Fc-competent multispecific PDL-1/TIGIT/LAG-3 antibodies potentiate superior anti-tumor T cell response
© 2023. The Author(s)..
The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is limited by primary and acquired resistance. The blockade of additional immune checkpoints, especially TIGIT and LAG-3, has been extensively explored, but so far only a LAG-3 antibody has been approved for combination with nivolumab to treat unresectable or metastatic melanoma. Here we report the development of a PDL1 × TIGIT bi-specific antibody (bsAb) GB265, a PDL1 × LAG3 bsAb GB266, and a PDL1 × TIGIT × LAG3 tri-specific antibody (tsAb) GB266T, all with intact Fc function. In in vitro cell-based assays, these antibodies promote greater T cell expansion and tumor cell killing than benchmark antibodies and antibody combinations in an Fc-dependent manner, likely by facilitating T cell interactions (bridging) with cancer cells and monocytes, in addition to blocking immune checkpoints. In animal models, GB265 and GB266T antibodies outperformed benchmarks in tumor suppression. This study demonstrates the potential of a new generation of multispecific checkpoint inhibitors to overcome resistance to current monospecific checkpoint antibodies or their combinations for the treatment of human cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Scientific reports - 13(2023), 1 vom: 18. Juni, Seite 9865 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Riyao [VerfasserIn] |
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| Links: |
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| Themen: |
31YO63LBSN |
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| Anmerkungen: |
Date Completed 20.06.2023 Date Revised 27.06.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41598-023-36942-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358336201 |
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| 520 | |a The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is limited by primary and acquired resistance. The blockade of additional immune checkpoints, especially TIGIT and LAG-3, has been extensively explored, but so far only a LAG-3 antibody has been approved for combination with nivolumab to treat unresectable or metastatic melanoma. Here we report the development of a PDL1 × TIGIT bi-specific antibody (bsAb) GB265, a PDL1 × LAG3 bsAb GB266, and a PDL1 × TIGIT × LAG3 tri-specific antibody (tsAb) GB266T, all with intact Fc function. In in vitro cell-based assays, these antibodies promote greater T cell expansion and tumor cell killing than benchmark antibodies and antibody combinations in an Fc-dependent manner, likely by facilitating T cell interactions (bridging) with cancer cells and monocytes, in addition to blocking immune checkpoints. In animal models, GB265 and GB266T antibodies outperformed benchmarks in tumor suppression. This study demonstrates the potential of a new generation of multispecific checkpoint inhibitors to overcome resistance to current monospecific checkpoint antibodies or their combinations for the treatment of human cancers | ||
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| 700 | 1 | |a Huang, Su |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Cai |e verfasserin |4 aut | |
| 700 | 1 | |a Fay, Nathan S |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yanan |e verfasserin |4 aut | |
| 700 | 1 | |a Putrevu, Saroja |e verfasserin |4 aut | |
| 700 | 1 | |a Wright, Kimberly |e verfasserin |4 aut | |
| 700 | 1 | |a Zaman, Mohd Saif |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Wenyan |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Betty |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Wright, Meredith |e verfasserin |4 aut | |
| 700 | 1 | |a Hoag, Matthew R |e verfasserin |4 aut | |
| 700 | 1 | |a Titong, Allison |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yue |e verfasserin |4 aut | |
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