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  • Nelson, Michelle H.Aptevo Therapeutics (author)

The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023
  • 13 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:2cfc42a5-f203-4a41-bbde-203e6e47e467
  • https://lup.lub.lu.se/record/2cfc42a5-f203-4a41-bbde-203e6e47e467URI
  • https://doi.org/10.1158/1535-7163.MCT-22-0395DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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

Notes

  • 4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Fritzell, SaraAlligator Biosciences AB(Swepub:lu)med-sfz (author)
  • Miller, RobertAptevo Therapeutics (author)
  • Werchau, DoreenAlligator Biosciences AB (author)
  • Van Citters, DanielleAptevo Therapeutics (author)
  • Nilsson, AnneliAlligator Biosciences AB (author)
  • Misher, LyndaAptevo Therapeutics (author)
  • Ljung, LillAlligator Biosciences AB (author)
  • Bader, RobertAptevo Therapeutics (author)
  • Deronic, AdnanAlligator Biosciences AB(Swepub:lu)med-ade (author)
  • Chunyk, Allison G.Aptevo Therapeutics (author)
  • Schultz, LenaAlligator Biosciences AB (author)
  • Varas, Laura A.Alligator Biosciences AB(Swepub:lu)immu-lva (author)
  • Rose, NadiaSARomics Biostructures AB (author)
  • Håkansson, MariaSARomics Biostructures AB (author)
  • Gross, JaneAptevo Therapeutics (author)
  • Furebring, ChristinaAlligator Biosciences AB(Swepub:lu)immt-cfu (author)
  • Pavlik, Peter (author)
  • Sundstedt, AnetteAlligator Biosciences AB(Swepub:lu)an3586su (author)
  • Veitonmäki, Niina (author)
  • Ramos, Hilario J. (author)
  • Säll, AnnaAlligator Biosciences AB(Swepub:lu)immu-ans (author)
  • Dahlman, Anna (author)
  • Bienvenue, David (author)
  • von Schantz, LauraAlligator Biosciences AB(Swepub:lu)med-lmt (author)
  • McMahan, Catherine J. (author)
  • Askmyr, MariaAlligator Biosciences AB(Swepub:lu)molm-mj0 (author)
  • Hernandez-Hoyos, Gabriela (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)
  • Aptevo TherapeuticsAlligator Biosciences AB (creator_code:org_t)

Related titles

  • In:Molecular Cancer Therapeutics22:1, s. 89-1011538-8514

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