2026-05-20T22:57:00Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/67022024-11-29T13:29:45Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
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
funder
Ministerio de Economía y Competitividad (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Instituto de Salud Carlos III
funder
Danish Council for Independent Research
2018-11-22T09:55:51Z
2018-11-22T09:55:51Z
2018-11-15
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
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.
eng
A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity
journal article
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