Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy
Background Vibostolimab is a humanized anti-T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) antibody was recently investigated in late-stage clinical trials. Vibostolimab was developed based on its specific binding property to the human and cynomolgus monkey TIGIT protein and...
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BMJ Publishing Group
2025-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/8/e008972.full |
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| author | Hongmei Wang Maribel Beaumont Wendy Blumenschein Laurence Fayadat-Dilman Mingmei Cai Jing Yuan Douglas Wilson Thierry O Fischmann Jeanne Baker Tanya Keenan Daniel Malashock Eunseon Ahn Komal Pradhan Jeffery Grein Srishti Chakravorty Soheila Bahmanjah David Ban Ellen Chien Mark Hsieh Todd Mayhood Janica C Wong Mark A McCoy Sybil M G Williams Wolfgang Seghezzi Jin-Hwan Han |
| author_facet | Hongmei Wang Maribel Beaumont Wendy Blumenschein Laurence Fayadat-Dilman Mingmei Cai Jing Yuan Douglas Wilson Thierry O Fischmann Jeanne Baker Tanya Keenan Daniel Malashock Eunseon Ahn Komal Pradhan Jeffery Grein Srishti Chakravorty Soheila Bahmanjah David Ban Ellen Chien Mark Hsieh Todd Mayhood Janica C Wong Mark A McCoy Sybil M G Williams Wolfgang Seghezzi Jin-Hwan Han |
| author_sort | Hongmei Wang |
| collection | DOAJ |
| description | Background Vibostolimab is a humanized anti-T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) antibody was recently investigated in late-stage clinical trials. Vibostolimab was developed based on its specific binding property to the human and cynomolgus monkey TIGIT protein and its functional blocking activity of the TIGIT:CD155 interaction.Methods The biochemical properties of vibostolimab, in a comparison with tiragolumab, were assessed with Biacore, nuclear magnetic resonance (NMR), and X-ray crystallography, while the T-cell activation was examined using engineered Jurkat cells in an in vitro co-culture system by measuring interleukin (IL)-2 production as a readout of T-cell activation. The mouse surrogate anti-TIGIT antibodies were identified and used to extensively investigate the mechanism of action of anti-TIGIT antibodies as monotherapy or in combination with anti-programmed cell death protein-1 (PD-1) antibody in vivo by gene expression profiling and flow cytometry analyses with a mouse syngeneic tumor model.Results Structural analyses with solution NMR and X-ray crystallography revealed that vibostolimab binds the CC’C’’FG loop interface of TIGIT, completely competing for the binding site of CD155 with a larger coverage area than another anti-TIGIT antibody tiragolumab, consistent with surface plasmon resonance analysis, though mouse models with similar antibodies revealed no functional difference in antitumor efficacy. Biacore-based binding data indicate that both vibostolimab and tiragolumab bind on TIGIT with comparable binding affinity (KD), but different binding kinetics characterized by faster on and off rates, which may contribute to enhanced T-cell activation with vibostolimab, as evidenced by greater IL-2 production in an in vitro cell-based assay. Functional experiments in mouse models demonstrated additional detailed biological mechanisms of the mouse equivalent of vibostolimab, including the differentiating role of myeloid cell activation in addition to improved T cell cytolytic activity, both of which are further enhanced by anti-PD-1 combination therapy.Conclusions Vibostolimab is a novel anti-TIGIT antibody that completely blocks CD155 binding and induces T-cell activation. From experiments using a mouse tumor model and mouse surrogate anti-TIGIT antibody, we demonstrate direct evidence where it not only activates cytotoxic T cells but also induces the activation of antigen-presenting cells. The clinical relevance of vibostolimab, based on these mechanisms, in combination with pembrolizumab was recently tested in registrational trials. |
| format | Article |
| id | doaj-art-9ab2be18c81b475196edaaa62cc052ba |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9ab2be18c81b475196edaaa62cc052ba2025-08-20T04:25:21ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-08-0113810.1136/jitc-2024-008972Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapyHongmei Wang0Maribel Beaumont1Wendy Blumenschein2Laurence Fayadat-Dilman3Mingmei Cai4Jing Yuan5Douglas Wilson6Thierry O Fischmann7Jeanne Baker8Tanya Keenan9Daniel Malashock10Eunseon Ahn11Komal Pradhan12Jeffery Grein13Srishti Chakravorty14Soheila Bahmanjah15David Ban16Ellen Chien17Mark Hsieh18Todd Mayhood19Janica C Wong20Mark A McCoy21Sybil M G Williams22Wolfgang Seghezzi23Jin-Hwan Han243 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA5 Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics, Merck & Co Inc, Rahway, New