2026-05-20T22:56:59Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/67022024-11-29T13:29:45Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Compte, Marta author Harwood, Seandean Lykke author Muñoz, Ines G author Navarro, Rocio author Zonca, Manuela author Perez-Chacon, Gema author Erce-Llamazares, Ainhoa author Merino, Nekane author Tapia-Galisteo, Antonio author Cuesta, Angel M author Mikkelsen, Kasper author Caleiras, Eduardo author Nuñez-Prado, Natalia author Aznar, M Angela author Lykkemark, Simon author Martinez Torrecuadrada, Jorge Luis author Melero, Ignacio author Blanco, Francisco J author Bernardino de la Serna, Jorge author Zapata, Juan M author Sanz, Laura author Álvarez-Vallina, Luis author 2018-11-15 The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy. Nat Commun. 2018; 9(1):4809. 10.1038/s41467-018-07195-w 2041-1723 2041-1723 Nature communications 30442944 http://hdl.handle.net/20.500.12105/6702 A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity