immune cell pathways, showed different kinetics of activation and significantly enhanced IFN-γ signature. Additionally, binding of toripalimab to PD-1 induced lower levels of SHP1 and SHP2 recruitment, the negative regulators of T cell activation, in Jurkat T cells ectopically expressing PD-1. Taken together, these data demonstrate that toripalimab is a potent anti-PD-1 antibody with high affinity PD-1 binding, strong functional attributes and demonstrated clinical activity that encourage its continued clinical investigation in several types of cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a FG loop | |
| 650 | 4 | |a Immune checkpoint inhibitor | |
| 650 | 4 | |a PD-1 signaling | |
| 650 | 4 | |a PD-L1 status irrespective | |
| 650 | 4 | |a Toripalimab | |
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| 700 | 1 | |a Wang, Xiaoguang |e verfasserin |4 aut | |
| 700 | 1 | |a Ravindranathan, Sruthi |e verfasserin |4 aut | |
| 700 | 1 | |a Chin, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Tseng, Su-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Klakamp, Scott L |e verfasserin |4 aut | |
| 700 | 1 | |a Widmann, Kate |e verfasserin |4 aut | |
| 700 | 1 | |a Kapoor, Varun N |e verfasserin |4 aut | |
| 700 | 1 | |a Vexler, Vladimir |e verfasserin |4 aut | |
| 700 | 1 | |a Keegan, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a LaVallee, Theresa |e verfasserin |4 aut | |
| 700 | 1 | |a Khare, Sanjay D |e verfasserin |4 aut | |
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