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Title

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

AuthorsCompte, Marta; Lykke Harwood, Seandean; Muñoz, Ines G.; Navarro, Rocio; Zonca, Manuela; Pérez-Chacón, Gema CSIC ORCID; Erce-Llamazares, Ainhoa; Merino, Nekane; Tapia-Galisteo, Antonio; Cuesta, Ángel M. ; Mikkelsen, Kasper; Nuñez-Prado, Natalia; Aznar, Maria A.; Lykkemark, Simon; Martínez Torrecuadrada, Jorge Luis; Melero, Ignacio; Blanco, Francisco J. CSIC ORCID ; Bernardino de la Serna, Jorge; Zapata, Juan M. CSIC ORCID; Sanz, Laura; Álvarez-Vallina, Luis
Issue Date2018
PublisherSpringer Nature
CitationNature Communications 9(1): 4809 (2018)
AbstractThe 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.
Publisher version (URL)https://doi.org/10.1038/s41467-018-07195-w
URIhttp://hdl.handle.net/10261/188031
DOI10.1038/s41467-018-07195-w
E-ISSN2041-1723
Appears in Collections:(IIBM) Artículos

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