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Search: id:"swepub:oai:lup.lub.lu.se:0f3a3908-b3cb-40b4-89fd-c6d7872c43e0" > ATOR-1017 (evunzeki...

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  • Enell Smith, KarinAlligator Biosciences AB (author)

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

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023
  • 15 s.

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  • LIBRIS-ID:oai:lup.lub.lu.se:0f3a3908-b3cb-40b4-89fd-c6d7872c43e0
  • https://lup.lub.lu.se/record/0f3a3908-b3cb-40b4-89fd-c6d7872c43e0URI
  • https://doi.org/10.1007/s00262-023-03548-7DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.

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  • Fritzell, SaraAlligator Biosciences AB (author)
  • Nilsson, AnneliAlligator Biosciences AB (author)
  • Barchan, Karin (author)
  • Rosén, Anna (author)
  • Schultz, Lena (author)
  • Varas, LauraAlligator Biosciences AB (author)
  • Säll, AnnaAlligator Biosciences AB (author)
  • Rose, Nadia (author)
  • Håkansson, MariaSARomics Biostructures AB (author)
  • von Schantz, LauraAlligator Biosciences AB(Swepub:lu)med-lmt (author)
  • Ellmark, PeterLund 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(Swepub:lu)immt-pel (author)
  • Alligator Biosciences ABSARomics Biostructures AB (creator_code:org_t)

Related titles

  • In:Cancer Immunology, Immunotherapy72:12, s. 4145-41590340-7004

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