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.

Autor:	Nelson MH; Aptevo Therapeutics Inc., Seattle, Washington., Fritzell S; Alligator Bioscience AB, Lund, Sweden., Miller R; Aptevo Therapeutics Inc., Seattle, Washington., Werchau D; Alligator Bioscience AB, Lund, Sweden., Van Citters D; Aptevo Therapeutics Inc., Seattle, Washington., Nilsson A; Alligator Bioscience AB, Lund, Sweden., Misher L; Aptevo Therapeutics Inc., Seattle, Washington., Ljung L; Alligator Bioscience AB, Lund, Sweden., Bader R; Aptevo Therapeutics Inc., Seattle, Washington., Deronic A; Alligator Bioscience AB, Lund, Sweden., Chunyk AG; Aptevo Therapeutics Inc., Seattle, Washington., Schultz L; Alligator Bioscience AB, Lund, Sweden., Varas LA; Alligator Bioscience AB, Lund, Sweden., Rose N; Saromics Biostructures AB, Lund, Sweden., Håkansson M; Saromics Biostructures AB, Lund, Sweden., Gross J; Aptevo Therapeutics Inc., Seattle, Washington., Furebring C; Alligator Bioscience AB, Lund, Sweden., Pavlik P; Aptevo Therapeutics Inc., Seattle, Washington., Sundstedt A; Alligator Bioscience AB, Lund, Sweden., Veitonmäki N; Alligator Bioscience AB, Lund, Sweden., Ramos HJ; Aptevo Therapeutics Inc., Seattle, Washington., Säll A; Alligator Bioscience AB, Lund, Sweden., Dahlman A; Alligator Bioscience AB, Lund, Sweden., Bienvenue D; Aptevo Therapeutics Inc., Seattle, Washington., von Schantz L; Alligator Bioscience AB, Lund, Sweden., McMahan CJ; Aptevo Therapeutics Inc., Seattle, Washington., Askmyr M; Alligator Bioscience AB, Lund, Sweden., Hernandez-Hoyos G; Aptevo Therapeutics Inc., Seattle, Washington., Ellmark P; Alligator Bioscience AB, Lund, Sweden.; Department of Immunotechnology, Lund University, Lund, Sweden.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2023 Jan 03; Vol. 22 (1), pp. 89-101.
DOI:	10.1158/1535-7163.MCT-22-0395
Abstrakt:	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. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu