ATG-101 is a tetravalent PD-L1×4-1BB bispecific antibody that stimulates anti-tumor immunity through PD-L1 blockade and PD-L1-directed 4-1BB activation
Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2" PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when crosslinked with PD-L1+ cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/Treg cells in the tumor microenvironment (TME), rendering an immunologically "cold" tumor "hot". Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA-sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well-tolerated and did not induce hepatotoxicity in non-human primates. According to computational semi-mechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 crosslinking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Cancer research - (2024) vom: 19. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yuwen, Hui [VerfasserIn] |
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| Anmerkungen: |
Date Revised 19.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1158/0008-5472.CAN-23-2701 |
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| Förderinstitution / Projekttitel: |
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NLM369916123 |
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| 245 | 1 | 0 | |a ATG-101 is a tetravalent PD-L1×4-1BB bispecific antibody that stimulates anti-tumor immunity through PD-L1 blockade and PD-L1-directed 4-1BB activation |
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| 520 | |a Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2" PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when crosslinked with PD-L1+ cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/Treg cells in the tumor microenvironment (TME), rendering an immunologically "cold" tumor "hot". Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA-sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well-tolerated and did not induce hepatotoxicity in non-human primates. According to computational semi-mechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 crosslinking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Wang, Huajing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Tengteng |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Yijing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yun-Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Ao |e verfasserin |4 aut | |
| 700 | 1 | |a Bian, Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Bohua |e verfasserin |4 aut | |
| 700 | 1 | |a Flowers, David |e verfasserin |4 aut | |
| 700 | 1 | |a Presler, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Subramanian, Kalyanasundaram |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jingjing |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Mei, Jay |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xiaowen |e verfasserin |4 aut | |
| 700 | 1 | |a Shan, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Bing |e verfasserin |4 aut | |
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