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
Author:
Nelson Michelle H.1ORCID, Fritzell Sara2ORCID, Miller Robert1ORCID, Werchau Doreen2ORCID, Van Citters Danielle1ORCID, Nilsson Anneli2ORCID, Misher Lynda1ORCID, Ljung Lill2ORCID, Bader Robert1ORCID, Deronic Adnan2ORCID, Chunyk Allison G.1ORCID, Schultz Lena2ORCID, Varas Laura A.2ORCID, Rose Nadia3ORCID, Håkansson Maria3ORCID, Gross Jane1ORCID, Furebring Christina2ORCID, Pavlik Peter1ORCID, Sundstedt Anette2ORCID, Veitonmäki Niina2ORCID, Ramos Hilario J.1ORCID, Säll Anna2ORCID, Dahlman Anna2ORCID, Bienvenue David1ORCID, von Schantz Laura2ORCID, McMahan Catherine J.1ORCID, Askmyr Maria2ORCID, Hernandez-Hoyos Gabriela1ORCID, Ellmark Peter24ORCID
Affiliation:
1. 1Aptevo Therapeutics Inc., Seattle, Washington. 2. 2Alligator Bioscience AB, Lund, Sweden. 3. 3Saromics Biostructures AB, Lund, Sweden. 4. 4Department of Immunotechnology, Lund University, Lund, Sweden.
Abstract
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 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.
Publisher
American Association for Cancer Research (AACR)
Subject
Cancer Research,Oncology
Cited by
1 articles.
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