التفاصيل البيبلوغرافية
| العنوان: |
ATOR-1017 (evunzekibart), an Fc-gamma receptor conditional 4-1BB agonist designed for optimal safety and efficacy, activates exhausted T cells in combination with anti-PD-1 |
| المؤلفون: |
Enell Smith, Karin, Fritzell, Sara, Nilsson, Anneli, Barchan, Karin, Rosén, Anna, Schultz, Lena, Varas, Laura, Säll, Anna, Rose, Nadia, Håkansson, Maria, von Schantz, Laura, Ellmark, Peter |
| المساهمون: |
Alligator Bioscience, Vinnova |
| المصدر: |
Cancer Immunology, Immunotherapy ; volume 72, issue 12, page 4145-4159 ; ISSN 0340-7004 1432-0851 |
| بيانات النشر: |
Springer Science and Business Media LLC |
| سنة النشر: |
2023 |
| مصطلحات موضوعية: |
Cancer Research, Oncology, Immunology, Immunology and Allergy |
| الوصف: |
Background 4-1BB (CD137) is a co-stimulatory receptor highly expressed on tumor reactive effector T cells and NK cells, which upon stimulation prolongs persistence of tumor reactive effector T and NK cells within the tumor and induces long-lived memory T cells. 4-1BB agonistic antibodies have been shown to induce strong anti-tumor effects that synergize with immune checkpoint inhibitors. The first generation of 4-1BB agonists was, however, hampered by dose-limiting toxicities resulting in suboptimal dose levels or poor agonistic activity. Methods ATOR-1017 (evunzekibart), a second-generation Fc-gamma receptor conditional 4-1BB agonist in IgG4 format, was designed to overcome the limitations of the first generation of 4-1BB agonists, providing strong agonistic effect while minimizing systemic immune activation and risk of hepatoxicity. The epitope of ATOR-1017 was determined by X-ray crystallography, and the functional activity was assessed in vitro and in vivo as monotherapy or in combination with anti-PD1. Results ATOR-1017 binds to a unique epitope on 4-1BB enabling ATOR-1017 to activate T cells, including cells with an exhausted phenotype, and NK cells, in a cross-linking dependent, FcγR-conditional, manner. This translated into a tumor-directed and potent anti-tumor therapeutic effect in vivo, which was further enhanced with anti-PD-1 treatment. Conclusions These preclinical data demonstrate a strong safety profile of ATOR-1017, together with its potent therapeutic effect as monotherapy and in combination with anti-PD1, supporting further clinical development of ATOR-1017. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1007/s00262-023-03548-7 |
| DOI: |
10.1007/s00262-023-03548-7.pdf |
| DOI: |
10.1007/s00262-023-03548-7/fulltext.html |
| الإتاحة: |
https://doi.org/10.1007/s00262-023-03548-7Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: |
edsbas.3AD9EF3E |
| قاعدة البيانات: |
BASE |
