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 and Luis Alvarez-Vallina ()
Additional contact information
Marta Compte: Leadartis SL
Seandean Lykke Harwood: Aarhus University
Ines G. Muñoz: Spanish National Cancer Research Centre (CNIO)
Rocio Navarro: Hospital Universitario Puerta de Hierro Majadahonda
Manuela Zonca: Leadartis SL
Gema Perez-Chacon: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM
Ainhoa Erce-Llamazares: Leadartis SL
Nekane Merino: Parque Tecnológico de Bizkaia
Antonio Tapia-Galisteo: Hospital Universitario Puerta de Hierro Majadahonda
Angel M. Cuesta: Hospital Universitario Puerta de Hierro Majadahonda
Kasper Mikkelsen: Aarhus University
Eduardo Caleiras: Spanish National Cancer Research Centre (CNIO)
Natalia Nuñez-Prado: Hospital Universitario Puerta de Hierro Majadahonda
M. Angela Aznar: University of Navarra
Simon Lykkemark: Aarhus University
Jorge Martínez-Torrecuadrada: Spanish National Cancer Research Centre (CNIO)
Ignacio Melero: University of Navarra
Francisco J. Blanco: Parque Tecnológico de Bizkaia
Jorge Bernardino de la Serna: Research Complex at Harwell
Juan M. Zapata: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm), CSIC-UAM
Laura Sanz: Hospital Universitario Puerta de Hierro Majadahonda
Luis Alvarez-Vallina: Aarhus University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07195-w

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