GT-00AxIL15, a Novel Tumor-Targeted IL-15-Based Immunocytokine for the Treatment of TA-MUC1-Positive Solid Tumors : Preclinical In Vitro and In Vivo Pharmacodynamics and Biodistribution Studies
GT-00AxIL15 is a novel interleukin-15-based immunocytokine targeting a tumor-specific, glycosylated epitope of MUC1 (TA-MUC1). We characterized mode of action, pharmacokinetic (PK) and pharmacodynamic (PD) properties and investigated the relevance of TA-MUC1 binding for the concept of delivering IL-15 to solid tumors. In vitro pharmacology was analyzed in binding and cell-based assays. The in vivo PK profile and IL-15-mediated PD effects of GT-00AxIL15 were investigated in tumor-free mice. Tumor accumulation, immune infiltration and anti-tumor activity were assessed in TA-MUC1+ syngeneic and xenogeneic murine tumor models. GT-00AxIL15 was shown to specifically bind TA-MUC1 on tumor cells via its mAb moiety, to IL-15 receptors on immune cells via its IL-15 fusion modules and to FcγRs via its functional Fc-part. In vitro, NK, NKT and CD8+ T cells were activated and proliferated, leading to anti-tumor cytotoxicity and synergism with antibody-dependent cellular cytotoxicity (ADCC)-mediating mAbs. In vivo, GT-00AxIL15 exhibited favorable PK characteristics with a serum half-life of 13 days and specifically accumulated in TA-MUC1+ tumors. In the tumor microenvironment, GT-00AxIL15 induced robust immune activation and expansion and mediated anti-metastatic and anti-tumor effects in syngeneic and xenograft tumor models. These results support the rationale to improve PK and anti-tumor efficacy of IL-15 by increasing local concentrations at the tumor site via conjugation to a TA-MUC1 binding mAb. The tumor-selective expression pattern of TA-MUC1, powerful immune activation and anti-tumor cytotoxicity, long serum half-life and tumor targeting properties, render GT-00AxIL15 a promising candidate for treatment of solid tumors with high medical need, e.g., ovarian, lung and breast cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
International journal of molecular sciences - 25(2024), 3 vom: 24. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gellert, Johanna [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.02.2024 Date Revised 22.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms25031406 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368281795 |
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| 100 | 1 | |a Gellert, Johanna |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a GT-00AxIL15, a Novel Tumor-Targeted IL-15-Based Immunocytokine for the Treatment of TA-MUC1-Positive Solid Tumors |b Preclinical In Vitro and In Vivo Pharmacodynamics and Biodistribution Studies |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a GT-00AxIL15 is a novel interleukin-15-based immunocytokine targeting a tumor-specific, glycosylated epitope of MUC1 (TA-MUC1). We characterized mode of action, pharmacokinetic (PK) and pharmacodynamic (PD) properties and investigated the relevance of TA-MUC1 binding for the concept of delivering IL-15 to solid tumors. In vitro pharmacology was analyzed in binding and cell-based assays. The in vivo PK profile and IL-15-mediated PD effects of GT-00AxIL15 were investigated in tumor-free mice. Tumor accumulation, immune infiltration and anti-tumor activity were assessed in TA-MUC1+ syngeneic and xenogeneic murine tumor models. GT-00AxIL15 was shown to specifically bind TA-MUC1 on tumor cells via its mAb moiety, to IL-15 receptors on immune cells via its IL-15 fusion modules and to FcγRs via its functional Fc-part. In vitro, NK, NKT and CD8+ T cells were activated and proliferated, leading to anti-tumor cytotoxicity and synergism with antibody-dependent cellular cytotoxicity (ADCC)-mediating mAbs. In vivo, GT-00AxIL15 exhibited favorable PK characteristics with a serum half-life of 13 days and specifically accumulated in TA-MUC1+ tumors. In the tumor microenvironment, GT-00AxIL15 induced robust immune activation and expansion and mediated anti-metastatic and anti-tumor effects in syngeneic and xenograft tumor models. These results support the rationale to improve PK and anti-tumor efficacy of IL-15 by increasing local concentrations at the tumor site via conjugation to a TA-MUC1 binding mAb. The tumor-selective expression pattern of TA-MUC1, powerful immune activation and anti-tumor cytotoxicity, long serum half-life and tumor targeting properties, render GT-00AxIL15 a promising candidate for treatment of solid tumors with high medical need, e.g., ovarian, lung and breast cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a TA-MUC1 | |
| 650 | 4 | |a anti-tumor cytotoxicity | |
| 650 | 4 | |a cancer | |
| 650 | 4 | |a immunocytokine | |
| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a interleukin-15 | |
| 650 | 4 | |a monoclonal antibody | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Interleukin-15 |2 NLM | |
| 650 | 7 | |a MUC1 protein, human |2 NLM | |
| 650 | 7 | |a Mucin-1 |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents, Immunological |2 NLM | |
| 700 | 1 | |a Jäkel, Anika |e verfasserin |4 aut | |
| 700 | 1 | |a Danielczyk, Antje |e verfasserin |4 aut | |
| 700 | 1 | |a Goletz, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Lischke, Timo |e verfasserin |4 aut | |
| 700 | 1 | |a Flechner, Anke |e verfasserin |4 aut | |
| 700 | 1 | |a Dix, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Günzl, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Kehler, Patrik |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ijms25031406 |3 Volltext |
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