Journal Article

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

Zonca, Manuela, Cuesta, Angel M., Aznar, M. Angela, Caleiras, Eduardo, Erce-Llamazares, Ainhoa, Merino, Nekane, Muñoz, Ines G., Melero, Ignacio, Harwood, Seandean Lykke, Blanco, Francisco J., Navarro, Rocio, Perez-Chacon, Gema, Compte, Marta, Mikkelsen, Kasper, Lykkemark, Simon, Tapia-Galisteo, Antonio, Bernardino de la Serna, Jorge, Zapata, Juan M., Sanz, Laura, Nuñez-Prado, Natalia, Alvarez-Vallina, Luis, Martínez-Torrecuadrada, Jorge

2018

Overview

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, 1D8 N/C EGa1, 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. The1D8 N/C EGa1 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 1D8 N/C EGa1 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. Cancer therapy using systemically administrated 4-1BB-targeting antibodies is often associated with severe toxicity due to the nonspecific activation of autoreactive T cells. Here, the authors have developed a trimeric antibody targeting both 4-1BB and EGFR, which activates T cells effectively and shows negligible cytotoxicity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
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