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

作者：M. Compte, S. Harwood, I. G. Muñoz, Rocío Navarro, M. Zonca, G. Perez-Chacon, Ainhoa Erce-Llamazares, N. Merino, Antonio Tapia-Galisteo, A. Cuesta, Kasper Mikkelsen, E. Caleiras, N. Nuñez-Prado, M. A. Aznar, S. Lykkemark, J. Martínez-Torrecuadrada, I. Melero, F. Blanco, J. Bernardino de la Serna, J. Zapata, L. Sanz, L. Álvarez-Vallina · 发表于：Nature Communications · 年份：2018 · DOI：10.1038/s41467-018-07195-w · 被引用次数：127 · 研究领域：Medicine、Chemistry

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. 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 4-1...