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ATOR-1017 (evunzeki...
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
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- Enell Smith, Karin (author)
- Alligator Biosciences AB
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- Fritzell, Sara (author)
- Alligator Biosciences AB
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- Nilsson, Anneli (author)
- Alligator Biosciences AB
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Barchan, Karin (author)
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Rosén, Anna (author)
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Schultz, Lena (author)
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- Varas, Laura (author)
- Alligator Biosciences AB
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- Säll, Anna (author)
- Alligator Biosciences AB
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Rose, Nadia (author)
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- Håkansson, Maria (author)
- SARomics Biostructures AB
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- von Schantz, Laura (author)
- Alligator Biosciences AB
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- Ellmark, Peter (author)
- Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Alligator Biosciences AB
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(creator_code:org_t)
- 2023
- 2023
- English 15 s.
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In: Cancer Immunology, Immunotherapy. - 0340-7004. ; 72:12, s. 4145-4159
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- 4-1BB
- Antibody
- CD137
- Immunotherapy
- PD-1
- T cell activation
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Enell Smith, Kar ...
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Fritzell, Sara
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Nilsson, Anneli
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Barchan, Karin
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Rosén, Anna
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Schultz, Lena
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show more...
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Varas, Laura
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Säll, Anna
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Rose, Nadia
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Håkansson, Maria
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von Schantz, Lau ...
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Ellmark, Peter
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Cancer Immunolog ...
- By the university
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Lund University