Jersey, USA4 Quantitative Biosciences, Merck & Co Inc, Rahway, New Jersey, USA2 Discovery Biologics, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA4 Quantitative Biosciences, Merck & Co Inc, Rahway, New Jersey, USA1 Discovery Chemistry, Merck & Co Inc, Rahway, New Jersey, USA2 Discovery Biologics, Merck & Co Inc, Rahway, New Jersey, USA6 Clinical Research, Merck & Co Inc, Rahway, New Jersey, USA2 Discovery Biologics, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA4 Quantitative Biosciences, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA1 Discovery Chemistry, Merck & Co Inc, Rahway, New Jersey, USA1 Discovery Chemistry, Merck & Co Inc, Rahway, New Jersey, USA2 Discovery Biologics, Merck & Co Inc, Rahway, New Jersey, USA2 Discovery Biologics, Merck & Co Inc, Rahway, New Jersey, USA1 Discovery Chemistry, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA1 Discovery Chemistry, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USA5 Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics, Merck & Co Inc, Rahway, New Jersey, USA3 Discovery Oncology, Merck & Co Inc, Rahway, New Jersey, USABackground Vibostolimab is a humanized anti-T cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) antibody was recently investigated in late-stage clinical trials. Vibostolimab was developed based on its specific binding property to the human and cynomolgus monkey TIGIT protein and its functional blocking activity of the TIGIT:CD155 interaction.Methods The biochemical properties of vibostolimab, in a comparison with tiragolumab, were assessed with Biacore, nuclear magnetic resonance (NMR), and X-ray crystallography, while the T-cell activation was examined using engineered Jurkat cells in an in vitro co-culture system by measuring interleukin (IL)-2 production as a readout of T-cell activation. The mouse surrogate anti-TIGIT antibodies were identified and used to extensively investigate the mechanism of action of anti-TIGIT antibodies as monotherapy or in combination with anti-programmed cell death protein-1 (PD-1) antibody in vivo by gene expression profiling and flow cytometry analyses with a mouse syngeneic tumor model.Results Structural analyses with solution NMR and X-ray crystallography revealed that vibostolimab binds the CC’C’’FG loop interface of TIGIT, completely competing for the binding site of CD155 with a larger coverage area than another anti-TIGIT antibody tiragolumab, consistent with surface plasmon resonance analysis, though mouse models with similar antibodies revealed no functional difference in antitumor efficacy. Biacore-based binding data indicate that both vibostolimab and tiragolumab bind on TIGIT with comparable binding affinity (KD), but different binding kinetics characterized by faster on and off rates, which may contribute to enhanced T-cell activation with vibostolimab, as evidenced by greater IL-2 production in an in vitro cell-based assay. Functional experiments in mouse models demonstrated additional detailed biological mechanisms of the mouse equivalent of vibostolimab, including the differentiating role of myeloid cell activation in addition to improved T cell cytolytic activity, both of which are further enhanced by anti-PD-1 combination therapy.Conclusions Vibostolimab is a novel anti-TIGIT antibody that completely blocks CD155 binding and induces T-cell activation. From experiments using a mouse tumor model and mouse surrogate anti-TIGIT antibody, we demonstrate direct evidence where it not only activates cytotoxic T cells but also induces the activation of antigen-presenting cells. The clinical relevance of vibostolimab, based on these mechanisms, in combination with pembrolizumab was recently tested in registrational trials.https://jitc.bmj.com/content/13/8/e008972.full |
| spellingShingle | Hongmei Wang Maribel Beaumont Wendy Blumenschein Laurence Fayadat-Dilman Mingmei Cai Jing Yuan Douglas Wilson Thierry O Fischmann Jeanne Baker Tanya Keenan Daniel Malashock Eunseon Ahn Komal Pradhan Jeffery Grein Srishti Chakravorty Soheila Bahmanjah David Ban Ellen Chien Mark Hsieh Todd Mayhood Janica C Wong Mark A McCoy Sybil M G Williams Wolfgang Seghezzi Jin-Hwan Han Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy |
| title_full | Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy |
| title_fullStr | Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy |
| title_full_unstemmed | Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy |
| title_short | Pharmacological and structural characterization of vibostolimab, a novel anti-TIGIT blocking antibody for cancer immunotherapy |
| title_sort | pharmacological and structural characterization of vibostolimab a novel anti tigit blocking antibody for cancer immunotherapy |
| url | https://jitc.bmj.com/content/13/8/e008972.full |
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