A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity
Marta Compte, Seandean Lykke Harwood, Ines G Muñoz, Rocio Navarro, Manuela Zonca, Gema Perez-Chacon, Ainhoa Erce-Llamazares, Nekane Merino, Antonio Tapia-Galisteo, Angel M Cuesta, Kasper Mikkelsen, Eduardo Caleiras, Natalia Nuñez-Prado, M Angela Aznar, Simon Lykkemark, Jorge Martínez-Torrecuadrada, Ignacio Melero, Francisco J Blanco, Jorge Bernardino de la Serna, Juan M Zapata, Laura Sanz, Luis Alvarez-Vallina
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.
CITATION Nat Commun. 2018 Nov 15;9(1):4809. doi: 10.1038/s41467-018-07195-w.