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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

Nelson, Michelle H. ; Fritzell, Sara LU ; Miller, Robert ; Werchau, Doreen ; Van Citters, Danielle ; Nilsson, Anneli ; Misher, Lynda ; Ljung, Lill ; Bader, Robert and Deronic, Adnan LU , et al. (2023) In Molecular Cancer Therapeutics 22(1). p.89-101
Abstract

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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Therapeutics
volume
22
issue
1
pages
13 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85145491758
  • pmid:36343381
ISSN
1538-8514
DOI
10.1158/1535-7163.MCT-22-0395
language
English
LU publication?
yes
id
2cfc42a5-f203-4a41-bbde-203e6e47e467
date added to LUP
2023-02-21 09:59:51
date last changed
2024-06-13 17:01:02
@article{2cfc42a5-f203-4a41-bbde-203e6e47e467,
  abstract     = {{<p>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.</p>}},
  author       = {{Nelson, Michelle H. and Fritzell, Sara and Miller, Robert and Werchau, Doreen and Van Citters, Danielle and Nilsson, Anneli and Misher, Lynda and Ljung, Lill and Bader, Robert and Deronic, Adnan and Chunyk, Allison G. and Schultz, Lena and Varas, Laura A. and Rose, Nadia and Håkansson, Maria and Gross, Jane and Furebring, Christina and Pavlik, Peter and Sundstedt, Anette and Veitonmäki, Niina and Ramos, Hilario J. and Säll, Anna and Dahlman, Anna and Bienvenue, David and von Schantz, Laura and McMahan, Catherine J. and Askmyr, Maria and Hernandez-Hoyos, Gabriela and Ellmark, Peter}},
  issn         = {{1538-8514}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{89--101}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Molecular Cancer Therapeutics}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1158/1535-7163.MCT-22-0395}},
  doi          = {{10.1158/1535-7163.MCT-22-0395}},
  volume       = {{22}},
  year         = {{2023}},
}