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The Bispecific Tumo...
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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 ...
Numbers
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LIBRIS-ID:oai:lup.lub.lu.se:2cfc42a5-f203-4a41-bbde-203e6e47e467
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https://lup.lub.lu.se/record/2cfc42a5-f203-4a41-bbde-203e6e47e467URI
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https://doi.org/10.1158/1535-7163.MCT-22-0395DOI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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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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Fritzell, SaraAlligator Biosciences AB(Swepub:lu)med-sfz
(author)
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Miller, RobertAptevo Therapeutics
(author)
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Werchau, DoreenAlligator Biosciences AB
(author)
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Van Citters, DanielleAptevo Therapeutics
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Nilsson, AnneliAlligator Biosciences AB
(author)
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Misher, LyndaAptevo Therapeutics
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Ljung, LillAlligator Biosciences AB
(author)
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Bader, RobertAptevo Therapeutics
(author)
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Deronic, AdnanAlligator Biosciences AB(Swepub:lu)med-ade
(author)
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Chunyk, Allison G.Aptevo Therapeutics
(author)
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Schultz, LenaAlligator Biosciences AB
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Varas, Laura A.Alligator Biosciences AB(Swepub:lu)immu-lva
(author)
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Rose, NadiaSARomics Biostructures AB
(author)
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Håkansson, MariaSARomics Biostructures AB
(author)
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Gross, JaneAptevo Therapeutics
(author)
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Furebring, ChristinaAlligator Biosciences AB(Swepub:lu)immt-cfu
(author)
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Pavlik, Peter
(author)
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Sundstedt, AnetteAlligator Biosciences AB(Swepub:lu)an3586su
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Veitonmäki, Niina
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Ramos, Hilario J.
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Säll, AnnaAlligator Biosciences AB(Swepub:lu)immu-ans
(author)
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Dahlman, Anna
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Bienvenue, David
(author)
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von Schantz, LauraAlligator Biosciences AB(Swepub:lu)med-lmt
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McMahan, Catherine J.
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Askmyr, MariaAlligator Biosciences AB(Swepub:lu)molm-mj0
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Hernandez-Hoyos, Gabriela
(author)
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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)
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Aptevo TherapeuticsAlligator Biosciences AB
(creator_code:org_t)
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In:Molecular Cancer Therapeutics22:1, s. 89-1011538-8514
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Nelson, Michelle ...
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Fritzell, Sara
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Miller, Robert
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Werchau, Doreen
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Van Citters, Dan ...
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Nilsson, Anneli
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Misher, Lynda
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Ljung, Lill
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Bader, Robert
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Deronic, Adnan
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Chunyk, Allison ...
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Schultz, Lena
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Varas, Laura A.
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Rose, Nadia
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Håkansson, Maria
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Gross, Jane
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Furebring, Chris ...
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Pavlik, Peter
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Sundstedt, Anett ...
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Veitonmäki, Niin ...
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Ramos, Hilario J ...
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Säll, Anna
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Dahlman, Anna
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Bienvenue, David
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von Schantz, Lau ...
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McMahan, Catheri ...
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Askmyr, Maria
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Hernandez-Hoyos, ...
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Ellmark, Peter
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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Molecular Cancer ...
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Lund University